A process for the preparation of imeglimin compounds

Abstract

The present disclosure generally relates to a process of preparation of heteroaromatic compound which essentially acts as anti-diabetic agent and their analogues / derivatives thereof. The invention specifically relates to a process of preparation of Imeglimin compound, and its analogues, derivatives, isomers and salt forms thereof of Formula I, by using a heterogeneous catalyst or ion exchange resin(s).

Description

[0001]PT / 2025 / 12145 A PROCESS FOR THE PREPARATION OF IMEGLIMIN COMPOUNDS FIELD OF THE INVENTION The present invention relates to a process for the preparation of Imeglimin compound of Formula I, their analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof. Particularly, present invention relates to the process of preparation of Imeglimin, their analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof, using heterogeneous catalyst or ion exchange resin(s). More particularly, present invention relates to the Imeglimin, their analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof which essentially act as an anti-diabetic agent. BACKGROUND OF THE INVENTION Diabetes mellitus (often simply known as diabetes), is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body becoming unresponsive to the hormone's effects. The major types of diabetes are type 1 and type 2, though other forms also exist. The most common treatment for type 1 is insulin replacement therapy (insulin injections), while anti- diabetic medications / agents / drugs (e.g. metformin– biguanide class of drug) and lifestyle modifications can be used to manage type 2. As of 2021, an estimated 537 million people had diabetes worldwide accounting for 10.5% of the adult population, with type 2 making up about 90% of all cases. The prevalence of the disease continues to increase, most dramatically in low and middle-income nations. Rates are similar in women and men, with diabetes being the 7th- leading cause of death globally. The total valuation of Insulin resistant drug(IRD) / medication market was 69.7B USD in the year of 2019. It is expected to grow @ the CAGR of 4.5% by year of 2025. North America followed by Asia-Pacific is biggest market of these drugs. Most common type of Insulin resistant drug / medication includes: α- Glucosidase Inhibitor, Biguanides, Dopamine Agonist, DPP-4 Inhibitors, GLP-1 Receptor Agonists, etc. In this regard, the simplest and most popular IRD is biguanide.Metformin.HCl salt is the most commonly used biguanide IRD. Its long-term use led to the reduction of Vitamin B-12 level and hypoglycaemic condition in patients. Metformin.HCl salt derived Imeglimin is considered as new wonder molecule due to its excellent IRD properties without these side effects. Imeglimin is a constrained cyclic “dihydro-1,3,5-triazine” derivative of biguanide, with chemical name as (6R)-(+)-4-dimethylamino-2-imino-6-methyl-1,2,5,6-tetrahydro-1,3,5-triazine hydrochloride. Imeglimin is cyclic biguanide, currently produced from metformin as per known methods provided in US patent US8703940B2, and PCT publication WO2012072663A1. Currently, brand name of Imeglimin is Twymeeg. Poxel SA tied up with Sumitomo Pharma in Japan. This Imeglimin product Twymeeg is launched in Japan in June 2021, and current market size of Twymeeg is very limited and expected to be at 230 million USD. Reference may be to the document “US8703940 B2” which reports the process of preparation of Imeglimin by using acetaldehyde solution in aqueous or methanol solution in the presence of base NaOH at room temperature. However, they have not reported conversion of metformin HCl and selectivity for imeglimin HCl. Reference may be to the application “WO2012072663A1”, wherein a method is disclosed that replaced the acetaldehyde with its diethyl acetal derivative, NaOH with PTSA as catalyst and methanol / H2O by 2-butanol (i-BuOH). Reference may be to the document” US8703940B2” which reports a completely reverse approach than the earlier report. It discloses a reaction media that is alkaline. More importantly the substrate Metformin.HCl was insoluble in 2-butanol, hence, not feasible for synthesis of Imeglimin which consequently led to the reduction in selectivity and yield of the product. Moreover, the processes reported in above patent applications have many drawbacks viz. raw material usage per kg of imeglimin HCl is very high, conversion of metformin.HCl and selectivity for imeglimin is very low, downstream processing for purification of imeglimin involves multiple steps, separation & recycle of catalyst PTSA and base NaOH is difficult and as resultant huge amount of wastewater is generated. In view of the abovementioned problems, it is clear that there is a need to provide effective and improved process for preparation of Imeglimin and their analogues / salts / isomers thereof with better or higher selectivity, conversion and yield and should be achieved in less reaction time, avoiding wastewater generation and reduction in purification steps. OBJECTS OF THE INVENTION Main object of the present invention is to provide Imeglimin compound of Formula I, analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof. Another object of the present invention is to provide the process for the preparation of Imeglimin compound of Formula I, analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof using a heterogeneous catalyst. Yet another object of the present invention is to provide the process for the preparation of Imeglimin compound of Formula I, analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof using an ion exchange resin as a catalyst. Still another object of the present invention is to provide the continuous process for the preparation of Imeglimin compound of Formula I, analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof using heterogeneous catalyst or an ion exchange resin as a catalyst. Still another object of the present invention is to provide the continuous process for the preparation of Imeglimin compound of Formula I, analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof which essentially act as an anti-diabetic agent. SUMMARY OF THE INVENTION Accordingly, the present invention provides a process of preparation of imeglimin compound of Formula I, its analogue, derivative, isomer and / or pharmaceutically acceptable salt thereof Formula I wherein R1is selected from the group consisting of (un)substituted C1-C20alkyl, (un)substitutedC2-C20 alkylene, (un)substituted C2-C20alkenyl, (un)substituted C2-C20alkynyl, (un)substituted C3- C12cycloalkyl, (un)substituted C1-C12alkoxy, (un)substituted C5-C14aryl, (un)substituted C5- C14heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6-C14arylalkyl, silyl, C1-C20alkylsilyl, (un)substituted C1-C20alkylether, (un)substituted C6-C14arylether, (un)substituted C1- C14heteroarylether, (un)substituted C2-C12allyl, (un)substituted (C3-C12) cyclic ring, heteroarylalkyl, halo, nitro, (un)substituted alkyl-ether-(un)substituted aryl, (un)substituted alkylether (un)substituted heteroaryl, (un)substituted alkylether (un)substituted alkyl, (un)substituted alkylthio (un)substituted aryl, (un)substituted alkylthio (un)substituted heteroaryl, (un)substituted alkyl thio (un)substituted alkyl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, amino, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, hydroxyl, thio, (C1-C5)alkylthio, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl, carboxyethyl, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate and carbonate; R is selected from the group consisting of hydrogen, protecting group, (un)substituted C1- C20alkyl, (un)substituted C2-C20alkylene, (un)substituted C2-C20alkenyl, (un)substituted C2- C20alkynyl, (un)substituted C3-C12cycloalkyl, (un)substituted C5-C14aryl, (un)substituted C5- C14heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6-C14arylalkyl, silyl, C1-C20alkylsilyl, (un)substituted C1-C20alkylether, (un)substituted C6-C14arylether, (un)substituted C1- C14heteroarylether, (un)substituted C2-C12allyl, (un)substituted (C3-C12)cyclic ring, arylalkyl, heteroarylalkyl, halo, and nitro; and R2, R3, R4and R5are independently selected from the group consisting of hydrogen, (un)substituted C1-C20alkyl, (un)substituted C2-C20alkylene, (un)substituted C2-C20alkenyl, (un)substituted C2-C20alkynyl, (un)substituted C3-C12cycloalkyl, (un)substituted C1-C12alkoxy, (un)substituted C5-C14aryl, (un)substituted C5-C14heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6- C14arylalkyl, silyl, C1-C20alkylsilyl, (un)substituted C1-C20alkylether, (un)substituted C6- C14arylether, (un)substituted C1-C14heteroarylether, (un)substituted C2-C12allyl, (un)substituted cyclic ring (C3-C12), arylalkyl, heteroarylalkyl, halo, nitro, (un)substituted alkyl- ether-(un)substituted aryl, (un)substituted alkyl-ether-(un)substituted heteroaryl, (un)substituted alkyl-ether-(un)substituted alkyl, (un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, amino, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano- alkyl, alkoxyalkyl, dialkylamino, hydroxyl, thio, (C1-C5) alkylthio, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl, carboxyethyl, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate and carbonate; and optionally R2 and R3 or R4 and R5 together form a cyclic ring which is substituted, R2 and R3, on the one hand, and R4 and R5, on the other hand, possibly forming a cyclic ring with the nitrogen atom to which they are linked an n-membered ring (n between 3 and 8) optionally comprising one or more hetero atoms chosen from N, O and S, and being optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (Cl- C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; the process comprising the steps of: a) reacting compound of Formula II with compound of Formula III in presence of a heterogeneous catalyst or an ion exchange resin, and a solvent or mixture of solvents in a container or reactor at temperature in the range of 25 to 120 ºC for a time period in the range of 0.5 to 24 hrs to obtain the compound of Formula I alone or in racemic mixtutre Formula II Formula III Wherein R, R1, R2, R3, R4 and R5 are as defined above; b) optionally purifying the compound of Formula I as obtained in step (a) to obtain pure imeglimin compound of Formula I, its analogue, derivative, isomer and / or pharmaceutically acceptable salt thereof. In an embodiment, the present invention provides a process of preparation of imeglimin compound of Formula I, its analogue, derivative, isomer and / or pharmaceutically acceptable salt thereof comprising the steps of: i. reacting a metformin or salt form of metformin with acetaldehyde in presence of a heterogeneous catalyst or ion exchange resin, and a methanol or water as solvent or mixture of water and methanol in a reactor at temperature in the range of 60 to 120 ºC for time period in the range of 0.5 to 24 hrs to obtain the imeglimin compound, isomer and salt form thereof. In another embodiment of the present invention, the process is carried out in a reactor or container comprising one or more of: a temperature sensor, pressure transducer, pressure gauge, vent valve, safety rupture disc, gas inlet-valve, liquid sampling valve, agitator, motor, solenoid valve, a sampling port, and / or reaction pressure, temperature and agitator speed being continuously monitored using PID control panel; and wherein the reactor or container for said process functions at a pressure up to 100 bar, and is capable of maintaining temperature up to 250°C via a jacketed heater. In yet another embodiment of the present invention, the heterogeneous catalyst is selected from the group consisting of functionalized activated charcoal-sulfonated (ACS), functionalized CuFe2O4-sulfonated (CFS), mesoporous functionalized TiO2 (MFT), mesoporous tin phosphate (SnPO4) (MSP), heteropolyacid (HPA) and tin-niobium pentoxide catalyst (Sn / Nb2O5). In yet another embodiment of the present invention, the heteropolyacid (HPA) is selected from HNbMo6and H4SiW12O40. In yet another embodiment of the present invention, the ion exchange resin is selected from the group consisting of cation exchange resin, anion exchange resin, strong acid cation resin, weak acid cation resin, strong base anion resin, and weak base anion resins comprising styrene- divinylbenzene-copolymer base with sulphonic acid groups in H-form. In yet another embodiment of the present invention, the ion exchange resin is selected from the group consisting of Lanxess K1131S, Lanxess K2629, Amberlite IR120, Lanxess K1221, Thermax T 3825, Thermax T 3830, Indion 225 H, Indion 740, Indion 730, Indion 790, Indion 180a, macro-porous sulfonic ion exchange acid resin (Amberlyst-15), uniform particle size macroporous anion exchange resins (Dowex-500), and Sn-Mont (montmorillonite clay combined with aqueous solutions of tin salt). In yet another embodiment of the present invention, the solvent is selected from the group consisting of polar solvent, protic polar solvent and aprotic polar solvent or any of mixture thereof; and wherein a molar ratio of the compounds of Formula II: Formula III is in range of 1:1 to 1:2. In yet another embodiment of the present invention, the amount / concentration of the heterogeneous catalyst is in range of 8.9 to 35.7 wt.%. In yet another embodiment of the present invention, the compound of Formula I is in a “R” isomeric form with yield ranging between 36 to 53% and the “S” isomeric form with yield ranging between 47 to 64; and rate of conversion rate of Formula II compound and / or Formula III compound into compound of Formula I is in the range of 32-99.7%. In yet another embodiment of the present invention, Formula II is selected from the group consisting of metformin, metformin hydrochloride and analogues or derivatives of metformin containing substituents R & R2-R5 as defined under Formula I provided herein. In yet another embodiment of the present invention, Formula III is selected from the group consisting of liquid acetaldehyde, gas acetaldehyde, acetaldehyde diethyl acetal (ADEA), and aldehyde or ketone with substituents R1 as defined under Formula I provided herein. BRIEF DESCRIPTION OF THE DRAWING FIG. 1A and 1B shows HPLC analysis graphs done on Welchrom C-18 Column: (A) calibration profile for Metformin.HCl and Imeglimin.HCl; and (B) the synthesized Imeglimin.HCl from the batch HCMI-45. FIG.2A and 2B shows HPLC analysis graphs done on DAICEL CHIRALPAK IK column: (A) R-Imeglimin Industry standard run; and (B) the synthesized Imeglimin.HCl from the batch HCMI 38. DETAILED DESCRIPTION OF THE INVENTION “Alkyl” as used herein is collection of carbon atoms that are covalently linked together in normal, secondary, tertiary or cyclic arrangements, i.e., in linear, branched, cyclic arrangement or some combination thereof. An alkyl substituent to structure is chain of carbon atoms that is covalently attached to structure through sp3carbon of substituent. The term “cycloalkyl” encompasses a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. The number of carbon atoms in an cycloalkyl substituent, moiety or group can vary and typically is 3 to about 50, e.g., about 1-30 or about 1-20, unless otherwise specified. “Alkylamine” as used herein means an —N(alkyl)xHy group, moiety or substituent where x and y are independently selected from the group x=1, y=1 and x=2, y=O. Alkylamine includes those — N(alkyl)xHy groups wherein x=2 and y=0 and the alkyl groups taken together with the nitrogen atom to which they are attached form a cyclic ring system. “Heteroalkylene” as used herein means alkylene (alkanediyl) group, moiety or substituent in which one or more skeletal atoms of alkyl are selected from atom other than carbon, e.g. oxygen, nitrogen, sulfur, phosphorus or combinations thereof. “Alkenyl” as used herein means a substituent, moiety or group that comprises one or more double bond moieties (e.g., —CH═CH—) or 1, 2, 3, 4, 5 or 6 or more, typically 1, 2 or 3 such moieties and can include an aryl moiety or group such as benzene, and additionally comprises linked normal, secondary, tertiary or cyclic carbon atoms. “Alkynyl” as used herein means substituent, moiety or group that comprises one or more triple bond moieties (i.e., —C≡C—) e.g., 1, 2, 3, 4, 5, 6 or more, typically 1 or 2 triple bonds, optionally comprising 1, 2, 3, 4, 5, 6 or more double bonds, with remaining bonds (if present) being single bonds and comprising linked normal, secondary, tertiary or cyclic carbon atoms, i.e., linear, branched, cyclic or any combination thereof, unless the alkynyl moiety is ethynyl. “Alkylaryl” as used herein means substituent, moiety or group where alkyl moiety is bonded to aryl moiety i.e. -aryl-alkyl, where aryl and alkyl groups are as described above, e.g. -C6H4-CH3 or -C6H4-CH2CH(CH3).When alkylaryl is used as Markush group (substituent), aryl moiety of alkylaryl is attached to Markush with which it is associated through sp2carbon of aryl moiety. “Heterocycle” or “heterocyclic” or “heteroaryl” as used herein means a cycloalkyl or aromatic ring system wherein one or more, typically 1, 2 or 3, but not all of the carbon atoms comprising the ring system are replaced by a heteroatom which is an atom other than carbon, including, N, O, S, Se, B, Si, P, typically N, O or S wherein two or more heteroatoms may be adjacent to each other or separated by one or more carbon atoms, typically 1-17 carbon atoms, 1-7 atoms or 1-3 atoms. “Heteroarylalkyl” as used