Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
“AN IMPROVED METHOD FOR THE MANUFACTURING LISDEXAMFETAMINE OR A SALT THEREOF”
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
Supriya Lifescience Limited Indian 207/208 Udyog Bhavan, Sonawala Road, Goregoan (East), Mumbai – 400063, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved method for the manufacturing of Lisdexamfetamine or a pharmaceutically acceptable salt thereof. More particularly, the invention provides a cost-effective, scalable, and industrially viable method for synthesizing Lisdexamfetamine with high purity and yield, suitable for pharmaceutical applications.

BACKGROUND OF THE INVENTION
Lisdexamfetamine dimesylate is a prodrug of the centrally active compound dextroamphetamine, widely used in the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) and Binge Eating Disorder. Chemically, it is designated as (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide, and its mesylate salt is the active pharmaceutical ingredient (API) used in the marketed formulation.
Lisdexamfetamine functions as an inactive prodrug that is gradually converted to dextroamphetamine upon enzymatic hydrolysis in the blood, thereby offering a controlled-release profile and reduced potential for abuse when compared to conventional amphetamine-based therapeutics.
Lisdexamfetamine was first disclosed in US 6838280 B2, assigned to New River Pharmaceuticals Inc., which describes the compound and its therapeutic applications. This patent also provides a general synthetic route for Lisdexamfetamine by coupling L-lysine and dextroamphetamine using standard peptide coupling techniques.
However, the process described in prior art suffers from several limitations, such as the use of expensive coupling reagents, low stereoselectivity, and the formation of impurities that are difficult to purge during downstream purification. Additionally, some methods involve chromatographic purification steps, which are unsuitable for commercial-scale manufacturing.
US6838280 B2 discloses the Lisdexamfetamine compound and outlines its synthesis using standard amide coupling conditions. It involves reaction between d-amphetamine and L-lysine with carbodiimide-based coupling agents, such as EDC or DCC, in the presence of solvents like DMF or dichloromethane. However, this method often results in the formation of urea by-products and requires extensive purification.
WO2005/054288 A2 describes improved pharmaceutical compositions of Lisdexamfetamine and outlines general methods of synthesis. However, these methods still rely heavily on solution-phase coupling and do not adequately address impurity profile and process scalability.
US2011/0118153 A1 discloses polymorphic forms and salts of Lisdexamfetamine and mentions process aspects; however, it lacks detailed process improvements or alternative synthesis routes.
WO2009/138651 A1 discusses methods for preparing Lisdexamfetamine salts, including dimesylate, with some improvements over the original process. Still, the methods involve multiple steps and use of hazardous solvents, raising environmental and safety concerns for commercial-scale manufacturing.
Salmi et al. (“Efficient Diastereoselective Titanium (IV) Reductive Amination of Ketones”, Letters in Organic Chemistry, 2006, 3, 384-389) describes a novel method for the reductive amination of carbonyl compounds using Zirconium (IV) isopropoxide (Zr(O-iPr)₄) as a mediator. There are several drawbacks that limit its broader application, particularly in pharmaceutical or industrial synthesis contexts. Zirconium (IV) isopropoxide is highly moisture-sensitive, requiring strict anhydrous conditions and inert atmosphere handling, which complicates large-scale manufacturing. It is also relatively costly and less readily available compared to more commonly used reductive amination reagents (e.g., NaBH4, NaBH₃CN or NaBH(OAc)₃). As with any metal-mediated reaction, there is a risk of residual zirconium contamination in the final product, which is a significant concern in the synthesis of active pharmaceutical ingredients (APIs) due to regulatory limits on heavy metals. Furthermore, the method does not offer control over stereoselectivity or enantioselectivity, which is critical for chiral drugs such as Lisdexamfetamine, where stereopurity directly impacts pharmacological activity. Handling of isopropoxide-based reagents and by-products requires proper waste disposal, and the reaction may generate flammable isopropanol or other volatile organics during the work-up.
While the zirconium-mediated one-pot method of Salmi et al. is synthetically useful for general reductive amination, it poses practical, economic, and regulatory limitations for pharmaceutical process development, especially for chiral amide synthesis such as that of Lisdexamfetamine. Thus, alternative methods that are metal-free, stereoselective, cost-effective, and scalable are preferred for API manufacturing.
US7223735 B2 discloses synthesis of Lisdexamfetamine via the coupling of d-amphetamine with L-lysine using conventional peptide coupling agents such as carbodiimides (e.g., EDC, DCC) and additives like HOBt. The process relies on carbodiimide-based coupling agents such as EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) and HOBt (1-hydroxybenzotriazole). HOBt is explosive when dry, posing significant handling and safety risks on a manufacturing scale. These reagents are also relatively expensive, increasing overall process cost. Carbodiimide coupling agents (like EDC) generate urea by-products, which can be difficult to remove completely and may co-elute during purification. These impurities can complicate API purity specifications, especially for regulatory compliance. The process conditions are not ideally suited for large-scale production, especially due to: (a) need for anhydrous and controlled pH conditions; (b) handling of hazardous reagents; (c) generation of waste requiring careful disposal.
While the process disclosed in US7223735 provides a workable synthetic route to Lisdexamfetamine, it suffers from significant drawbacks in terms of safety, environmental impact, process complexity, and scalability. For commercial manufacturing, there is a strong need for improved methods that use safer reagents, generate fewer impurities, and are more robust and cost-effective.
US7655630 provides a route to pharmaceutically acceptable salts of Lisdexamfetamine (e.g., dimesylate), it suffers from lack of detailed experimental disclosure, safety considerations, purification protocols, and control of stereochemistry. These limitations pose challenges for industrial adoption, regulatory approval, and reproducible scale-up. Improved processes that provide clear reaction parameters, safer reagents, better impurity control, and validated analytical data would offer significant advantages over this prior art.
There remains a need for an improved, scalable, and cost-effective process for the manufacture of Lisdexamfetamine or its pharmaceutically acceptable salts, particularly dimesylate, that minimizes the use of hazardous reagents, offers a better impurity profile, and eliminates the need for chromatographic purification. The present invention aims to address these deficiencies by providing a novel synthetic route that is robust, industrially viable, and provides high purity of the desired product.

