DESC:TITLE OF THE INVENTION
An improved process for the preparation of Lisdexamphetamine and salts thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No. 202321066394 filed on October 04, 2023.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of pure Lisdexamphetamine or its pharmaceutically acceptable salts. Further, the present invention relates to a novel intermediate and their use in the process for the preparation of Lisdexamphetamine or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION
Lisdexamphetamine is presented as formula (I)is a conjugate of D-amphetamine and L-lysine and chemically named as (2S)-2,6-diamino-N-[(1 S)-methyl-2-phenylethyl]hexan amide.

Formula (I)
Lisdexamphetamine is marketed under trade name Vyvanse® in USA. Lisdexamphetamine stimulate central nervous system (CNS) and is prescribed for the treatment of various disorders such as attention deficit/hyperactivity disorder (ADHD) and Binge eating disorder (BED). It is approved as Lisdexamphetamine dimesylate presented as formula (IA).

Formula (IA)
US 7,662,787 discloses a process for the preparation of Lisdexamphetamine and its pharmaceutically acceptable salts, specifically exemplified as hydrochloride salt. The process for preparation of Lisdexamphetamine involves the reaction of BOC-Lys­(BOC)-hydroxysuccinimido ester intermediate with D-amphetamine using diisopropyl ethyl amine (DIPEA) as a base to obtain BOC-protected intermediate, which is then purified using flash chromatography and further reacted with a mixture of 4M hydrochloric acid /dioxane to yield Lisdexamphetamine hydrochloride salt. The process is as shown in following scheme:

US 7,659,253 B2 discloses a process for the preparation of mesylate salt of Lisdexamphetamine as shown below, wherein the process involves preparation of BOC-Lys-(BOC)-hydroxysuccinimido ester intermediate. The reaction is carried out using compounds like N-hydroxy-succinimide (NHS) and N, N-dicyclohexyl-carbodimiide (DCC). The process requires use of flash column chromatography to purify crude BOC- protected L-lysine-D-amphetamine intermediate. The use of column chromatography makes the process tedious and time consuming, therefore, not advisable at commercial scale. Further, the use of N, N-dicyclohexylcarbodimiide (DCC) leads to formation of highly toxic N, N -dicyclohexyl urea (DCU) in large amount as bye product. Therefore, use of DCC is not advisable at industrial scale.

WO 2010/042120 discloses the process for preparing Lisdexamphetamine and its salts by reacting D-amphetamine with protected lysine or its salt by using an alkylphosphonic acid anhydride as coupling agent in presence of a base and solvent. Alkylphosphonic acid anhydrides are expensive and needs additional testing to show absence of phosphorus impurities in intermediate or final compound to meet regulatory requirements. Hence, it is not advisable to use alkylphosphonic anhydrides for scale up operations. The process is as shown in the below scheme:

WO2010/148305 discloses the process for the preparation of Lisdexamphetamine by removal of chlorine from N, N'-bistrifluoroacetyl-chloro­Lisdexamphetamine intermediate by using hydrogenation catalyst like Pd/C, under hydrogen gas to form N, N' -bistrifluoroacetyl-lisdexamphetamine which on further deprotected by using deprotecting agent to form Lisdexamphetamine. Alternatively, first deprotection by using deprotecting agent and then chlorine is removed by using hydrogenation catalyst like Pd/C under hydrogen gas. The process involves additional steps of inserting chloro group and thereafter removing chloro group. Further, Pd/C is an expensive compound.
WO 2013/011526 discloses the process for the preparation of Lisdexamphetamine and its salts wherein, the process involves use of the chloroformate compounds as an acid activating agent. However, the process needs additional purification step to obtain pure product.
US 8,779,191 B2 discloses the process for the preparation of Lisdexamphetamine and its salt wherein, the process involves preparation of benzyl protected intermediate and then deprotection of benzyl protected intermediate to obtain the Lisdexamphetamine as represented in the below scheme. However, the deprotection of benzyl groups requires significantly stronger acidic conditions.