herein means substituent, moiety or group where heteroaryl moiety is bonded to alkyl moiety, i.e.,-alkyl-heteroaryl, where alkyl and heteroaryl groups are as described above. “Halogen” or “halo” as used herein means fluorine, chlorine, bromine or iodine. “Haloalkyl” as used herein means an alkyl substituent moiety or group in which one or more of its hydrogen atoms are replaced by one or more independently selected halide atoms. Haloalkyl includes C1-C4haloalkyl. Example but non-limiting C1-C4haloalkyls are —CH2Cl, CH2Br, —CH2I, —CHBrCl, —CHCl—CH2Cl and —CHCl—CH2I. “Haloalkylene” as used herein means an alkylene substituent, moiety or group in which one or more hydrogen atoms are replaced by one or more halide atoms. Haloalkylene includes C1- C6 haloalkylenes or C1-C4 haloalkylenes. The term “heteroalkyl” refers to alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. In one aspect, a heteroalkyl is a C1-C6heteroalkyl. “Ester” as used herein means a substituent, moiety or group that contains a —C(O)—O— structure (i.e., ester functional group) wherein the carbon atom of the structure is not directly connected to another heteroatom and is directly connected to —H or another carbon atom. “Acetal”, “thioacetal”, “ketal”, “thioketal” and the like as used herein means a moiety, group or substituent comprising or consisting of a carbon to which is bonded two of the same or different heteroatoms wherein the heteroatoms are independently selected S and O. “Ether” as used herein means an organic moiety, group or substituent that comprises or consists of 1, 2, 3, 4 or more —O— moieties, usually 1 or 2, wherein no two —O— moieties are immediately adjacent (i.e., directly attached) to each other. “Carbonate” as used here means a substituent, moiety or group that contains a —O—C(═O)— O— structure (i.e., carbonate functional group). “Carbamate” or “urethane” as used here means a substituent, moiety or group that contains a —O—C(═O)N(RPR)—, —O—C(═O)N(RPR)2, —O— C(═O)NH (optionally substituted alkyl) or —O—C(═O)N (optionally substituted alkyl)2- structure (i.e., carbamate functional group) where RPRand optionally substituted alkyl are independently selected and RPRare independently —H, a protecting group or an organic moiety as described for ester, alkyl or optionally substituted alkyl. As used herein, the term “alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group. Examples of alkylene groups include, but are not limited to, ethan- 1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl- propan-1,3-diyl, and the like. As used herein, the term “alkoxy”, employed alone or in combination with other terms, refers to a group of Formula —O-alkyl, wherein the alkyl group as defined above. Example alkoxy groups include but not limited to methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. As used herein, the term “alkylamino” refers to a group of Formula —NH(alkyl), wherein the alkyl group is as defined above. As used herein, the term “alkoxycarbonyl” refers to a group of Formula —C(O)O-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylcarbonyl” refers to a group of Formula —C(O)- alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylcarbonylamino” refers to a group of Formula —NHC(O)-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylsulfonylamino” refers to a group of Formula —NHS(O)2-alkyl, wherein the alkyl group is as defined above. As used herein, the term “aminosulfonyl” refers to a group of Formula —S(O)2NH2. As used herein, the term “alkylaminosulfonyl” refers to a group of Formula —S(O)2NH(alkyl), wherein the alkyl group is as defined above. As used herein, the term “dialkylaminosulfonyl” refers to a group of Formula —S(O)2N(alkyl)2, wherein each alkyl group independently is as defined above. As used herein, the term “aminosulfonylamino” refers to a group of Formula —NHS(O)2NH2. As used herein, the term “alkylaminosulfonylamino” refers to a group of Formula — NHS(O)2NH(alkyl), wherein the alkyl group is as defined above. As used herein, the term “dialkylaminosulfonylamino” refers to a group of Formula —NHS(O)2N(alkyl)2, wherein each alkyl group independently is as defined above. As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of Formula —NHC(O)NH2. As used herein, the term “alkylaminocarbonylamino” refers to a group of Formula — NHC(O)NH(alkyl), wherein the alkyl group is as defined above. As used herein, the term “dialkylaminocarbonylamino” refers to a group of Formula —NHC(O)N(alkyl)2, wherein each alkyl group independently is as defined above. As used herein, the term “alkylcarbamoyl” refers to a group of Formula —C(O)—NH(alkyl), wherein the alkyl group is as defined above. As used herein, the term “thio” refers to a group of Formula —SH. As used herein, the term “alkylthio” refers to a group of Formula —S-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylsulfinyl” refers to a group of Formula —S(O)-alkyl, wherein the alkyl group is as defined above. As used herein, the term “alkylsulfonyl” refers to a group of Formula —S(O)2-alkyl, wherein the alkyl group is as defined above. As used herein, the term “amino” refers to a group of Formula —NH2. As used herein, the term “carbamyl” to a group of Formula —C(O)NH2. As used herein, term “carbonyl”, employed alone or in combination with other terms, refers to —C(O)— group. As used herein, the term “cyanoalkyl” refers to a group of Formula —(alkylene)-CN where the alkylene group is as defined above. As used herein, the term “HO—alkyl” refers to a group of Formula —(alkylene)-OH where the alkylene group is as defined above. As used herein, the term “alkoxyalkyl” refers to a group of Formula —(alkylene)-O(alkyl) where the alkyl and alkylene group is as defined above. As used herein, the term “carboxy” refers to a group of Formula —C(O)OH. As used herein, the term “dialkylamino” refers to a group of Formula —N(alkyl)2, wherein the two alkyl groups each is as defined above. As used herein, the term “dialkylcarbamyl” refers to a group of Formula — C(O)N(alkyl)2, wherein the two alkyl groups each is as defined above. The compounds of the invention, or salts thereof, are substantially isolated. The present invention relates to a process of preparation of Imeglimin compound of Formula I, analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof Formula I wherein R1is selected from the group consisting of (un)substituted C1-C20 alkyl, (un)substituted C2-C20 alkylene, (un)substituted C2-C20 alkenyl, (un)substituted C2-C20 alkynyl,(un)substituted C3-C12 cycloalkyl, (un)substituted C1-C12 alkoxy, (un)substituted C5-C14 aryl, (un)substituted C5-C14 heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10 heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6-C14 arylalkyl, silyl, C1-C20 alkylsilyl, (un)substituted C1-C20 alkylether, (un)substituted C6-C14 arylether, (un)substituted C1-C14 heteroarylether, (un)substituted C2-C12 allyl, (un)substituted cyclic ring (C3-C12), arylalkyl,heteroarylalkyl, halo, nitro, (un)substituted alkyl-ether-(un)substituted aryl, (un)substituted alkyl-ether-(un)substituted heteroaryl,(un)substituted alkyl-ether-(un)substituted alkyl, (un)substitutedalkyl-thio-(un)substitutedaryl, (un)substitutedalkyl-thio- (un)substitutedheteroaryl, (un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, amino, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano- alkyl, alkoxyalkyl, dialkylamino, hydroxyl, thio, (C1-C5) alkylthio, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl, carboxyethyl, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; R is selected from the group consisting of hydrogen, protecting group, (un)substituted C1-C20 alkyl, (un)substituted C2-C20 alkylene, (un)substituted C2-C20 alkenyl, (un)substituted C2-C20 alkynyl,(un)substituted C3-C12 cycloalkyl, (un)substituted C5-C14 aryl, (un)substituted C5-C14 heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10 heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6-C14 arylalkyl, silyl, C1-C20 alkylsilyl, (un)substituted C1-C20 alkylether, (un)substituted C6-C14 arylether, (un)substituted C1-C14 heteroarylether, (un)substituted C2-C12 allyl, (un)substituted cyclic ring (C3-C12), arylalkyl,heteroarylalkyl, halo, or nitro; and R2, R3, R4and R5all are independently selected from the group consisting of hydrogen, (un)substituted C1-C20 alkyl, (un)substituted C2-C20 alkylene, (un)substituted C2-C20 alkenyl, (un)substituted C2-C20 alkynyl,(un)substituted C3-C12 cycloalkyl, (un)substituted C1-C12 alkoxy, (un)substituted C5-C14 aryl, (un)substituted C5-C14 heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10 heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6-C14 arylalkyl, silyl, C1-C20 alkylsilyl, (un)substituted C1-C20 alkylether, (un)substituted C6-C14 