OBJECTS OF THE INVENTION
The primary object of the present invention is to provide an improved, efficient, and industrially scalable method for the manufacturing of Lisdexamfetamine or its pharmaceutically acceptable salts, such as Lisdexamfetamine dimesylate.
Another object of the invention is to develop a cost-effective process that avoids the use of hazardous, toxic, or expensive coupling reagents such as carbodiimides (e.g., EDC, DCC) and additives like HOBt, which pose safety, regulatory, and environmental concerns.
It is a further object of the invention to provide a method that ensures high chemical purity and enantiomeric integrity of Lisdexamfetamine, thereby making it suitable for pharmaceutical applications without the need for extensive purification.
Yet another object of the invention is to offer a green and environmentally benign synthetic route, reducing the generation of hazardous waste and minimizing the environmental impact of the process.
A still further object of the invention is to develop a robust and reproducible process that can be scaled up for commercial production, offering consistent yield, purity, and polymorphic stability of the final salt form.
Another object of the present invention is to provide a method with a simplified work-up and isolation procedure, avoiding the need for chromatographic purification and enabling easy separation and crystallization of the final product.
It is also an object of the invention to eliminate or significantly reduce the formation of process-related impurities and by-products, thereby simplifying compliance with ICH guidelines on impurity profiling.

SUMMARY OF THE INVENTION
One of the aspects of the present invention provides a method for synthesising Lisdexamfetamine
(I)
or pharmaceutically acceptable salt thereof, the method comprising:
a) reacting a compound of formula 1 with a compound of formula 2 in presence of an acid to obtain a compound of formula 3;
b) reducing the compound of formula 3 with a reducing agent to obtain a compound of formula 4;
c) hydrogenating the compound of formula 4 with hydrogenating agent and thereafter resolving with a chiral resolving agent to obtain a compound of formula 5;
d) contacting the compound of formula 5 with a compound of formula 6 to obtain a compound of formula 7;
e) treating the compound of formula 7 with an acid to obtain a free base of the compound of formula (I);
f) contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I);
wherein the compound of formula 4 is obtained in-situ or without isolating the compound of formula 3.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a novel and improved process for the preparation of Lisdexamfetamine or its pharmaceutically acceptable salts, such as dimesylate. The process involves the direct amidation of d-amphetamine base or a pharmaceutically acceptable salt thereof with N-protected L-lysine, followed by deprotection and salt formation, preferably using methanesulfonic acid.
The process avoids the use of expensive coupling agents, minimizes by-product formation, and provides the final product in high chemical and optical purity.
One of the embodiments of the present invention provides a method for synthesising Lisdexamfetamine

or pharmaceutically acceptable salt thereof, the method comprising:
a) reacting a compound of formula 1 with a compound of formula 2 in presence of an acid to obtain a compound of formula 3;
b) reducing the compound of formula 3 with a reducing agent to obtain a compound of formula 4;
c) hydrogenating the compound of formula 4 with a hydrogenating agent and thereafter resolving with a chiral resolving agent to obtain a compound of formula 5;
d) contacting the compound of formula 5 with a compound of formula 6 to obtain a compound of formula 7;
e) treating the compound of formula 7 with an acid to obtain a free base of the compound of formula (I);
f) contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I);
wherein the compound of formula 4 is obtained in-situ or without isolating the compound of formula 3.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the acid is organic acid or inorganic acid.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein reacting the compound of formula 1 with compound of formula 2 to obtain a compound of formula 3 is carried out in presence of an acid selected from organic acids, inorganic acids and combinations thereof at a temperature in the range of 0oC to 15oC.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 1 is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 2 is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein reacting a compound of formula 1 with a compound of formula 2 in presence of an acid to obtain a compound of formula 3 is carried out at a temperature in the range of 00C to 150C for a time period in the range of 30 min to 60 min.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 3 is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein reducing the compound of formula 3 with a reducing agent to obtain a compound of formula 4 is carried out at a temperature in the range of 00C to 400C for a time period in the range of 180 min to 240 min.

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 4 is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein hydrogenating the compound of formula 4 with a hydrogenating agent to obtain a compound of formula 5 is carried out at a temperature in the range of 500C to 1000C for a time period in the range of 480 min to 720 min.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein resoluting agent is selected from (+)-Di-O,O'-toluoyl-D-tartaric acid, (-)-di-O,O'-toluoyl-L-tartaric acid, (+)-di-O,O'-benzoyl-D-tartaric acid, (-)-di-O,O'-benzoyl-L-tartaric acid, (+)-di-O,O'-anisoyl-D-tartaric acid, and (-)-di-O,O'-anisoyl-L-tartaric acid, l-(+)-mandelic acid, L-tartaric acid, D-tartaric acid (S)-(-)-N-(1-Phenylethyl)- phthalamic Acid, (S)-(+)-αMethoxyphenylacetic Acid, (R)-(-)-αMethoxyphenylacetic Acid, (+)-MTPA, (-)-MTPA, (S)-(+)-γ-Carboxyγ-butyrolactone, (R)-(-)-γ-Carboxyγ-butyrolactone, R)-(-)-Hydratropic Acid, (S)-(+)-Hydratropic Acid, D-(+)-Malic Acid, L-(-)-Malic Acid, (-)-Menthoxyacetic Acid, L-(+)-Mandelic Acid, D-(-)-Mandelic Acid, D-(-)-Quinic Acid, D-Aspartic Acid, L-Aspartic Acid, L-Glutamic Acid, D-Glutamic Acid, D-Pyroglutamic Acid, L-Pyroglutamic Acid, L-Valine, Tosyl-L-phenylalanyl Chloride, (+)-Camphor-10-sulfonic acid, (-)-Camphor-10-sulfonic acid
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 5 is