Therefore, there is a necessity to overcome problems associated with the prior art disclosed processes and to provide an efficient process for the preparation of Lisdexamphetamine and its pharmaceutically acceptable salts using readily available, less expensive, easy to handle raw materials.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved and efficient process for the preparation of Lisdexamphetamine of compound of formula (I) and its pharmaceutically acceptable salts using a novel intermediate of compound of formula (IV).

In another objective, the present invention provides a novel intermediate used for the preparation of Lisdexamphetamine or its pharmaceutically acceptable salts.
In yet another objective, the present invention provides the process for the preparation of a novel intermediate of Lisdexamphetamine or its pharmaceutically acceptable salts.

In yet another objective, the present invention provides a scalable, cost-effective and simple process for the preparation of Lisdexamphetamine dimesylate salt.
In yet another objective, the present invention provides Lisdexamphetamine dimesylate with reduced level of impurities.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides an improved process for the preparation of Lisdexamphetamine or pharmaceutically acceptable salt thereof. The process of the present invention comprising following steps.
a) reacting the L-lysine monohydrochloride with amine protecting group in the presence of a base and suitable solvent to give the diamino protected L-lysine compound of formula (II);

Wherein PG is an amine protecting group
b) reacting the diamino protected L-lysine compound of formula (II) with the acid activating compound of formula (III);

wherein R is selected from alkyl or aryl or substituted aryl groups and X is halogen selected from chlorin, bromine and Iodine,
in the presence of a base and suitable solvent to form the anhydride intermediate of formula (IV);

wherein PG is an amine protecting group
c) optionally, isolating the anhydride intermediate of formula (IV);
d) reacting the anhydride intermediate of formula (IV) with D-amphetamine of formula (V) to give the diamino protected amide compound of formula (VI);


wherein PG is same as defined above
e) deprotecting the diamino protected amide compound of formula (VI) to give the Lisdexamphetamine or its pharmaceutically acceptable salt.
In an embodiment, present invention provides a novel anhydride intermediate of formula (IV), used for the preparation of Lisdexamphetamine or its pharmaceutically acceptable salts.

wherein PG is an amine protecting group and R is selected from alkyl or aryl or substituted aryl groups
In another embodiment, the present invention provides the process for the preparation of a novel anhydride intermediate of formula (IV). The process for the novel intermediate comprises following steps:
a) reacting the L-lysine monohydrochloride with the amine protecting group in the presence of a base and suitable solvent to give the diamino protected L-lysine compound of formula (II);

wherein PG is an amine protecting group
b) reacting the diamino protected L-lysine compound of formula (II) with the acid activating compound of formula (III);

wherein R is selected from alkyl or aryl or substituted aryl groups and X is halogen selected from chlorin, bromine, Iodine
in the presence of a base and a suitable solvent to form the anhydride intermediate of formula (IV);

wherein PG is an amine protecting group
c) optionally isolating and purifying the anhydride intermediate of formula (IV).
In an embodiment, the present invention provides Lisdexamphetamine dimesylate with reduced amount of impurities.
In an embodiment, the present invention provides a solid form of Lisdexamphetamine dimesylate characterized by PXRD, DSC and TGA.
Further, the present invention provides a pharmaceutical composition for oral administration comprising Lisdexamphetamine dimesylate and one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF DRAWINGS OF THE INVENTION
Fig. 1 illustrates the PXRD pattern of Lisdexamphetamine dimesylate obtained by the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Lisdexamphetamine or its pharmaceutically acceptable salts. The process of the present invention comprising following steps.
a) reacting the L-lysine monohydrochloride with the amine protecting group in the presence of a base and a suitable solvent to give the diamino protected L-lysine compound of formula (II);

wherein PG is an amine protecting group
b) reacting the diamino protected L-lysine compound of formula (II) with the acid activating compound of formula (III);

wherein R is selected from alkyl or aryl or substituted aryl groups and X is halogen selected from chlorin, bromine, Iodine
in the presence of a base and a suitable solvent to form the anhydride intermediate of formula (IV);

wherein PG is an amine protecting group
c) optionally, isolating the anhydride intermediate of formula (IV);
d) reacting the anhydride intermediate of compound of formula (IV) with the D-amphetamine of compound of formula (V) to give the diamino protected amide compound of formula (VI);


wherein PG is same as defined above
e) deprotecting the diamino protected amide compound of formula (VI) to give the Lisdexamphetamine or its pharmaceutically acceptable salt.