arylether, (un)substituted C1-C14 heteroarylether, (un)substituted C2- C12 allyl, (un)substituted cyclic ring (C3-C12), arylalkyl,heteroarylalkyl, halo, nitro, (un)substituted alkyl-ether-(un)substituted aryl, (un)substituted alkyl-ether-(un)substituted heteroaryl,(un)substituted alkyl-ether-(un)substituted alkyl, (un)substitutedalkyl-thio- (un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl, (un)substitutedalkyl-thio- (un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, amino, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, hydroxyl, thio, (C1-C5) alkylthio, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl, carboxyethyl, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate or carbonate; Optionally R2 and R3 together form a cyclic ring which is further substituted, R4 and R5 together form a cyclic ring which is further substituted, or R2 and R3, on the one hand, and R4 and R5, on the other hand, possibly forming with the nitrogen atom to which they are linked an n-membered ring (n between 3 and 8) optionally comprising one or more hetero atoms chosen from N, O and S and possibly being substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (Cl- C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; the process comprising: a) reacting compound of Formula II with compound of Formula III in presence of a heterogeneous catalyst or ion exchange resin, and a solvent or mixture of solvents in a container or reactor at temperature in the range of 25 to 120 ºC for time period in the range of 0.5 to 24 hrs to obtain the compound of Formula I alone or in racemic mixtutre; Formula II Formula III wherein R, R1, R2, R3, R4 and R5 are same as defined above; and b) optionally purifying the obtained compound of Formula I to afford pure Imeglimin compound of Formula I, analogues, derivatives, isomers and / or pharmaceutically acceptable salt thereof. The Formula I reciting R1 is selected from the group consisting of -(C1-C20) alkyl optionally substituted by amino, hydroxyl, thio, halogen, (Cl- C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C2-C20) alkylene optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C2-C20) alkyne optionally substituted by amino, hydroxyl, thio, halogen, (Cl- C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C3-C8) cycloalkyl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C3-C8) heterocycloalkyl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (Cl- C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C6-C14) aryl optionally substituted by amino, hydroxyl, thio, halogen, (Cl- C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C5-C13) heteroaryl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C6-C14) arylalkyl(Cl-C5) optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6- C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl. The Formula I reciting R is selected from the group consisting of hydrogen, protecting group, (un)substituted C1-C20 alkyl, (un)substituted C2-C20 alkylene, (un)substituted C2-C20 alkenyl, (un)substituted C2-C20 alkynyl, (un)substituted C3-C12 cycloalkyl, (un)substituted C5-C14 aryl, (un)substituted C5-C14 heteroaryl bearing one or more hetero atoms, silyl, C1-C20 alkylsilyl, (un)substituted C2-C12 allyl, (un)substituted cyclic ring (C3-C12), halo, or nitro. The Formula I reciting R2, R3, R4and R5all are independently selected from hydrogen,(C1- C20)alkyl optionally substituted by halogen, (C1-C5)alkyl, (C1-C5) alkoxy or (C3-C8) cycloalkyl; - (C2-C20) alkylene optionally substituted by halogen, (C1-C5) alkyl or (C1-C5) alkoxy; -(C2-C20) alkyne optionally substituted by halogen, (C1-C5) alkyl or (C1-C5) alkoxy; - (C3-C8) cycloalkyl optionally substituted by (C1-C5) alkyl or (C1-C5) alkoxy; -(C3-C8) heterocycloalkyl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by (C1-C5) alkyl or (C1- C5) alkoxy; -(C6-C14) arylalkyl (C1-C20) optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6- C14) aryloxy, (C6- C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; -(C6- C14) aryl optionally substituted by amino, hydroxyl, thio, halogen, (Cl- C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; and -(C5-C13) heteroaryl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1-C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; and / or R2 and R3, on the one hand, and R4 and R5, on the other hand, possibly forming with the nitrogen atom to which they are linked an n-membered ring (n between 3 and 8) optionally comprising one or more hetero atoms chosen from N, O and S and possibly being substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (Cl- C5), cyano, trifluoromethyl, carboxymethyl or carboxyethyl. A process of preparation of imeglimin compound, isomer and salt form thereof, comprising: i. reacting a metformin or salt form of metformin with acetaldehyde in presence of a heterogeneous catalyst or ion exchange resin, and a methanol or water as solvent or mixture of water and methanol in a reactor at temperature in the range of 60 to 120 ºC for time period in the range of 0.5 to 24 hrs to obtain the imeglimin compound, isomer and salt form thereof. The present invention provides a process of preparation of Imeglimin, isomer and salt form thereof, the process comprises of reacting metformin or salt form of metformin with acetaldehyde agent in presence of a heterogeneous catalyst or ion exchange resin, and a methanol, water or mixture thereof in a container or reactor at temperature in the range of 60 to 120 ºC for time period in the range of 0.5 to 24 hrs to obtain the Imeglimin, isomer and salt form thereof, optionally purifying the Imeglimin, isomer and salt form thereof to afford pure Imeglimin, isomer and salt form thereof. The process is carried out in a reactor or container comprising one or more of: a temperature sensor, pressure transducer, pressure gauge, vent valve, safety rupture disc, gas inlet-valve, liquid sampling valve, agitator, motor, solenoid valve, a sampling port, and / or reaction pressure, temperature and agitator speed being continuously monitored using PID control panel. The agitator consisted of 2 impellers each having 4 pitched blades. The high-pressure reactor was designed at pressure rating of 100 bar and can be heated up to 250°C via jacketed heater. Acetaldehyde gas is taken from gas cylinder or supply vessel. The reaction pressure, temperature and agitator speed has been continuously monitored using PID control panel. The heterogeneous catalyst is selected from but not limited to functionalized activated charcoal- sulfonated (ACS), functionalized CuFe2O4-sulfonated (CFS), mesoporous functionalized TiO2 (MFT), mesoporous tin phosphate (SnPO4) (MSP), heteropolyacid and tin-niobium pentoxide catalyst (Sn / Nb2O5). The heteropolyacids (HPA) is selected from HNbMo6and H4SiW12O40. The ion exchange resin is selected from cation exchange resin, anion exchange resin, strong acid cation resin, weak acid cation resin, strong base anion resin, and weak base anion resins comprising styrene-divinylbenzene-copolymer base with sulphonic acid groups in H-form. The ion exchange resin is selected from but not limited to Lanxess K1131S, Amberlyst 15, Lanxess K2629, Amberlite IR120, Lanxess K1221, Thermax T 3825, Thermax T 3830, Indion 225 H, Indion 740, Indion 730, Indion 790, Indion 180a, macro-porous sulfonic ion exchange acid resin (Amberlyst-15), uniform particle size macroporous anion exchange resins (Dowex-500), Sn- Mont (montmorillonite clay combined with aqueous solutions of tin salt), etc. The solvent is selected from but not limited to polar solvent, protic polar solvent and aprotic polar solvent or mixture thereof. The solvent is selected from but not limited to water, methanol, ethanol, isopropanol and 2- butanolor mixture thereof. The compounds and isomers obtained by said process may cover R and S isomers. Specifically, the process provides “R” isomers of Formula I ranging between36 to 53%, and the “S” isomers of Formula I ranging between 64 to 47%. The compound of Formula I as synthesized herein is optionally purified by literature methods known to a person skilled in the art e.g. drying, evaporation, concentration methods, chromatographic techniques (conventional or advanced such as column chromatography, flash chromatography, HPLC, etc.) and so on. Specifically, the compound of Formula I as synthesized herein is Imeglimin or salt and / or isomeric form thereof, and the analogues or derivatives of Imeglimin containing substituents R & R1-R5 as defined under Formula I provided herein. The conversion rate of Formula II compound or Formula III compound, or isomer, salt, derivative and analogue thereof into Formula I is in range of 32-99.7% The selectivity of formation of Formula I compound, or isomer, salt, derivative and analogue thereof is in range of 30-100%. The yield of formation of Formula I compound, or isomer, salt, derivative and analogue thereof is in range of 85-98%. Specifically, inventors provide an efficient process for Imeglimin production from Metformin.HCl salt by providing a simple process at elevated temperature in very short reaction time, with more than 99% selectivity for Imeglimin. The reaction was critically screened on various reaction parameters with taking the note of principles of green chemistry. The compound obtained by the process provides single isomeric compound (enantiomeric excess)or mixture of isomeric forms / compounds from a single reaction / process. The process for synthesis of compound of Formula I may be done in batch mode or in continuous mode. The molar ratio of compounds of Formula II: Formula III is in range of 1:1 to 1:2. In another embodiment, the molar ratio of metformin: acetaldehyde agent is in range of 1:1 to 1:2. The amount / concentration of the heterogeneous catalyst is in range of 8.9 to 35.7 wt.