OR

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein contacting the compound of formula 5 with a compound of formula 6 to obtain a compound of formula 7 is carried out at a temperature in the range of 200C to 1000C for a time period in the range of 120 min to 480 min.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 6 is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 7 is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein treating the compound of formula 7 with an acid to obtain a free base of the compound of formula (I) is carried out at a temperature in the range of 200C to 1000C for a time period in the range of 120 min to 360 min.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the free base of compound of formula (I) is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I) is carried out at a temperature in the range of 200C to 1000C for a time period in the range of 120 min to 360 min.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt of compound of formula (I) is

Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein the compound of formula 4 is obtained in-situ or without isolating the compound of formula 3.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein organic acid is selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, Citric acid, Tartaric acid, Lactic acid, Succinic acid, Maleic acid, Fumaric acid, Malic acid, Oxalic acid, Benzoic acid, p-Toluenesulfonic acid (p-TSA), Camphorsulfonic acid (CSA), Gluconic acid, Salicylic acid, Ascorbic acid, Levulinic acid and combinations thereof.
In an embodiment, wherein organic acid is acetic acid.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein reducing agent is selected from Sodium borohydride (NaBH₄), Sodium cyanoborohydride (NaBH₃CN), Sodium tri-acetoxy borohydride (NaBH(OAc)₃), Lithium aluminum hydride (LiAlH₄), Di-isobutyl-aluminum hydride (DIBAL-H), Red-Al (sodium bis(2-methoxyethoxy) aluminum hydride) and combinations thereof.
In an embodiment, wherein reducing agent is Sodium borohydride (NaBH₄).
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein hydrogenating agent is selected from Hydrogen gas (H₂) with Palladium on carbon (Pd/C), Hydrogen gas (H₂) with Platinum (Pt) catalyst, Hydrogen gas (H₂) with Raney Nickel, Hydrogen gas (H₂) with Ruthenium or Rhodium catalysts.
In an embodiment of the present invention, wherein hydrogenating agent is Hydrogen gas (H₂) with Palladium on carbon (Pd/C).
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein treating the compound of formula 7 to obtain a free base of the compound of formula (I) is carried out by using acid selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, p-Toluenesulfonic acid (p-TSA), Hydrochloric acid (HCl), Sulfuric acid (H₂SO₄), Nitric acid (HNO₃), Phosphoric acid (H₃PO₄), Hydrobromic acid (HBr), Hydroiodic acid (HI), Perchloric acid (HClO₄), Trifluoroacetic acid, Polyphosphoric acid (PPA) or Lewis acids like AlCl₃ or ZnBr₂, and reagents like trimethylsilyl iodide (TMSI) and combinations thereof.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I); wherein acid is selected from methane sulphonic acid (MSA).
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein pharmaceutically acceptable salts is non-toxic, inorganic and organic acid addition salts.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein pharmaceutically acceptable salt is selected from acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, carbonate, citrate, estolate, esylate, ethanesulfonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexafluorophosphate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, malate, maleate, mandelate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, phosphate, pivalate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, tartrate, thiocyanate, tosylate and the like.
Pharmaceutically acceptable salts, e.g., non-toxic, inorganic and organic acid addition salts, are known in the art. Exemplary salts include, but are not limited to, 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, finnarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, laurylsulphonate, malate, maleate, mandelate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthylate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, undecanoate, and valerate salts, and the like.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein said method is carried out in presence of solvent, wherein solvent is selected from polar and/or non-polar solvent.
Another embodiment of the present invention provides a method for synthesising Lisdexamfetamine or pharmaceutically acceptable salt thereof, wherein solvent is selected from Water Methanol, Ethanol, Isopropanol (IPA),n-propanol, n-Butanol, t-Butanol, Acetic acid, Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), Acetonitrile (MeCN), Tetrahydrofuran (THF), methyl t-butyl ether (MTBE), 1,4-Dioxane, Ethyl acetate, Isopropyl acetate, Dichloromethane (DCM or CH₂Cl₂), Chloroform, Toluene, Xylene, Hexane,Heptane, Cyclohexane, Acetone, methyl ethyl ketone (MEK),Methyl isobutyl ketone (MIBK), cyclohexanone, Diethyl ether, pyridine, Diisopropyl ether ,Dimethoxy ethane, Ethylene glycol and combinations thereof.
Advantages of the Invention:
1. Avoids use of chromatographic purification.
2. High yield and purity (≥99.5% by HPLC).
3. Industrially scalable and environmentally benign.
4. Reduces formation of process-related impurities.
Another example of this invention is a method for synthesizing lisdexamfetamine or a pharmaceutically acceptable salt thereof, wherein the method is provided with a schematic representation as follows.

