DESC:FIELD OF THE INVENTION
The present invention relates to a process for preparation of Lisdexamfetamine dimesylate.

BACKGROUND OF THE INVENTION
Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Lisdexamfetamine dimesylate is available as VYVANSE for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in the USA. It is chemically (2S)-2,6-diaminoN-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate. The chemical structure is shown below.

(Formula I)

EP1644019B2 patent discloses lisdexamfetamine mesylate.

Various processes for the preparation of lisdexamfetamine mesylate were disclosed in WO2013011526A1, WO2019108542A1, WO2017003721, WO2010042120A1 WO2010058206 WO2010148305 and WO2017098533A2.

SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of Lisdexamfetamine dimesylate of Formula I

comprising steps of
a) treating L-Lysine HCl of Formula II with a base and water,
(Formula II)
b) adding di-tert-butyl dicarbonate (Boc anhydride) and a suitable organic solvent,
c) isolating a solution of Bis Boc lysine of Formula III in a suitable organic solvent
(Formula III),
d) adding pivaloyl chloride and base,
e) providing a solution of (S)-1-phenylpropan-2-amine of Formula IV in a suitable organic solvent
(Formula IV),
f) adding the solution of step e) in the mixture of step d),
g) isolating Bis Boc Lisdexamfetamine of Formula V,
(Formula V), and
h) treating Bis Boc Lisdexamfetamine of Formula V with methane sulfonic acid in a suitable organic solvent to obtain Lisdexamfetamine dimesylate of Formula I,
i) optionally, crystallizing Lisdexamfetamine dimesylate of Formula I from a suitable solvent.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention relates to a process for preparation of Lisdexamfetamine dimesylate of Formula I

comprising steps of
a) treating L-Lysine HCl of Formula II with a base and water,
(Formula II)
b) adding di-tert-butyl dicarbonate (Boc anhydride) and a suitable organic solvent,
c) isolating a solution of Bis Boc lysine of Formula III in a suitable organic solvent
(Formula III),
d) adding pivaloyl chloride and base,
e) providing a solution of (S)-1-phenylpropan-2-amine of Formula IV in a suitable organic solvent
(Formula IV),
f) adding the solution of step e) in the mixture of step d),
g) isolating Bis Boc Lisdexamfetamine of Formula V,
(Formula V), and
h) treating Bis Boc Lisdexamfetamine of Formula V with methane sulfonic acid in a suitable organic solvent to obtain Lisdexamfetamine dimesylate of Formula I,
i) optionally, crystallizing Lisdexamfetamine dimesylate of Formula I from a suitable solvent.

The process for preparation of Lisdexamfetamine dimesylate of Formula I according to the present invention is presented in scheme 1.
Scheme 1

The base used in step a) is an inorganic base selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate, lithium hydroxide, ammonia, or ammonium hydroxide, or an organic base selected from triethyl amine, N N-Diisopropyl amine, isopropyl amine, diethyl amine, tert butyl amine, preferably inorganic base is sodium or potassium hydroxide, and preferably organic base is tert butyl amine or triethyl amine, more preferably base is potassium hydroxide or potassium carbonate.

The suitable organic solvent used in step b) is selected from a polar protic solvent for example tert-butyl alcohol, isobutyl alcohol, 1-butanol, 2- butanol, 2-butanone, methanol, ethanol, 1-propanol, or 2-propanol, or a polar aprotic solvent for example acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide or non-polar solvent for example toluene, diethyl ether, methyl t-butyl ether (MTBE), petroleum ether dichloromethane, chlorobenzene, chloroform, 1,2-dichloroethane, ethyl acetate, o-xylene, m-xylene, p-xylene, or a non-polar aprotic solvent for example 1,4 dioxane, tetrahydrofuran, more preferably isobutyl alcohol, tert-butyl alcohol or isopropyl alcohol. Furthermore, solvent can be mixture of water and tert-butyl alcohol. Instead of water - DMF, acetonitrile, can be used.

The suitable organic solvent used in step c) and e) is selected from acetone, acetonitrile, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, isobutyl acetate (IPAc), chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, heptane, hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyroolidionone (NMP), nitromethane, pentane, 1-propanol, 2-propanol, tetrahydrofuran (THF), toluene, o-xylene, m-xylene or p-xylene. The suitable organic solvent used in step c) and e) optionally contains 1% water. Preferably mixture of n-heptane and ethyl acetate can be used, more preferably ethyl acetate and isopropyl acetate with 1 % water can be used to achieve the higher yield.

The base used in step d) is an organic base selected from N,N-Diisopropylethylamine (NEDIPA), isoproyldiethylamine triethyl amine, methyl amine, ethyl amine, aniline, pyridine, imidazole, benzimidazole or dimethyl amino pyridine (DMAP).

The suitable organic solvent used in step h) selected from acetone, acetonitrile, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, isobutyl acetate (IPAc), chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, heptane, hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyroolidionone (NMP), nitromethane, pentane, 1-propanol, 2-propanol, tetrahydrofuran (THF), toluene, o-xylene, m-xylene or p-xylene. More preferred solvent is ethanol and isopropyl acetate.