%. The predetermined weight ratio of the metformin HCl to an acetaldehyde solution or acetaldehyde diethyl acetal solution or acetaldehyde gas to solvent is in the range of 1:1 to 1:2. The rate of conversion rate of Formula II compound and / or Formula III compound into compound of Formula I is in the range of 32-99.7%. The selectivity of formation of compound of Formula I is in the range of 55-100%. The yield of formation of compound of Formula I is in the range of 55-98%. The time period of the process of preparation of Formula I compounds is in the range of 0.5-9 h. The time period of the process of preparation of Formula I compounds is in the range of 5-9 h. The compound of Formula I obtained by said process does not require purification step. The process is done without the need or use of base and organic solvent(s). In the process of the present invention, the solvent water and / or methanol helps in achieving the desired selectivity. Metformin HCl are mixed with an acetaldehyde solution or acetaldehyde Diethylacetal solution or acetaldehyde gas in the ratios 1:1 to 1:2 and solvent in a predetermined weight ratio mixed in an autoclave (high pressure) reactor using heterogeneous catalyst or ion exchange resin loading varying from 8.9 to 35.7% w / w metformin.HCl. The metformin HCl initial concentration was varied from 3.5% to 14 w / v%. In second step, the reaction mixture is heated at a temperature in the range of 25 °C to 110 °C under stirring at a 250 to 1000 rpm and reaction was continued for 0.5 hrs to 24 hrs. EXAMPLES The following examples are given as a way of illustration only and should not be construed to limit the scope of the present invention. Comparative Example: Preparation of imeglimin using conventional route i.e. using base via. NaOH, KOH, Na2CO3, K2CO3, NaHCO3, homogeneous catalyst viz. PTSA, and solvent 1.65 g (10 mmol) of metformin.HCl was taken in 10 mL of water and agitated till the mixture become homogeneous. In a separate beaker equimolar amount (0.4 g) of NaOH was dissolved in 10 mL of water and added in the homogeneous mixture in a manner that addition completed in 10 minutes. Equimolar amount of 15-20% solution of acetaldehyde (0.56 mL) was dissolved in 4 mL of water and added drop wise into the reaction mixture. Commencement of reaction was assumed after complete addition of acetaldehyde and reaction was conducted till 4 hr at different temperature under nitrogen atmosphere. The progress of reaction was analyzed on high performance liquid chromatography equipped with MWD detector. The conversion of metformin.HCl and imeglimin selectivity were estimated using following Formulas Metformin. ^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^ (%) =^^^^^^^^^^ ^^^^ ^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^. ^^^^^^ ^^^^^^^^^^^^^^^^ × 100Analysis of synthesized products The progress of reaction was measured taking periodicallyreaction samples and analysed using HPLC method. The sample was diluted in water / methanol (90 / 10 v / v). Analysis of samples was done on Agilent 1260 HPLC equipped with MWD using Welch C18 (4.6 x 250mm, 5.0µm) column at room temperature [mobile phase: water / methanol (90 / 10 v / v),pH 4.0 with o-phosphoric acid] having mobile phase flow rate of 1.0 mL / min at wavelength 234 nm. Figure 1 shows the HPLC analysis of Imeglimin HCl reaction mixture using Welchrom C-18 Column (A) Calibration profile for Metformin.HCl and Imeglimin.HCl (B) illustrates the synthesized Imeglimin.HCl (refer, tables A and B): Table A Table B Effect of reaction temperature on preparation of Imeglimin The imeglimin was prepared conventional route i.e. by reacting metformin HCl with 15-20% solution of acetaldehyde or ADEA solution at different temperature in the presence of base viz. NaOH. The conversion of metformin HCl and imeglimin selectivity at different temperature was shown in Table 1. At room temperature, 44% conversion of metformin HCl with 92% selectivity to Imeglimin was achieved. On repetitive run it was observed that at room temperature reaction get arrested at 44% metformin HCl conversion. Even after monitoring the reaction till 4 h no further change in conversion of metformin HCl was observed. Table 1: Effect of temperature on the synthesis of Imeglimin from Metformin.HCl using acetaldehyde aqueous solution SN Temperature (°C) %Conversion Metformin %Selectivity HCl Imeglimin isomers 1 25 44 92 2 35 51 92 3 50 85 92 Reaction Conditions: Metformin.HCl= 1.65 g, NaOH= 0.4 g, (15-20%) Acetaldehyde= 0.56 mL, Water=20.4 mL, Nitrogen pressure, Agitation Speed= 1000 rpm, time (t) = 4hr Effect of alkali (base) on preparation of Imeglimin The effect of different alkaline moieties (base) viz. NaOH, KOH, Na2CO3,K2CO3,NaHCO3etc. on the formation of imeglimin has been studied. Table 2 shows the influence of alkaline moieties on the conversion of metformin HCl and imeglimin selectivity. It was observed that NaOH was the best alkaline moiety as compared to KOH, Na2CO3, K2CO3, NaHCO3. Table 2: Effect of base taken for conversion of Metformin.HCl to Imeglimin SN Base taken %Conversion %Selectivity Metformin HCl Imeglimin isomers 1 NaOH 94 93 2 KOH 75 92 3 Na2CO3 42 90 4 K2CO344 90 5 NaHCO3 51 90 Reaction Conditions: Metformin.HCl= 1.65 g, Alkali = 0.4 g, (15-20%) Acetaldehyde = 0.56 mL, Water = 20.4 mL, PN2 = atmospheric, Agitation Speed = 1000 rpm, and time (t) = 4h. The deviation from–OH ions led to drastic decline in the conversion of metformin though selectivity remained only slightly affected. Conversion reduced to just 42% in the presence of Na2CO3 whereas it was 44% for K2CO3 (Table 2, entry 3 and 4 respectively). HCO3- ions proved slightly better than CO32-but not better than –OH- (Table 2, entry 4). Role of reaction solvent in the synthesis of Imeglimin Trials for Imeglimin synthesis were conducted in 500 mL (high pressure) reactor equipped withpressure gauge, agitator & spiral cooling tube. The reactions were conducted in presence ofsolvent(s) such as water, methanol, ethanol and / or 2-butanol at different reaction temperature ranging from 25-100°C. Different degree of conversion & selectivity were observed for said conditions. Table 3: Screening of solvent, catalyst for the preparation of imeglimin SN Metformin Reaction Conditions %Conversion %Selectivity Scale (g) T Reagent Solvent Time Metformin HCl Imeglimin isomers 1* 25 25 NaOH Water 6 34.55 92 2* 25 60 NaOH Water 6 90.26 92 3* 25 60 NaOH Water 6 87.39 90 4* 25 70 NaOH Water 6 98.01 93 5* 25 70 NaOH Water 6 90.26 91 6#25 60 PTSA 2-butanol 6 8.66 61 7#13 60 PTSA MeOH 6 NIL NIL 8#13 60 PTSA EtOH 6 NIL NIL 9* 13 70 NaOH MeOH 3 59.42 90 *= 15-20% acetaldehyde solution;#= ADEA solution was used As mentioned in the literature PTSA along with ADEA was attempted in 2-butanol, methanol and ethanol (Table 3, Entries 6-8). The activation of ADEA over PTSA was very slow and solubility of metformin.HCl was extremely poor in 2-butanol which led to 8.66% conversion and 61% Imeglimin selectivity. No reaction was observed in lower alcohols like methanol and ethanol in presence of PTSA and ADEA. Satisfactory results were observed for methanol as solvent as shown in Table 3, Entry 9. Reaction trials were done at 70°C with around 59.42% conversion within 3h. Example 1: Preparation of Imeglimin using heterogeneous catalysts or ion exchange resin Synthesis of Heterogeneous catalysts Activated Charcoal- Sulfonated (ACS): Catalyst synthesis was carried out using 3 steps viz. oxidation, reduction, and sulfonation. Initially, 10g of the activated charcoal (AC) was refluxed with nitric acid (30% w / v) for 3h. After that the oxidized AC was dispersed in toluene using ultrasonicationfor 