The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
EXAMPLES
Example 1: Preparation of (2S)-1-phenylpropan-2-amine tartrate (Dextroamphetamine Tartrate):
To a stirred solution of S-Phenylethyl amine (100 gm) in methylene dichloride (500ml) added Phenyl acetone (166 gm). The reaction mixture cooled to 0 to 10°C and slowly added acetic acid (59.5 gm). Maintained reaction mass for 60 min at 0 to 15°C. Sodium borohydride (31.3gm) added in lot wise at about 0 to 15°C. The reaction mixture was stirred for about 15 minutes at about 0 to 15°C and then temperature was raised to 40 to 45°C and maintained for 3 to 6 hours. Completion of the reaction was checked by HPLC. Then reaction mass cooled to 0oC to 10°C and aq. HCl solution added slowly to reaction mass. organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene di chloride. The combined organic layer was washed with aq. NaOH solution and water. The organic layer was evaporated under vacuum to get (2S)-1-phenyl-N-(1-phenylethyl)propan-2-amine as an oil (250 gm) which then hydrogenated in autoclave with acetic acid as solvent Pd/C as catalyst and hydrogen pressure till HPLC complies. After completion of reaction, reaction mass unloaded from autoclave and filtered through celite bed under nitrogen. Filtrate then concentrated under vacuum to give oil which is then extracted with methylene dichloride by adjusting to basic pH with caustic lye. Organic layer then concentrated under vacuum to get oil (155 gm). To this oily mass added aq. Methanol and l-tartaric acid and heated to reflux then cooled and filtered. The solid was dried under vacuum to form titled compound as a white solid. Yield: 130 gm, (Molar yield 55.0%).
Example 2: Preparation of (2S)-1-phenylpropan-2-amine tartrate (Dextroamphetamine Tartrate):
To a stirred solution of S-Phenylethyl amine (100 gm) in methylene dichloride (500ml) added Phenyl acetone (166 gm). The reaction mixture cooled to 0 to 10°C and slowly added acetic acid (59.5 gm). Maintained reaction mass for 60 min at 0 to 15°C. Sodium borohydride (31.3gm) added in lot wise at about 0 to 15°C. The reaction mixture was stirred for about 15 minutes at about 0 to 15°C and then temperature was raised to 40 to 45°C and maintained for 3 to 6 hours. Completion of the reaction was checked by HPLC. Then reaction mass cooled to 0 to 10°C and aq. HCl solution added slowly to reaction mass. organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene di chloride. The combined organic layer was washed with aq. NaOH solution and water. The organic layer was evaporated under vacuum to get (2S)-1-phenyl-N-(1-phenylethyl)propan-2-amine as an oil (250 gm) which then hydrogenated in autoclave with acetic acid as solvent Pd/C as catalyst and hydrogen pressure till HPLC complies. After completion of reaction, reaction mass unloaded from autoclave and filtered through celite bed under nitrogen. Filtrate then concentrated under vacuum to give oil which is then extracted with methylene dichloride by adjusting to basic pH with caustic lye. Organic layer then concentrated under vacuum to get oil (155 gm). To this oily mass added Methanol and l-tartaric acid and heated to reflux then cooled and filtered. The solid was dried under vacuum to form titled compound as a white solid. Yield: 132 gm, (Molar yield 55.85%).
Example 3: Preparation of (2S)-1-phenylpropan-2-amine tartrate (Dextroamphetamine Tartrate):
To a stirred solution of S-Phenylethyl amine (100 gm) in methylene dichloride (500ml) added Phenyl acetone (166 gm). The reaction mixture cooled to 0 to 10°C and slowly added acetic acid (59.5 gm). Maintained reaction mass for 60 min at 0 to 15°C. Sodium borohydride (31.3gm) added in lot wise at about 0 to 15°C. The reaction mixture was stirred for about 15 minutes at about 0 to 15°C and then temperature was raised to 40 to 45°C and maintained for 3 to 6 hours. Completion of the reaction was checked by HPLC. Then reaction mass cooled to 0 to 10°C and aq. HCl solution added slowly to reaction mass. organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene di chloride. The combined organic layer was washed with aq. NaOH solution and water. The organic layer was evaporated under vacuum to get (2S)-1-phenyl-N-(1-phenylethyl)propan-2-amine as an oil (250 gm) which then hydrogenated in autoclave with acetic acid as solvent Pd/C as catalyst and hydrogen pressure till HPLC complies. After completion of reaction, reaction mass unloaded from autoclave and filtered through celite bed under nitrogen. Filtrate then concentrated under vacuum to give oil which is then extracted with methylene dichloride by adjusting to basic pH with caustic lye. Organic layer then concentrated under vacuum to get oil (155 gm). To this oily mass added aq. ethanol and l-tartaric acid and heated to reflux then cooled and filtered. The solid was dried under vacuum to form titled compound as a white solid. Yield: 129 gm, (Molar yield 54.58%).