In an embodiment, the amine protecting group may be selected from any group which is suitable to protect amine group. In general, the suitable amine protecting group can include, but not limited to Di-tert-Butyl Dicarbonate (BOC), benzyloxycarbonyl (CBz), allyloxycarbonyl (Alloc) fluorenyl methyloxycarbonyl (Fmoc), trimethylsilylethyloxycarbonyl (Teoc), pivaloyl, trifluoro acetyl etc. Preferably the amine protecting group is t­butyloxycarbonyl (BOC).
In an embodiment, the base used in the step a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium carbonate, sodium hydride, potassium hydride and lithium hydride. Preferably, the base is selected from sodium hydroxide or potassium hydroxide. Most preferably, the base is potassium hydroxide.
In an embodiment, the suitable solvent used in step a) is an organic solvent selected from the group consisting of an alcoholic solvent, an ester solvent, a ketone solvent and mixtures thereof. In an embodiment, the solvent used in step a) is selected from the group consisting of water, toluene, acetone, ethyl acetate, isopropyl acetate, chloroform, ethanol, acetonitrile, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol, methylene chloride, dimethylformamide, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. Preferably, the suitable solvent is tert-butyl alcohol and water.
In an embodiment, the reaction of step a) can be carried out at temperature range of 20 to 40 ?C.

In an embodiment, the acid activating compound of formula (III) used for the preparation of anhydride intermediate of formula IV in step b) is selected from the group consisting of isobutyryl chloride, pivaloyl chloride, isovaleroyl chloride, butanoyl chloride, 2-ethylbutyryl chloride, cyclohexane carboxylic acid chloride, pentanoyl chloride, benzoyl chloride, phenylacetyl chloride etc. Preferably, the acid activating compound is pivaloyl chloride.
In an embodiment, the base used for the preparation of anhydride intermediate of formula (IV) in step b) is selected from the group consisting of, but not limited to triethylamine (TEA), di-isopropyl ethyl amine (DIPEA), tri-n-propyl amine, tri-n-butyl amine, pyridine, lutidine and the like thereof. Preferably, the base used is triethyl amine or di-isopropyl ethyl amine.
In an embodiment, the suitable solvent used in the process of the present invention is selected from the group consisting of aliphatic or aromatic hydrocarbons such as n-pentane, n-hexane, n-heptane, cyclopentane, cyclohexane, cycloheptane, toluene, xylene; C1-4 halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane; CJ-6 esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and like; C4•8 ethers such as diethyl ether, di-isopropyl ether, methyl t-butyl ether, 1,2-dimethoxy ethane, 1,2-diethoxy ethane, tetrahydrofuran, 2-methyl tetrahydrofuran and dioxane; C3-6 ketones such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, and alkylnitriles such as acetonitrile, propionitrile and amides such as N,N-dimethylformamide, N,N dimethyl acetamide.
In an embodiment, the reaction for the preparation of anhydride intermediate of formula (IV) in step b) can be carried out at temperature range of 30 to 50?C.
In an embodiment, the base used in the reaction for the preparation of diamino protected amide compound of formula (VI) in step d) is selected from the group consisting of alkali or alkaline metal hydroxides, carbonates, alkoxides and hydrides, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium methoxide, potassium methoxide, sodium hydride, potassium hydride, lithium hydride and the like; preferably, the base used is sodium or potassium hydroxide.