30 min. In this dispersion, 5.0 g of sodium borohydride(NaBH4) was added gradually. The resultingsolution is stirred for 1 hr at ambient temperature. Finally, the solution is filtered and washed with toluene followed by absolute ethanol and acetone, respectively. The filter cake was placed in vacuum oven at temperature 110°C overnight until the reduced activated carbon was produced. Finally, 2.25 g of chlorosulfonic acid was added dropwise to 10 g of reduced activated carbon for 30 min at ambient temperature, subsequently HCl gas was released from the reaction. After completion of the reaction, the synthesized compound was stirred for 30 min. A black solid of activated carbon sulfuric acid (AC– OSO3H) was formed. CuFe2O4-SO3H (CFS - Sulfonated Copper Ferrite) Step-I: Preparation of CuFe2O4 nanoparticles A mixture of ferric nitrate nonahydrate [Fe(NO3)3.9H2O](40.13 g, 99.33 mmol) and Copper(II) nitrate trihydrate [Cu(NO3)2.3H2O](12.0 g, 49.66 mmol) was dissolved in 250 mL of deionized water in a two neck round bottom flask at room temperature. To this solution, 36 g (5M) of NaOH was dissolved in 180 mL of water at room temperature over a period of 10 min, during which a reddish-black precipitate was formed. Then, the reaction mixture was heated to 90°C by placing the round bottom flask in an oil bath and stirred continuously. After 2 h, it was cooled to room temperature, and the magnetic particles formed were separated by a magnetic separator. It was then washed thrice with deionized water (1500 mL), and the catalyst was kept in an air oven overnight at 110°C. Then, the catalyst was crushed in a mortar and pestle, kept in a furnace at 550°C for 5 hrs and then cooled to room temperature.Step-II: Preparation of nano-CuFe2O4@SO3HTo a flask, equipped with a dropping funnel and a gas inlet tube, a suspension of nano-CuFe2O4 (10 g) in dichloromethane (CH2Cl2)(200 mL) was poured. Next, a solution of chlorosulfonic acid (4.64 mL) in CH2Cl2 (50 mL) was added dropwise over a period of 0.5 h at 0–5°C. HCl gas directly evolved from the reaction solution. Then, the mixture stirred for 1 h at room temperature. The resulting solid was filtered and washed with CH2Cl2 (2 × 50 mL) and dried in a vacuum desiccator to give nano- CuFe2O4@SO3H as a brown stable powder. Mesoporous functionalized TiO2 (MFT) The mesoporous sulfated titania solid acid catalyst was prepared in one step organic template-free method by hydrolysis of titanium oxysulfate (TiOSO4). For uniform hydrolysis of TiOSO4 and control of particle size, the synthesis of mesoporous sulfated titania requires seed solution. To prepare seed solution, 1 g titanium oxysulfate was dissolved in water (50 mL) and reaction mixture was heated to 70°C under vigorous stirring. Then, the solution of NaOH (10%) was added dropwise to attain 2.3 pH value of reaction mixture. The temperature of reaction mixture was maintained at 70 °C for 1 h. Theresulting solution was used as a precipitation seed. To prepare MFT catalyst, 12 g of TiOSO4 wasmixed well with water (100 mL) in another 250 mL round bottom flask. The aqueous solution of sodium hydroxide (10%) was then added dropwise to above solution under continuous stirring until the pH value came out to be 1.4 and solution became slightly turbid.1 mL of seed solution (prepared above) was added to reaction mixture and hydrolysis was performed at 100 °C for 4 h. After 4 h of hydrolysis, the resulting mixture was transferred into a beaker containing excess of water for complete precipitation of TiO2. The mixture was then filtered and washed thoroughly with distilled water until 7 pH value. The precipitates obtained were dried at 100 °C for 12 h in an oven. The obtained solid was crushed into fine powder and was calcined at different temperatures (350, 450, 550, and 650 °C) for 2 h with a heating rate of 5°C min−1in flowing air. General Synthetic Procedure of preparation of Formula I using said heterogeneous catalyst In the present process, an inventor has designed various heterogeneous catalysts to perform the cyclodehydration of metformin.HCl. The catalytic transformation i.e. cyclodehydration is promoted by Brӧnsted acidity. The heterogeneous catalysts with Brӧnsted acidic sites were designed and screened for the reaction as shown in Table 4. The process of said conversion of metformin.HCl into imeglimin.HCl comprises: reacting 0.0423 mol (7 gm) of metformin.HCl with 0.0423 mol of acetaldehyde agent in the presence of a heterogeneous catalyst2.5 gm, using 250mL of methanol, water or mixture there of as solvent in a high pressure reactor at temperature in the range of 60 to 120 ºC for time period in the range of 0.5 to 24 hrs to obtain the Imeglimin isomer salt form thereof.Here, the high pressure reactor comprises 500 ml high pressure autoclave (effective volume 450 ml)is be equipped with a temperature sensor, pressure transducer, pressure gauge, vent valve, safety rupture disc, gas inlet-valve, liquid sampling valve, agitator, motor, solenoid valve, a sampling port etc. The agitator consisted of 2 impellers each having 4 pitched blades. The high-pressure reactor was designed at pressure rating of 100 bar and can be heated up to 250°C via jacketed heater. Acetaldehyde gas is taken from gas cylinder or supply vessel. The reaction pressure, temperature and agitator speed has been continuously monitored using PID control panel. Table 4: Screening for catalytic cyclodehydration of metformin SN Catalyst Metformin.HCl Imeglimin.HCl Conversion (%) Selectivity(%) 1 Commercial Cu / Al2O3 NIL NIL 2 Commercial Cu / Al2O3 NIL NIL 3 Reduced nano-CuFe2O4@SO3H 65 84 4 Calcined nano-CuFe2O4@SO3H 71 30 5# Activated carbon sulfuric acid (ACS) 100 97 6* Activated carbon sulfuric acid (ACS) 90 72 8 Mesoporous functionalized TiO2 32 90 Reaction Conditions: Metformin.HCl (7 g, 0.0423 mol), ADEA (5 g, 0.0423 mol), Catalyst (2.5 g), MeOH (250 ml), *Reaction with Acetaldehyde gas, #Reaction repeated with ADEA for 3h. Example 2: General Synthetic Procedure of preparation of Formula I using Ion exchange resin as a catalyst: The process of said conversion of metformin.HCl into Imeglimin.HCl comprises: reacting 7 gm of salt form of metformin (e.g. metformin.HCl) with 5 gm of acetaldehyde reagent or ADEA or acetaldehyde gas in the presence of 2.5 gm of ion exchange resin (IER), and 100 to 500 mL of methanol or water or mixture there of as solvent in a container or reactor at temperature in the range of 50 to 120 ºC for time period in the range of 0.5 to 14 hrs to obtain the Imeglimin isomers salt are given in Table 5. Table 5: Preparation of Imeglimin salts by reacting Metformin HCl with acetaldehyde agent in the presence of ion exchange resin as catalyst using alcohol, water or mixture: Batch Metfor ADE Catalyst MeOH Speed of Temp Time Metformi (%) min A (g) (2.5 g) (ml) agitation (°C) (hr) n HCl Imeglimin HCl (RPM) Conversi Selectivity (g) on% HCMI- 7 5 Lanxess 250 1000 110 3 12.26 89.51 7 K1131S HCMI- 7 5 Amberlyst 250 1000 110 3 11.71 86.50 8 15 HCMI- 7 5 Lanxess 250 1000 120 8 62.75 98.31 10 K1131S HCMI- 7 1.86 Lanxess 250 1000 110 3 25.66 99.03 12 gm K1131S Acet aldeh yde gas HCMI- 7 5 Lanxess 250 1000 110 5 36.88 90.96 15 K2629 HCMI- 7 5 Lanxess 250 1000 110 5 55.00 89.00 16 K2649 HCMI- 7 5 Amberlite 250 1000 110 5 49.00 94.30 17 IR120 HCMI- 7 5 Lanxess 250 1000 110 5 45.00 93.16 18 K1221 HCMI- 7 5 Thermax 250 1000 110 5 33.01 93.00 19 T 3825 HCMI- 7 5 Thermax 250 1000 110 5 41.05 81.09 20 T 3830 HCMI- 7 5 Indion 250 1000 110 5 30.3 81.9 21 225 H HCMI- 7 5 Indion 250 1000 110 5 44.74 85.2 22 740 HCMI- 7 5 Indion 250 1000 110 5 45.01 85.13 23 730 HCMI- 7 5 Indion 250 1000 110 5 39.73 89.81 24 790 HCMI- 7 5 Indion 250 1000 110 5 32.3 89.82 25 180 Wet HCMI- 7 5 Lanxess 200 ml 250 110 5 86 100 38 K1131S DI water Lanxess K1131S, Lanxess K1221 & Lanxess K2629: Crosslinked polystyrene having strong acidic groups specifically –SO3H groups. Amberlyst 15: a Brønsted acidic resin catalyst comprised of styrene-divinylbenzene with sulfonic acid functional group. Amberlite IR120: Sodium resin is a gel type strongly acidic cation exchange resin of the sulfonated polystyrene type. Thermax T 3825 & Thermax T 3830: Strong acid Polystyrene Nuclear Sulphonic Hydrogen. Indion 225 H: a premium grade strong acid cation exchange resin containing sulphonic acid groups with crosslinked polystyrene and has a gel structure. Indion 740, Indion 730, Indion 180 Wet & Indion 790: a macroporous strongly acidic cation exchanger covering styrene divinylbenzene copolymer with sulphonic acid groups. Effect of temperature on conversion of Metformin.HCl The effect of reaction temperature was studied by performing reaction at different temperatures (70̊C- 110°C). As temperature was increased from 70°C to 110 °C the conversion of metformin.HCl was also increased. The results are illustrated in Table 6. Table 6: Effect of temperature on conversion of metformin.HCl to imeglimin.HCl %Metformin.HCl % Imeglimin.HCl Reaction temperature (°C) conversion selectivity 70 45.67 100 90 88.01 100 110 98.46 100 Reaction conditions: Metformin.HCl:ADEA (1:1.5 moles), Water (200 mL), reaction temperature 70 to 110°C, Time 5 hrs, Agitation speed 750 rpm, IER loading 20% (w / w) (reactants), Reactor 500 mL high pressure reactor. Effect of mole ratios To study the effect of molar ratios (metformin.HCl:ADEA) on conversion of metformin.HCl and selectivity of Imeglimin.HCl, three set of experiments were performed. The molar ratios were varied from 1:1 to 1:2. From this study, it is revealed that 1:2 (metformin.HCl:ADEA) molar ratio is required for maximum conversion of metformin.HCl. The results are illustrated in Table 7.Table 7: Effect of mole ratios on conversion of metformin HCl to Imeglimin.HCl%Metformin.HCl % Imeglimin.HCl SN Molar ratios conversion selectivity 1 1:1 90.72 100 2 1:1.5 98.46 100 3 1:2 99.75 100 Reaction conditions: Metformin.HCl : ADEA (1:1 to 1:2 ), Water (200mL), reaction temperature 110°C, Time 5h, Agitation Speed 750rpm, IER loading 20%w / w (reactants), Reactor 500 mL high pressure reactor. Effect of speed of agitation The effect of speed of agitation on rate of reaction and mass transfer was studied. The speed of agitation was varied from 250-1000 rpm, at agitation speed of 750 rpm, 90.72% conversion of Metformin.HCl with 100% selectivity of Imeglimin.HCl was obtained. Further, increasing the speed of agitation didn’t show any major change in conversion as well selectivity of Imeglimin.HCl. Therefore, agitation speed of 750 rpm is an optimized speed of agitation. The results are illustrated in Table 8. Table 8: Effect of speed of agitation on conversion of Metformin.HCl to Imeglimin.HCl Speed of agitation %Metformin.HCl % Imeglimin.HCl SN (RPM) conversion selectivity 1 250 86.25 100 2 500 84.97 100 3 750 90.72 100 4 1000 87.87 100 Reaction conditions: Metformin.HCl : ADEA (1:1 moles), Water (200mL), reaction temperature 110ºC, time 5 hrs, agitation speed 250 to 1000 rpm, IER loading 20%w / w (reactants), Reactor 500 mL high pressure reactor. Effect of reaction time To determine the optimized reaction time for complete conversion of Metformin.HCl, reaction samples were collected after every hour and analyzed by HPLC. The conversion of Metformin.HCl increased with increase in reaction time. Almost complete conversion of metformin.HCl was achieved after 5thhour of reaction. The results are illustrated in Table 9. Table 9: Effect of reaction time for synthesis of Imeglimin.HCl from Metformin.HCl %Metformin.HCl % Imeglimin.HCl SN Time (hr) conversion selectivity 1 1 58.74 100 2 2 71.24 100 3 3 91.24 100 4 4 99.21 100 5 5 99.75 100 Reaction conditions: Metformin.HCl:ADEA(1:2 moles), Water (200mL), reaction temperature 110ºC, time 1 to 5 hr, agitation speed 750 rpm, IER loading 20 %w / w (reactants), Reactor 500 mL high pressure reactor. Effect of initial concentration of metformin.HCl in waterThe effect of initial concentration of metformin.HCl was studied by using four different concentrationsranging between 3.5-14% in water. The conversion of metformin.HCl decreases with increase in concentration of metformin.HCl. The results are illustrated in Table 10. Table 10: Effect of Metformin.HCl concentration for synthesis of Imeglimin.HCl from Metformin.HCl %Metformin.HCl % Metformin.HCl SN % Imeglimin.HCl Selectivity concentration conversion 1 3.5 90.72 100 2 7 83.56 100 3 10.5 74.74 100 4 14 66.89 100 Reaction conditions: Metformin.HCl:ADEA (1:1 moles), Water (200mL), reaction temperature 110ºC, time 5 hrs, agitation speed 750 rpm, IER loading 20%w / w (reactants), Reactor 500 mL high pressure reactor Effect of catalyst loading To determine the optimum catalyst amount needed to reach maximum conversion of Metformin.HCl, the effect of catalyst loading in the range of 8.9 to 35.7% (w / w) w.r.t Metformin.HCl was studied. With8.9% (w / w) of catalyst, Metformin.HCl conversion reached 89.12% with 100% selectivity toImeglimin.HCl. When the catalyst loading was increased to 17.8 % (w / w), conversion of metformin.HCl reached to 96.14% with 100% selectivity of Imeglimin.HCl. From this study, it is revealed that maximum 35.7% (w / w) catalyst loading is required to reach maximum conversion of metformin.HCl. The results are illustrated in Table 11. Table 11: Effect of catalyst loading for Synthesis of Imeglimin.HCl Catalyst % Metformin.HCl % Imeglimin.HCl SN (g) conversion Selectivity 1 2.5 89.12 100 2 5 96.14 100 3 7.5 99.74 100 4 10 99.75 100 Reaction conditions: Metformin.HCl : ADEA(1:1.5 moles), Water (200mL), Metformin.HCl Concentration 14%, reaction temperature 110ºC, time 5 hr, agitation speed 750 rpm, Reactor 500 mL high pressure reactor. Example 3: Analysis of %S-Imeglimin.HCl and %R-Imeglimin.HCl using Chiral PAK IK HPLC column The mixture of 7g Imeglimin.HCl, 5g Acetaldehyde diethyl acetal (1:1 mole ratio) and 2.5g of Lanxess K1131S Ion exchange resin as a catalyst in 200ml of water as solvent was charged to the 500 ml high-pressure reactor. The reaction was performed at 110 °C for 5 h. After completion of reaction, the reaction mixture was filtered to recover the catalyst and reaction crude was analysed using High performance liquid chromatography. To monitor hourly conversion, reaction samples were collected after every hour and diluted in n- Hexane / Ethanol (50 / 50 v / v). Analysis of samples was done on Agilent 1260 HPLC equipped with MWD using CHIRALPAK IK (4.6 x 250mm, 5.0µm) column at 40°C [mobile phase: n- Hexane / IPA / TFA / DEA (80 / 20 / 0.2 / 0.1 v / v / v / v)] having flow rate of 1.0 mL / min at wavelength 240 nm. The conversion of metformin.HCl increased with increase in reaction time. The results are illustrated in Table 12. Figure 2 shows the HPLC analysis standard R-Imeglimin and synthesized R and S Imeglimin.HCl mixture using DAICEL CHIRALPAK IK column (A) Illustrates the standard R-Imeglimin chromatogram (B) Illustrates the synthesized Imeglimin.HCl (refer, tables C and D). Table C Table 12: Results of HPLC analysis for analysis of R & S Imeglimin.HCl SN Time (hr) %Metformin.HCl %S-Imeglimin.HCl %R-Imeglimin.HCl Conversion 1 1 28.89 14.18 85.82 2 2 64.84 39 61 3 3 84.17 44.89 55.11 4 4 87.08 45.86 54.14 5 5 90.72 46.34 53.66 Reaction conditions: Imeglimin.HCl 7g, Acetaldehyde Diethyl Acetal 5 g, Ion exchange resin 2.5g, Imeglimin.HCl:ADEA (1:1 moles), Water 200ml, reaction temperature 110ºC, time 1 to 5 hr, agitation speed 750 rpm Table 13: Results of HPLC analysis for Enantiomeric analysis of % S& R Imeglimin.HCl SN Batch %S-Imeglimin.HCl %R-Imeglimin.HCl 1 HCMI 38 54.98 45.02 2 HCMI 40 53.66 46.34 3 HCMI 42 60.98 39.02 4 HCMI 45 49.91 50.09 ADVANTAGES OF THE INVENTION: • Provides robust and economically efficient heterogeneous catalyst or ion exchange resin for synthesis of Imeglimin.HCl using metformin.HCl and acetaldehyde solution or ADEA solution with high selectivity and conversion rate.• Provides an inexpensive heterogeneous catalyst preferably containing acidic sites such as ACS, CFS, MST, MTP and Sn-Nb for selective cyclodehydration of Metformin.HCl to Imeglimin.HCl for the first time with > 90% selectivity. • For the first time, use of acidic Ion Exchange Resins as catalyst preferably containing acidic sites for selective cyclodehydration of Metformin.HCl to Imeglimin.HCl with selectivity close to 99%. • Use of NaOH was eliminated by present process, which reduced the overall cost of the process. • The water footprint of complete process was reduced by present process, which was attributed to the use of heterogeneous catalysis. • The inventors of present invention found novel process for preparation of Imeglimin and related analogues, derivatives, salts or isomers thereof by using heterogeneous catalysts and / or ion exchange resin, avoiding use of NaOH and methanol. (as reported by earlier US patent), and keeping the selectivity and conversion above 95%. •Also, it is very preferable process in terms of cost effectiveness, easy to perform, avoidinggeneration of wastewater and other purification steps. • The use of Ion exchange resin provides many advantages over conventional route viz. selective conversion of Metformin.HCl into Imeglimin.HCl, no byproduct formation; kinetics of reaction is fast, cost effective, environmentally friendly process, simple downstream processing, ion-exchange can be reused / regenerated and recycled multiple times. • Continuous process for the production of Imeglimin.HCl from the Metformin.HCl & hence footprint process is small as compared to conventional route.