Example 4: Preparation of (2S)-1-phenylpropan-2-amine tartrate (Dextroamphetamine Tartrate):
To a stirred solution of S-Phenylethyl amine (10 gm) in tetrahydrofuran (50ml) added Phenyl acetone (16.6 gm). The reaction mixture cooled to 0 to 10°C and slowly added acetic acid (5.9 gm). Maintained reaction mass for 60 min at 0 to 15°C. Sodium borohydride (3.1gm) added in lot wise at about 0 to 15°C. The reaction mixture was stirred for about 15 minutes at about 0 to 15°C and then temperature was raised to 40 to 50°C and maintained for 3 to 6 hours. Completion of the reaction was checked by HPLC. Then reaction mass cooled to 30°C and MDC charged, reaction mass was further cooled to 0 to 10°C and aq. HCl solution added slowly to reaction mass. organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene di chloride. The combined organic layer was washed with aq. NaOH solution and water. The organic layer was evaporated under vacuum to get (2S)-1-phenyl-N-(1-phenylethyl)propan-2-amine as an oil (25 gm) which then hydrogenated in autoclave with acetic acid as solvent Pd/C as catalyst and hydrogen pressure till HPLC complies. After completion of reaction, reaction mass unloaded from autoclave and filtered through celite bed under nitrogen. Filtrate then concentrated under vacuum to give oil which is then extracted with methylene dichloride by adjusting to basic pH with caustic lye. Organic layer then concentrated under vacuum to get oil (15.5 gm). To this oily mass added aq. Methanol and l-tartaric acid and heated to reflux then cooled and filtered. The solid was dried under vacuum to form titled compound as a white solid. Yield: 12.0 gm, (Molar yield 50.7%).
Example 5: Preparation of (2S)-1-phenylpropan-2-amine tartrate (Dextroamphetamine Tartrate):
To a stirred solution of S-Phenylethyl amine (10 gm) in Methylene dichloride(50ml) added Phenyl acetone (16.6 gm). The reaction mixture cooled to 0oC to 10°C and slowly added para toluene sulphonic acid (7.0 gm). Maintained reaction mass for 60 min at 0 to 15°C. Sodium borohydride (3.1gm) added in lot wise at about 0 to 15°C. The reaction mixture was stirred for about 15 minutes at about 0 to 15°C and then temperature was raised to 20 to 30°C and maintained for 5 to 8 hours. Completion of the reaction was checked by HPLC. The reaction mass was cooled to 0 to 10°C and aq. HCl solution added slowly to reaction mass. organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene di chloride. The combined organic layer was washed with aq. NaOH solution and water. The organic layer was evaporated under vacuum to get (2S)-1-phenyl-N-(1-phenylethyl)propan-2-amine as an oil (25 gm) which then hydrogenated in autoclave with acetic acid as solvent Pd/C as catalyst and hydrogen pressure till HPLC complies. After completion of reaction, reaction mass unloaded from autoclave and filtered through celite bed under nitrogen. Filtrate then concentrated under vacuum to give oil which is then extracted with methylene dichloride by adjusting to basic pH with caustic lye. Organic layer then concentrated under vacuum to get oil (15.5 gm). To this oily mass added aq. Methanol and l-tartaric acid and heated to reflux then cooled and filtered. The solid was dried under vacuum to form titled compound as a white solid. Yield: 10.2 gm, (Molar yield :43.4 %).
Example 6: Preparation of (2S)-1-phenylpropan-2-amine tartrate (Dextroamphetamine Tartrate):
To a stirred solution of S-Phenylethyl amine (10 gm) in Methylene dichloride(50ml) added Phenyl acetone (16.6 gm). The reaction mixture cooled to 0 to 10°C and slowly added methane sulphonic acid (7.9 gm). Maintained reaction mass for 60 min at 0 to 15°C. Sodium borohydride (3.1gm) added in lot wise at about 0 to 15°C. The reaction mixture was stirred for about 15 minutes at about 0 to 15°C and then temperature was raised to 20o to 30°C and maintained for 5 to 8 hours. Completion of the reaction was checked by HPLC. The reaction mass was cooled to 0 to 10°C and aq. HCl solution added slowly to reaction mass. organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene di chloride. The combined organic layer was washed with aq. NaOH solution and water. The organic layer was evaporated under vacuum to get (2S)-1-phenyl-N-(1-phenylethyl)propan-2-amine as an oil (25 gm) which then hydrogenated in autoclave with acetic acid as solvent Pd/C as catalyst and hydrogen pressure till HPLC complies. After completion of reaction, reaction mass unloaded from autoclave and filtered through celite bed under nitrogen. Filtrate then concentrated under vacuum to give oil which is then extracted with methylene dichloride by adjusting to basic pH with caustic lye. Organic layer then concentrated under vacuum to get oil (15.5 gm). To this oily mass added aq. Methanol and l-tartaric acid and heated to reflux then cooled and filtered. The solid was dried under vacuum to form titled compound as a white solid. Yield: 10.2 gm, (Molar yield :43.4 %).