In an embodiment, the acid used in the reaction for the preparation of the diamino protected amide compound of formula (VI) in step d), is selected from the group consisting of hydrochloric acid, phosphoric acid, Hydrobromic acid, hydroiodic acid, nitric acid. Preferably, the acid is phosphoric acid.
In an embodiment, the deprotection of the diamino protected amide compound of formula (VI) to obtain Lisdexamphetamine of compound of formula (I) is carried out using an acid selected from the group consisting of hydrochloric acid, methanesulphonic acid, phosphoric acid, Hydrobromic acid, hydroiodic acid and nitric acid. Preferably, the acid is methanesulphonic acid.
In an embodiment, the deprotection of the diamino protected amide compound of formula (VI) to give Lisdexamphetamine of compound of formula (I) may be carried out at temperature ranging from 50 to 70°C. Preferably, the reaction may be carried out at temperature at about 55 to 65 °C.
In an embodiment, the present invention provides the pharmaceutically acceptable salts of Lisdexamphetamine of compound of formula (I) such as mesylate, hydrochloride, iodide, hydrobromide etc. Preferably, the salt is mesylate.
In an embodiment, the present invention provides a novel intermediate of formula (IV) which used in the process for the preparation of Lisdexamphetamine or its pharmaceutically acceptable salts.

wherein PG is an amine protecting group and R is selected from alkyl or aryl or substituted aryl groups
Further, the present invention provides the process for the preparation of a novel anhydride intermediate of formula (IV). The process for the novel intermediate comprises following steps:
a) reacting the L-lysine monohydrochloride with amine protecting group in the presence of a base and a suitable solvent to give the diamino protected L-lysine compound of formula (II);

wherein PG is an amine protecting group
b) reacting the diamino protected L-lysine compound of formula (II) with the acid activating compound of formula (III);

wherein R is selected from alkyl or aryl or substituted aryl groups and X is halogen selected from chlorin, bromine, Iodine
in the presence of a base in a solvent to form the anhydride intermediate of formula (IV);

wherein PG is an amine protecting group
c) optionally, isolating and purifying the anhydride intermediate of formula (IV).
In an embodiment, the amine protecting group may be selected from any group which is suitable to protect amine group. In general, suitable amine protecting group includes, but not limited to Di-tert-Butyl Dicarbonate (BOC), benzyloxycarbonyl (CBz), allyloxycarbonyl (Alloc) fluorenyl methyloxycarbonyl (Fmoc), trimethylsilylethyloxycarbonyl (Teoc), pivaloyl, trifluoro acetyl etc. Preferably, the amine protecting group is t­butyloxycarbonyl (BOC).
In an embodiment, the base used in the step a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium carbonate, sodium hydride, potassium hydride, lithium hydride. Preferably, the base is selected from sodium hydroxide or potassium hydroxide. Most preferably, the base is potassium hydroxide.
In an embodiment, the suitable solvent used in step a) is an organic or an inorganic solvent selected from the group consisting of an alcoholic solvent, an ester solvent, ketone solvent and mixtures thereof. In an embodiment, the solvent used in step a) is selected from the group consisting of water, toluene, acetone, ethyl acetate, isopropyl acetate, chloroform, ethanol, acetonitrile, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol, methylene chloride, dimethylformamide, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. Preferably, the suitable solvent is tert-butyl alcohol and water.
In an embodiment, the reaction of step a) can be carried out at temperature range of 20 to 40 ?C.
In an embodiment, the acid activating compound of formula (III) used for the preparation of anhydride intermediate of formula (IV) in step b) is selected from the group consisting of isobutyryl chloride, pivaloyl chloride, isovaleroyl chloride, butanoyl chloride, 2-ethylbutyryl chloride, cyclohexane carboxylic acid chloride, pentanoyl chloride, benzoyl chloride, phenylacetyl chloride etc. Preferably, the acid activating compound is pivaloyl chloride.
In an embodiment, the base used for the preparation of the compound of formula (IV) in step b) is selected from the group consisting of but not limited to triethylamine (TEA), di-isopropyl ethyl amine (DIPEA), tri-n-propyl amine, tri-n-butyl amine, pyridine, lutidine and like thereof. Preferably, the base used is triethyl amine or di-isopropyl ethyl amine.
In a preferred embodiment, the present invention provides the process for the preparation of Lisdexamphetamine. The process of the present invention comprising following steps:
a) reacting the L-lysine monohydrochloride with Di-tert-Butyl Dicarbonate (BOC) in the presence of a base and a suitable solvent to give the Boc protected L-lysine compound of formula (II);