Claims

AMENDED CLAIMS received by the International Bureau on 17 October 2025 (17.10.2025) WE CLAIM:

1. A process of preparation of imeglimin compound of Formula I, its analogue, derivative, isomer and / or pharmaceutically acceptable salt thereofwhereinR1is selected from the group consisting of (un)substituted C1 -C20alkyl, (un)substitutedC2-C20 alkylene, (un)substituted C2-C20alkenyl, (un)substituted C2- C20alkynyl, (un)substituted C3-C12cycloalkyl, (un)substituted C1-C12alkoxy, (un)substituted C5-C14aryl, (un)substituted C5-C14heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6-C14arylalkyl, silyl, C1 -C20alkylsilyl, (un)substituted C1 - C20alkylether, (un)substituted C6-C14arylether, (un)substituted C1 - C14heteroarylether, (un)substituted C2-C12allyl, (un)substituted (C3-C12) cyclic ring, heteroarylalkyl, halo, nitro, (un)substituted alkyl-ether-(un)substituted aryl, (un)substituted alkylether (un)substituted heteroaryl, (un)substituted alkylether (un)substituted alkyl, (un)substituted alkylthio (un)substituted aryl, (un)substituted alkylthio (un)substituted heteroaryl, (un)substituted alkyl thio (un)substituted alkyl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, amino, alkylamino, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aminocarbonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, alkylaminocarbonylamino, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, hydroxyl, thio, (C1 -C5)alkylthio, (C6-C14)aryloxy, (C6-C14)aryl-(C1 -C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl, carboxyethyl, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate and carbonate;R is selected from the group consisting of hydrogen, protecting group, (un)substituted C1 -C20alkyl, (un)substituted C2-C20alkylene, (un)substituted C2-C20alkenyl, (un)substituted C2-C20alkynyl, (un)substituted C3-C12cycloalkyl, (un)substituted C5- C14aryl, (un)substituted C5-C14heteroaryl bearing one or more hetero atoms, (un)substituted C3-C10heterocycloalkyl bearing one or more hetero atoms, (un)substituted C6-C14arylalkyl, ssiillyyll,, C1 -C20alkylsilyl, (un)substituted C1 - C20alkylether, (un)substituted C6-C14arylether, (un)substituted C1 -C14heteroarylether, (un)substituted C2-C12allyl, (un)substituted (C3-C12)cyclic ring, arylalkyl, heteroarylalkyl, halo, and nitro; andR2, R3, R4and R5are independently selected from the group consisting of hydrogen, (un)substituted C1 -C20alkyl, (un)substituted C2-C20alkylene, (un)substituted C2- C20alkenyl, (un)substituted C2-C20alkynyl, (un)substituted C3-C12cycloalkyl, (un)substituted C1 -C12alkoxy, (un)substituted C5-C14aryl, (un)substituted C5- C14heteroaryl bearing oonnee or mmoorree hetero atoms, (un)substituted C3-Cl Oheterocycloalkyl bearing one or more hetero atoms, (un)substituted C6- C14arylalkyl, silyl, C1 -C20alkylsilyl, (un)substituted C1 -C20alkylether, (un)substituted C6-C14arylether, (un)substituted C1 -C14heteroarylether, (un)substituted C2-C12allyl, (un)substituted cyclic ring (C3-C12), arylalkyl, heteroarylalkyl, halo, nitro, (un)substituted alkyl-ether-(un)substituted aryl, (un)substituted alkyl-ether-(un)substituted heteroaryl, (un)substituted alkyl-ether-(un)substituted alkyl, (un)substitutedalkyl-thio- (un)substitutedaryl, (un)substitutedalkyl-thio-(un)substitutedheteroaryl,(un)substitutedalkyl-thio-(un)substitutedalkyl, alkylaryl, alkylheteroaryl, alkylalkenyl, alkylalkenylalkyl, arylalkenyl, arylalkenylaryl, heterocycloalkyl, haloalkyl, heteroalkyl, amino, alkylamino, aallkkooxxyyccaarrbboonnyyll,, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, aammiinnoossuullffoonnyyll,, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonylamino, aammiinnooccaarrbboonnyyllaammiinnoo,, alkylaminosulfonylamino, dialkylaminosulfonylamino, aallkkyyllaammiinnooccaarrbboonnyyllaammiinnoo,, alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamyl, cyano-alkyl, alkoxyalkyl, dialkylamino, hydroxyl, thio, (C1 -C5) alkylthio, (C6-C14) aryloxy, (C6-C14) arylalkoxy (C1 -C5), cyano, trifluoromethyl, carboxyl, carboxymethyl, carboxyethyl, dialkylcarbamyl, haloalkoxy, haloalkyl, ester, ether, acetal, thioacetal, ketal, thioketal, carbamate and carbonate; and optionally R2 and R3 or R4 and R5 together form a cyclic ring which is substituted, R2 and R3, on the one hand, and R4 and R5, on the other hand, possibly forming a cyclic ring with the nitrogen atom to which they are linked an n-membered ring (n between 3 and 8) optionally comprising one or more hetero atoms chosen from N, O and S, andbeing optionally substituted by amino, hydroxyl, thio, halogen, (C1 -C5) alkyl, (C1 -C5) alkoxy, (C1 -C5) alkylthio, (C1 -C5) alkylamino, (C6-C14) aryloxy, (C6-C14) arylalkoxy (Cl- C5), cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; the process comprising the steps of: a) reacting compound of Formula II with compound of Formula III in presence of a heterogeneous catalyst or an ion exchange resin, and water as a solvent or mixture of water and methanol in a container or reactor at temperature in the range of 25 to 120gC for a time period in the range of 0.5 to 24 hrs to obtain the compound of Formula I alone or in racemic mixtutreWherein R, R1 , R2, R3, R4 and R5 are as defined above; b) optionally purifying the compound of Formula I as obtained in step (a) to obtain pure imeglimin compound of Formula I, its analogue, derivative, isomer and / or pharmaceutically acceptable salt thereof.

2. A process of preparation of imeglimin compound of Formula I, its analogue, derivative, isomer and / or pharmaceutically acceptable salt thereof comprising the steps of: reacting a metformin or salt form of metformin with acetaldehyde in presence of a heterogeneous catalyst or ion exchange resin, and water as a solvent or mixture of water and methanol in a reactor at temperature in the range of 60 to 120gC for time period in the range of 0.5 to 24 hrs to obtain the imeglimin compound, isomer and salt form thereof.

3. The process as claimed in claim 1 or 2, wherein the process is carried out in a reactor or container comprising one or more of: a temperature sensor, pressure transducer, pressure gauge, vent valve, safety rupture disc, gas inlet-valve, liquid sampling valve, agitator, motor, solenoid valve, a sampling port, and / or reaction pressure, temperature and agitator speed being continuously monitored using PID control panel; and whereinthe reactor or container for said process functions at a pressure up to 100 bar, and is capable of maintaining temperature up to 250°C via a jacketed heater.

4. The process as claimed in claim 1 or 2, wherein the heterogeneous catalyst is selected from the group consisting of functionalized activated charcoal-sulfonated (ACS), functionalized CuFe2O4-sulfonated (CFS), mesoporous functionalized TiO2 (MFT), mesoporous tin phosphate (SnPO4) (MSP), heteropolyacid (HPA) and tin-niobium pentoxide catalyst (Sn / Nb2O5).

5. The process as claimed in claim 4, wherein the heteropolyacid (HPA) is selected from HNbMoe and H4SiW12O40.

6. The process as claimed in claim 1 or 2, wherein the ion exchange resin is selected from the group consisting of cation exchange resin, anion exchange resin, strong acid cation resin, weak acid cation resin, strong base anion resin, and weak base anion resins comprising styrene-divinylbenzene-copolymer base with sulphonic acid groups in H- form.

7. The process as claimed in claim 1 or 2, wherein the ion exchange resin is selected from the group consisting of Lanxess K1 131 S, Lanxess K2629, Amberlite IR120, Lanxess K1221 , Thermax T 3825, Thermax T 3830, Indion 225 H, Indion 740, Indion 730, Indion 790, Indion 180a, macro-porous sulfonic ion exchange acid resin (Amberlyst-15), uniform particle size macroporous anion exchange resins (Dowex-500), and Sn-Mont (montmorillonite clay combined with aqueous solutions of tin salt).

8. The process as claimed in claim 1 or 2, wherein a molar ratio of the compounds of Formula II: Formula III is in range of 1 :1 to 1 :2.

9. The process as claimed in claim 1 or 2, wherein amount / concentration of the heterogeneous catalyst is in range of 8.9 to 35.7 wt.%.

10. The process as claimed in claim 1 , wherein the compound of Formula I is in a “R” isomeric form with yield ranging between 36 to 53% and the “S” isomeric form with yield ranging between 47 to 64; and rate of conversion rate of Formula II compound and / or Formula III compound into compound of Formula I is in the range of 32-99.7%.

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