Example 7: Preparation of (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide(Crude lisdexamfetamine):
In a dry round bottom flask acetone (500mL) was charged followed by addition of Dextroamphetamine Tartrate (100g) and potassium carbonate (145.3 g). The reaction mixture was stirred for 30 min at 20 to 30°C and then Di-Boc-L-Lysine 4-Nitrophenyl Ester (172.1g) was added to the reaction mass. Temperature of the reaction mass was raised to about 50 to 60°C and stirred for about 3 hours. After completion of the reaction, the reaction mass Distilled out under vacuum to get the residue and methylene dichloride, and water was added at temperature below 30°C. The aqueous and organic layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with aq. NaOH and water The filtrate was concentrated under vacuum to obtain 162 g Di-tert-butyl((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl) dicarbamate as an oil. The obtained oil was taken in ethanol (600ml) and added dropwise 84.24 g methanesulfonic acid. Then stirred reaction mass for about 5 hours at 50 to 60°C. After completion of the reaction, the reaction mass was cooled, and the precipitated solid was filtered and dried under vacuum at about 50-60°C to form 140 gm of titled compound. (Molar Yield: 88.0%)
Example 8: Preparation of (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide(Crude lisdexamfetamine):
In a dry round bottom flask Dimethylformamide (300mL) was charged followed by addition of Dextroamphetamine Tartrate (100g) and potassium carbonate (145.3 g). The reaction mixture was stirred for 30 min at 20 to 30°C and then Di-Boc-L-Lysine 4-Nitrophenyl Ester (172.1g) was added to the reaction mass. Temperature of the reaction mass was raised to about 50 to 60°C and stirred for about 3 hours. After completion of the reaction, the reaction mass Distilled out under vacuum to get the residue and methylene dichloride, and water was added at temperature below 30°C. The aqueous and organic layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with aq. NaOH and water The filtrate was concentrated under vacuum to obtain 162 g Di-tert-butyl((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl) dicarbamate as an oil. The obtained oil was taken in ethanol (1000ml) and added dropwise 84.24 g methanesulfonic acid. Then stirred reaction mass for about 5 hours at 50 to 60°C. After completion of the reaction, the reaction mass was cooled, and the precipitated solid was filtered and dried under vacuum at about 50-60°C to form 135 gm of titled compound. (Molar Yield: 84.9%)
Example 9: Preparation of (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide(Crude lisdexamfetamine):
In a dry round bottom flask Acetone (500mL) was charged followed by addition of Dextroamphetamine Tartrate (100g) and potassium carbonate (145.3 g). The reaction mixture was stirred for 30 min at 20 to 30°C and then Di-Boc-L-Lysine 4-Nitrophenyl Ester (172.1g) was added to the reaction mass. Temperature of the reaction mass was raised to about 50 to 60°C and stirred for about 3 hours. After completion of the reaction, the reaction mass Distilled out under vacuum to get the residue and methylene dichloride, and water was added at temperature below 30°C. The aqueous and organic layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with aq. NaOH and water The filtrate was concentrated under vacuum to obtain 162 g Di-tert-butyl((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl) dicarbamate as an oil. The obtained oil was taken in isopropyl alcohol (1000ml) and added dropwise 260 g methanesulfonic acid. Then stirred reaction mass for about 5 hours at 50 to 60°C. After completion of the reaction, the reaction mass was cooled, and the precipitated solid was filtered and dried under vacuum at about 50-60°C to form 136 gm of titled compound. (Molar Yield: 85.0%)
Example 10: Purification of crude lisdexamphetamine di mesylate:
Crude lisdexamphetamine di mesylate (100 gm) was refluxed in isopropyl alcohol and suspension was stirred for about 30 minutes at reflux temperature and cooled to room temperature gradually. The thick slurry of reaction mass was stirred for about four hours at about 15-20° C. and precipitated solid was filtered and suck dried. The wet material further dried under vacuum titled compound. Molar Yield:92.0% HPLC purity: 99.5%, Chiral purity: 100%.
Example 11: Purification of crude lisdexamphetamine di mesylate:
Crude lisdexamphetamine di mesylate (100 gm) was refluxed in ethanol and suspension was stirred for about 30 minutes at reflux temperature and cooled to room temperature gradually. The thick slurry of reaction mass was stirred for about four hours at about 15-20° C. and precipitated solid was filtered and suck dried. The wet material further dried under vacuum titled compound. Molar Yield:94.0% HPLC purity: 99.8 %, Chiral purity: 100%.
 