b) reacting the Boc protected L-lysine compound of formula (II) with pivaloyl chloride of formula (III);

in the presence of a base and a suitable solvent to form the anhydride intermediate of formula (IV);

c) optionally isolating the anhydride intermediate of formula (IV);
d) reacting the anhydride intermediate of formula (IV) with D-amphetamine to give the Boc protected amide compound of formula (VI);

e) deprotecting the Boc protected amide compound of formula (VI) to give Lisdexamphetamine or its pharmaceutically acceptable salt.
In a preferred embodiment, the base used in the step a) is potassium hydroxide. In a preferred embodiment, the suitable solvent used in step a) is a mixture of tert-butyl alcohol and water. In a preferred embodiment, the reaction of step a) can be carried out at temperature range of 20 to 40 ?C.
In a preferred embodiment, the base used for the preparation of anhydride intermediate of formula (IV) in step b) is di-isopropyl ethyl amine. In a preferred embodiment, the acid used in the reaction for the preparation of diamino protected amide compound of formula (VI) in step d), is phosphoric acid.
In a specific embodiment, the present invention provides the process for preparation of the dimesylate salt of Lisdexamphetamine comprising following steps:
a) reacting the L-lysine monohydrochloride with Di-tert-Butyl Dicarbonate (BOC) in the presence of the potassium hydroxide and tert-Butyl alcohol to give the Boc protected L-lysine compound of formula (II);

b) reacting the Boc protected L-lysine compound of formula (II) with pivaloyl chloride of formula (III);

in the presence of the di-isopropyl ethylamine and isopropyl acetate to form the anhydride intermediate of formula (IV);

c) optionally, isolating the anhydride intermediate of formula (IV);
d) reacting the anhydride intermediate of formula (IV) with D-amphetamine to give the Boc protected amide compound of formula (VI);

e) reacting the Boc protected amide compound of formula (VI) with methanesulphonic acid in the presence of isopropanol at temperature 55 to 65 °C to give dimesylate salt of Lisdexamphetamine;
f) isolating the dimesylate salt of Lisdexamphetamine using isopropanol.
In an embodiment, the process of the present invention provides a pure Lisdexamphetamine or pharmaceutically acceptable salt thereof containing reduced amount of total impurities wherein the total impurities are not more than 1 %.
In an embodiment, the process of the present invention provides Lisdexamphetamine or pharmaceutically acceptable salt thereof containing nitrosamine impurities within the acceptable levels as provided by USFDA guidance of August 2023(See https://www.fda.gov/regulatory-information/search-fda-guidance-documents/updated-information-recommended-acceptable-intake-limits-nitrosamine-drug-substance-related) wherein the N-nitrosamine impurities include, but are not limited to, N-Nitroso Lisdexamfetamine, N-Nitrosodimethyl amine (“NDMA”), N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), N-Nitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N-phenylnitrosamine (“NMPA”).
In an embodiment, the present invention provides a solid form of the Lisdexamphetamine dimesylate characterized by PXRD, DSC and TGA disclosed in the present invention. The solid form of the Lisdexamphetamine dimesylate is characterized by an XRPD pattern as depicted in the Fig 1.
In an embodiment, the Lisdexamphetamine dimesylate obtained by the process of the present invention is characterized by particle size distribution of less than about 200µm. Preferably, Lisdexamphetamine dimesylate is having at least one of a d10 ranging from about 10 to about 25 µm; a d50 ranging from about 40 to about 80 µm; and a d90 particle size ranging from about 100 to about 200 µm.
In an embodiment, the present invention provides the oral solid pharmaceutical composition comprising Lisdexamphetamine dimesylate and one or more pharmaceutically acceptable excipients.
The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration. The pharmaceutical composition of the present invention may comprise also a solid dispersion, and any possible carrier.
The workability of the present invention has been exemplified below based on some non-limiting illustrations.
EXAMPLES
Example 1: Preparation of D-amphetamine
A mixture of (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone (91.2 gm, 1.0 mole eq.), 2% palladium-on-carbon type 890 (50% water wet) and denatured ethanol (274 ml) was stirred under a hydrogen gas for 30-45 minutes at 35 to 45 °C until no more oxazolidinone was detected by HPLC. The reaction mixture was then filtered to remove the catalyst and washed using ethanol (46 ml) and Distilled out ethanol from the reaction mixture and isopropyl acetate (274 ml) were added to prepare a solution containing D-amphetamine.