We Claim:
1. A method for synthesising Lisdexamfetamine
(I)
or pharmaceutically acceptable salt thereof, the method comprising:
a) reacting a compound of formula 1 with a compound of formula 2 in presence of an acid to obtain a compound of formula 3;
b) reducing the compound of formula 3 with a reducing agent to obtain a compound of formula 4;
c) hydrogenating the compound of formula 4 with a hydrogenating agent and thereafter resolving with a chiral resolving agent to obtain a compound of formula 5;
d) contacting the compound of formula 5 with a compound of formula 6 to obtain a compound of formula 7.
e) treating the compound of formula 7 with an acid to obtain a free base of the compound of formula (I).
f) contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I).
wherein the compound of formula 4 is obtained in-situ or without isolating the compound of formula 3.
2. The method as claimed in claim 1, wherein the acid is organic acid or inorganic acid.
3. The method as claimed in claim 1, wherein reacting the compound of formula 1 with compound of formula 2 to obtain a compound of formula 3 is carried out in presence of an acid selected from organic acids, inorganic acids and combinations thereof.
4. The method as claimed in claim 1, wherein organic acid is selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, Citric acid, Tartaric acid, Lactic acid, Succinic acid, Maleic acid, Fumaric acid, Malic acid, Oxalic acid, Benzoic acid, p-Toluenesulfonic acid (p-TSA), Camphorsulfonic acid (CSA), Gluconic acid, Salicylic acid, Ascorbic acid, Levulinic acid and combinations thereof.
5. The method as claimed in claim 1, wherein reducing agent is selected from Sodium borohydride (NaBH₄), Sodium cyanoborohydride (NaBH₃CN), Sodium tri-acetoxy borohydride (NaBH(OAc)₃), Lithium aluminum hydride (LiAlH₄), Di-isobutyl-aluminum hydride (DIBAL-H), Red-Al (sodium bis(2-methoxyethoxy) aluminum hydride) and combinations thereof.
6. The method as claimed in claim 1, wherein hydrogenating agent is selected from Hydrogen gas (H₂) with Palladium on carbon (Pd/C), Hydrogen gas (H₂) with Platinum (Pt) catalyst, Hydrogen gas (H₂) with Raney Nickel, Hydrogen gas (H₂) with Ruthenium or Rhodium catalysts.
7. The method as claimed in claim 1, wherein resoluting agent is selected from (+)-Di-O,O'-toluoyl-D-tartaric acid, (-)-di-O,O'-toluoyl-L-tartaric acid, (+)-di-O,O'-benzoyl-D-tartaric acid, (-)-di-O,O'-benzoyl-L-tartaric acid, (+)-di-O,O'-anisoyl-D-tartaric acid, and (-)-di-O,O'-anisoyl-L-tartaric acid, l-(+)-mandelic acid, L-tartaric acid, D-tartaric acid (S)-(-)-N-(1-Phenylethyl)- phthalamic Acid, (S)-(+)-αMethoxyphenylacetic Acid, (R)-(-)-αMethoxyphenylacetic Acid, (+)-MTPA, (-)-MTPA, (S)-(+)-γ-Carboxyγ-butyrolactone, (R)-(-)-γ-Carboxyγ-butyrolactone, R)-(-)-Hydratropic Acid, (S)-(+)-Hydratropic Acid, D-(+)-Malic Acid, L-(-)-Malic Acid, (-)-Menthoxyacetic Acid, L-(+)-Mandelic Acid, D-(-)-Mandelic Acid, D-(-)-Quinic Acid, D-Aspartic Acid, L-Aspartic Acid, L-Glutamic Acid, D-Glutamic Acid, D-Pyroglutamic Acid, L-Pyroglutamic Acid, L-Valine, Tosyl-L-phenylalanyl Chloride, (+)-Camphor-10-sulfonic acid, (-)-Camphor-10-sulfonic acid
8. The method as claimed in claim 1, wherein treating the compound of formula 7 to obtain a free base of the compound of formula (I) is carried out by using any organic or inorganic acid selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, p-.Toluenesulfonic acid (p-TSA), Hydrochloric acid (HCl), Sulfuric acid (H₂SO₄), Nitric acid (HNO₃), Phosphoric acid (H₃PO₄), Hydrobromic acid (HBr), Hydroiodic acid (HI), Perchloric acid (HClO₄), Trifluoroacetic acid, Polyphosphoric acid (PPA) or Lewis acids like AlCl₃ or ZnBr₂, and reagents like trimethylsilyl iodide (TMSI) and combinations thereof.
9. The method as claimed in claim 1, wherein contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I); wherein acid is organic or inorganic acid selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, Citric acid, Tartaric acid, Lactic acid, Succinic acid, Maleic acid, Fumaric acid, Malic acid, Oxalic acid, Benzoic acid, p-Toluenesulfonic acid (p-TSA), Camphorsulfonic acid (CSA), Gluconic acid, Salicylic acid, Ascorbic acid, Levulinic acid ,wherein inorganic acid is selected from Hydrochloric acid (HCl), Sulfuric acid (H₂SO₄), Nitric acid (HNO₃), Phosphoric acid (H₃PO₄), Hydrobromic acid (HBr), Hydroiodic acid (HI), Perchloric acid (HClO₄), Boric acid (H₃BO₃), Polyphosphoric acid (PPA).
10. The method as claimed in claim 1, wherein solvent is selected from Water Methanol, Ethanol, Isopropanol (IPA),n-propanol, n-Butanol, t-Butanol, Acetic acid, Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), Acetonitrile (MeCN), Tetrahydrofuran (THF), methyl t-butyl ether (MTBE), 1,4-Dioxane, Ethyl acetate, Isopropyl acetate, Dichloromethane (DCM or CH₂Cl₂), Chloroform, Toluene, Xylene, Hexane,Heptane, Cyclohexane, Acetone, methyl ethyl ketone (MEK),Methyl isobutyl ketone (MIBK), cyclohexanone, Diethyl ether, pyridine, Di-isopropyl ether, Dimethoxy ethane, Ethylene glycol and combinations thereof.

Dated this: July 22, 2025

Vijaykumar Shivpuje
IN/PA- 1096
Agent for the Applicants
To
The Controller of Patents,
The Patent Office, Mumbai

ABSTRACT
“AN IMPROVED METHOD FOR THE MANUFACTURING LISDEXAMFETAMINE OR A SALT THEREOF”

The present invention relates to an improved method for the manufacturing of Lisdexamfetamine or a pharmaceutically acceptable salt thereof. The said method is carried out by: (a) reacting a compound of formula 1 with a compound of formula 2 in presence of an acid to obtain a compound of formula 3; (b) reducing the compound of formula 3 with a reducing agent to obtain a compound of formula 4; (c) hydrogenating the compound of formula 4 with hydrogenating agent and thereafter resolving with a chiral resolving agent to obtain a compound of formula 5; (d) contacting the compound of formula 5 with a compound of formula 6 to obtain a compound of formula 7; (e) treating the compound of formula 7 with an acid to obtain a free base of the compound of formula (I); (f) contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I); wherein the compound of formula 4 is obtained in-situ or without isolating the compound of formula 3.

, Claims:We Claim:
1. A method for synthesising Lisdexamfetamine
(I)
or pharmaceutically acceptable salt thereof, the method comprising:
a) reacting a compound of formula 1 with a compound of formula 2 in presence of an acid to obtain a compound of formula 3;
b) reducing the compound of formula 3 with a reducing agent to obtain a compound of formula 4;
c) hydrogenating the compound of formula 4 with a hydrogenating agent and thereafter resolving with a chiral resolving agent to obtain a compound of formula 5;
d) contacting the compound of formula 5 with a compound of formula 6 to obtain a compound of formula 7.
e) treating the compound of formula 7 with an acid to obtain a free base of the compound of formula (I).
f) contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I).
wherein the compound of formula 4 is obtained in-situ or without isolating the compound of formula 3.
2. The method as claimed in claim 1, wherein the acid is organic acid or inorganic acid.
3. The method as claimed in claim 1, wherein reacting the compound of formula 1 with compound of formula 2 to obtain a compound of formula 3 is carried out in presence of an acid selected from organic acids, inorganic acids and combinations thereof.
4. The method as claimed in claim 1, wherein organic acid is selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, Citric acid, Tartaric acid, Lactic acid, Succinic acid, Maleic acid, Fumaric acid, Malic acid, Oxalic acid, Benzoic acid, p-Toluenesulfonic acid (p-TSA), Camphorsulfonic acid (CSA), Gluconic acid, Salicylic acid, Ascorbic acid, Levulinic acid and combinations thereof.
5. The method as claimed in claim 1, wherein reducing agent is selected from Sodium borohydride (NaBH₄), Sodium cyanoborohydride (NaBH₃CN), Sodium tri-acetoxy borohydride (NaBH(OAc)₃), Lithium aluminum hydride (LiAlH₄), Di-isobutyl-aluminum hydride (DIBAL-H), Red-Al (sodium bis(2-methoxyethoxy) aluminum hydride) and combinations thereof.
6. The method as claimed in claim 1, wherein hydrogenating agent is selected from Hydrogen gas (H₂) with Palladium on carbon (Pd/C), Hydrogen gas (H₂) with Platinum (Pt) catalyst, Hydrogen gas (H₂) with Raney Nickel, Hydrogen gas (H₂) with Ruthenium or Rhodium catalysts.
7. The method as claimed in claim 1, wherein resoluting agent is selected from (+)-Di-O,O'-toluoyl-D-tartaric acid, (-)-di-O,O'-toluoyl-L-tartaric acid, (+)-di-O,O'-benzoyl-D-tartaric acid, (-)-di-O,O'-benzoyl-L-tartaric acid, (+)-di-O,O'-anisoyl-D-tartaric acid, and (-)-di-O,O'-anisoyl-L-tartaric acid, l-(+)-mandelic acid, L-tartaric acid, D-tartaric acid (S)-(-)-N-(1-Phenylethyl)- phthalamic Acid, (S)-(+)-αMethoxyphenylacetic Acid, (R)-(-)-αMethoxyphenylacetic Acid, (+)-MTPA, (-)-MTPA, (S)-(+)-γ-Carboxyγ-butyrolactone, (R)-(-)-γ-Carboxyγ-butyrolactone, R)-(-)-Hydratropic Acid, (S)-(+)-Hydratropic Acid, D-(+)-Malic Acid, L-(-)-Malic Acid, (-)-Menthoxyacetic Acid, L-(+)-Mandelic Acid, D-(-)-Mandelic Acid, D-(-)-Quinic Acid, D-Aspartic Acid, L-Aspartic Acid, L-Glutamic Acid, D-Glutamic Acid, D-Pyroglutamic Acid, L-Pyroglutamic Acid, L-Valine, Tosyl-L-phenylalanyl Chloride, (+)-Camphor-10-sulfonic acid, (-)-Camphor-10-sulfonic acid
8. The method as claimed in claim 1, wherein treating the compound of formula 7 to obtain a free base of the compound of formula (I) is carried out by using any organic or inorganic acid selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, p-.Toluenesulfonic acid (p-TSA), Hydrochloric acid (HCl), Sulfuric acid (H₂SO₄), Nitric acid (HNO₃), Phosphoric acid (H₃PO₄), Hydrobromic acid (HBr), Hydroiodic acid (HI), Perchloric acid (HClO₄), Trifluoroacetic acid, Polyphosphoric acid (PPA) or Lewis acids like AlCl₃ or ZnBr₂, and reagents like trimethylsilyl iodide (TMSI) and combinations thereof.
9. The method as claimed in claim 1, wherein contacting a compound of formula (I) with an acid to obtain a pharmaceutically acceptable salt of compound of formula (I); wherein acid is organic or inorganic acid selected from Methanesulfonic acid (MSA), Formic acid Acetic acid, Propionic acid, Butyric acid, Citric acid, Tartaric acid, Lactic acid, Succinic acid, Maleic acid, Fumaric acid, Malic acid, Oxalic acid, Benzoic acid, p-Toluenesulfonic acid (p-TSA), Camphorsulfonic acid (CSA), Gluconic acid, Salicylic acid, Ascorbic acid, Levulinic acid ,wherein inorganic acid is selected from Hydrochloric acid (HCl), Sulfuric acid (H₂SO₄), Nitric acid (HNO₃), Phosphoric acid (H₃PO₄), Hydrobromic acid (HBr), Hydroiodic acid (HI), Perchloric acid (HClO₄), Boric acid (H₃BO₃), Polyphosphoric acid (PPA).
10. The method as claimed in claim 1, wherein solvent is selected from Water Methanol, Ethanol, Isopropanol (IPA),n-propanol, n-Butanol, t-Butanol, Acetic acid, Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), Acetonitrile (MeCN), Tetrahydrofuran (THF), methyl t-butyl ether (MTBE), 1,4-Dioxane, Ethyl acetate, Isopropyl acetate, Dichloromethane (DCM or CH₂Cl₂), Chloroform, Toluene, Xylene, Hexane,Heptane, Cyclohexane, Acetone, methyl ethyl ketone (MEK),Methyl isobutyl ketone (MIBK), cyclohexanone, Diethyl ether, pyridine, Di-isopropyl ether, Dimethoxy ethane, Ethylene glycol and combinations thereof.