Example 2: Preparation of compound of Boc protected L-lysine (formula II)
To a solution of L-lysine monohydrochloride (100g, 1 mole eq.), potassium hydroxide (83 gm, 2.70 mole eq.) in water (800 ml) and t-BuOH (11.6 gm), Di-tert-butyl dicarbonate (322.6 gm, 2.70 mole eq.) was added. The reaction mixture was stirred for 60 minutes at temperature 25 to 35 °C. After completion of the reaction, the reaction mixture was cooled and PH was adjusted to 2.5- 4.0 with phosphoric acid and stirred for 30 min at temperature 30 to 40 °C. The reaction mass was then extracted with isopropyl acetate (720 ml) and combined organic layer was successively washed with water (500 ml) and brine (500 ml). Further, isopropyl acetate (1000 ml) was added to organic layer and distilled under vacuum at below 40 °C, up to 2.5 to 3.5 residual volume to obtain mixture containing Boc protected L-lysine of formula II.
Example 3: Preparation of Boc protected anhydride intermediate of formula IV
To a mixture obtained in Example 1, Diisopropylethylamine (84.90 gm, 1.20 mole eq.) was added at 10-20°C. The resulting solution was cooled to 8 to 10°C and pivaloyl chloride (64.7 gm, 0.98 mole eq.) was slowly added and stirred for 10 to 15 minutes at 5 to 25 °C. Then a solution of D-amphetamine (91.2 gm and 0.94 mole eq.) in isopropyl acetate (270 ml) was slowly added and the reaction mixture was stirred at 5 to 30°C for 30 to 40 minutes. Phosphoric acid solution was then added (9 gm in 400 ml water) and raised temperature 30 to 37 °C. The reaction mixture the stirred for 15 to 20 minutes. Organic layer was separated and added potassium carbonate solution (0.8 %w/w, in 800 ml water). Obtained wet cake was washed using mixture of ethanol (760 ml) water (1140 ml) (1:2) and filtered and dried on hot air oven to get pure Boc protected anhydride intermediate of formula IV with = 99% purity and 75% yield.
Example 4: Preparation of Lisdexamphetamine Dimesylate
Boc protected anhydride intermediate of formula IV was mixed with 3% w/w Isopropanol solution and heated to 55-65 °C until fully dissolved and transferred through an in-line filter to remove any particulate matter. The solution is heated to reflux and then portions of Methane sulfonic acid are added to the reactor at a controlled rate with stirring. IPC sampling and check is performed after at least 3 hours of stirring. Once the IPC specification is confirmed to have passed, the reaction is cooled at a controlled rate to 0-5 °C and then held for 1-2 hours. The Lisdexamphetamine dimesylate slurry is filtered and washed with cooled Isopropanol. The material wet cake is dried in a filter dryer with nitrogen purge at 60-70 °C for at least 8 hours before a sample of the solid dried product is checked for drying endpoint to obtain pure Lisdexamphetamine dimesylate with = 99% purity and 93 % yield.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:We Claim:
1. An improved process for the preparation of Lisdexamphetamine of formula I or its pharmaceutically acceptable salts which comprises steps of:

a) reacting the L-lysine monohydrochloride with the amine protecting group in the presence of a base and suitable solvent to give the diamino protected L-lysine compound of formula (II);

wherein PG is an amine protecting group;
b) reacting the diamino protected L-lysine compound of formula (II) with the acid activating compound of formula (III);

wherein R is selected from alkyl or aryl or substituted aryl groups and X is halogen selected from chlorin, bromine and Iodine in the presence of a base and suitable solvent to form the anhydride intermediate of formula (IV);

wherein PG is an amine protecting group;
c) optionally, isolating the anhydride intermediate of formula (IV);
d) reacting the anhydride intermediate of compound of formula (IV) with the D-amphetamine of compound of formula (V) to give the diamino protected amide compound of formula (VI);


wherein PG is same as defined above;
e) deprotecting the diamino protected amide compound of formula (VI) to give the Lisdexamphetamine or its pharmaceutically acceptable salt.
2. The process according to claim 1, wherein in step a) the base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium carbonate, sodium hydride, potassium hydride, lithium hydride and a combination thereof.
3. The process according to claim 1, wherein in the suitable solvent is selected from water, toluene, acetone, ethyl acetate, isopropyl acetate, chloroform, ethanol, acetonitrile, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol, methylene chloride, dimethylformamide, tetrahydrofuran, 1,4-dioxane, and a combination thereof.
4. The process according to claim 1, wherein in the amino protecting group is selected from Di-tert-Butyl Dicarbonate (BOC), benzyloxycarbonyl (CBz), allyloxycarbonyl (Alloc) fluorenyl methyloxycarbonyl (Fmoc), trimethylsilylethyloxycarbonyl (Teoc), pivaloyl, trifluoro acetyl.
5. A process for the preparation formula IV which comprises steps of:

a) reacting L-lysine monohydrochloride with amine protecting group in the presence of a base and suitable solvent to give diamino protected L-lysine compound of formula II;

b) reacting diamino protected L-lysine compound of formula II with acid activating compound of formula III

in presence of a base in a solvent to form an anhydride intermediate of formula IV;
c) isolating and purifying the anhydride intermediate of formula IV.
6. The process according to claim 5, wherein in step b) the base is selected from triethylamine (TEA), di-isopropyl ethyl amine (DIPEA), tri-n-propyl amine, tri-n-butyl amine, pyridine, lutidine and a combination thereof.
7. The process according to claim 5, where in the suitable solvent is selected from water, toluene, acetone, ethyl acetate, isopropyl acetate, chloroform, ethanol, acetonitrile, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol, methylene chloride, dimethylformamide, tetrahydrofuran, 1,4-dioxane, and a combination thereof.
8. An improved process for the preparation of Lisdexamphetamine of formula I or its pharmaceutically acceptable salts which comprises steps of:

a) reacting the L-lysine monohydrochloride with Di-tert-Butyl Dicarbonate (BOC) in the presence of a base and suitable solvent to give the BOC protected L-lysine compound of formula (II);

b) reacting the Boc protected L-lysine compound of formula (II) with pivaloyl chloride of formula (III)

in presence of a base and suitable solvent to form the anhydride intermediate of formula (IV);

c) optionally isolating the anhydride intermediate of formula (IV);
d) reacting the anhydride intermediate of formula IV with D-amphetamine to give Boc protected amide compound of formula (VI);

e) deprotecting BOC protected amide compound of formula (VI) to obtain Lisdexamphetamine or its pharmaceutically acceptable salt.
9. Compound of formula (IV);

wherein PG is an amine protecting group and R is selected from alkyl or aryl or substituted aryl groups
10. The compound of formula IV as claimed in claim 9, wherein PG is selected from Di-tert-Butyl Dicarbonate (BOC), benzyloxycarbonyl (CBz), allyloxycarbonyl (Alloc) fluorenyl methyloxycarbonyl (Fmoc), trimethylsilylethyloxycarbonyl (Teoc), pivaloyl, trifluoro acetyl and R is isopropyl or tert-butyl.

Date: 03st day of October, 2024

Mr. Thirupathi Bendram
VP & Head - IPR
Alkem Laboratories Limited