The solution of (S)-1-phenylpropan-2-amine of Formula IV in a suitable organic solvent of step e) may be prepared by dissolving (S)-1-phenylpropan-2-amine of Formula IV in a suitable organic solvent. Alternatively, the said solution can be obtained during the preparation of (S)-1-phenylpropan-2-amine.

In another embodiment, the present invention provides a process for the preparation of (S)-1-phenylpropan-2-amine of Formula IV. The various route of synthesis of (S)-1-phenylpropan-2-amine of Formula IV are presented in scheme 2.
Scheme 2

The crystallization of Lisdexamfetamine dimesylate of Formula I can be carried out in a suitable solvent selected from methanol, ethanol, isopropanol or mixture thereof, or mixture with water.

In another embodiment, the present invention relates to Lisdexamfetamine dimesylate having purity of at least 95 %w/w, at least 97 %w/w, at least 98 %w/w, at least 99 %w/w, at least 99.7 %w/w, at least 99.8 %w/w or at least 99.9 %w/w.

In another embodiment, the present invention relates to pure Lisdexamfetamine dimesylate having less than 5 %w/w, less than 3 %w/w, less than 2 %w/w, less than 1 %w/w, less than 0.5 %w/w, less than 0.2 %w/w or less than 0.1 %w/w impurity.

In another embodiment, the present invention relates to pure Lisdexamfetamine dimesylate obtainable according to the process of the present invention.

In another embodiment, the present invention relates to pure Lisdexamfetamine dimesylate having less than 0.5 %w/w of impurity 1 having Formula VI or impurity 2 having Formula VII
(Impurity 1; Formula VI)
(Impurity 2; Formula VII)

The following examples illustrate specific embodiments; however, the full scope of the disclosure is not limited to the examples described below.
EXAMPLES
Example 1
Processes for the preparation of (S)-1-phenylpropan-2-amine of Formula IV
Route 1 and 2: Procedure for reduction (Hydrogenation using Pd/C)
(S)-2-(benzylamino)-1-phenylpropan-1-one (100 g) and methanol (300 mL) were charged to 5 Lit. autoclave. 2% Pd/C (50% wet) (3.0 g) was charged. Hydrogen gas 2.0 to 3.0 kg/cm2 was applied and reaction mixture was stirred to 180 min. The solvent was distilled out under vacuum below 45 °C keeping residual volume 1.5 to 3.0. Strip out by (2 x 200 ml) isopropyl acetate (IPAc) under vacuum below 45 °C keeping residual volume 1.5 to 3.0. Residue as such used for next stage without isolation (Yield 90% based on residue).

Route 3: Procedure for deprotection of tert-butyl ((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)carbamate (3):
tert-butyl ((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)carbamate (100g) and MDC (300 ml) were charged in RBF. 1N HCl solution (35 ml) was charged and stirred for 3-4 hrs. Reaction mixture was basified with 1 N NaOH solution. Aqueous layer was extracted with MDC 2-4 times. Combined MDC layer were dried over MgSO4. The solvent was distilled out under vacuum to give the product. Yield 90%.

Route 4: Procedure for deprotection of diphenyl (S)-(1-phenylpropan-2-yl)phosphoramidate
tert-butyl ((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)carbamate (100g) and MDC (300 ml) were charged in RBF. 1N HCl solution (35 ml) was charged for stirred for 3-4 hrs. Reaction mixture was basified with 1 N NaOH solution. Aqueous layer was extracted with MDC 2-4 times. Combined MDC layer were dried over MgSO4. The solvent was distilled out under vacuum to give the product. Yield 90%.

Route 5: Procedure for deprotection of (1R,2S)-2-(2,5-dimethylpyrrolidin-1-yl)-1-phenylpropan-1-ol
(1R,2S)-2-(2,5-dimethylpyrrolidin-1-yl)-1-phenylpropan-1-ol (100 gm) and methanol 100 ml: water 20 ml were charged in RBF. hydroxylamine hydrochloride (80 ml) and potassium hydroxide 40 ml (10 g in 40 ml). Reaction mixture was refluxed for 40-50 hrs. Reaction mixture was diluted with water, acidified with HCl solution, washed with MDC, basified with aqueous sodium hydroxide, and extracted with MDC. MDC layer dried over on MgSO4 and evaporated on rota, gives 85% yield.
Route 6: Procedure for deprotection of (S)-2-(hydroxyamino)-1-phenylpropan-1-one
THF 200 ml and (S)-2-(hydroxyamino)-1-phenylpropan-1-one (100 gm) were charged in RBF. Sodium borohydride (17g) lot wise and stirred reaction mass for 3-4 hrs. Reaction mixture was quenched by water. Aqueous layer extracted with ethyl acetate. Ethyl acetate layer was dried over on MgSO4 and solvent was evaporated on rota gives 80% yield.
Route 7:
1-phenyl 2-propan-one (100 g) charged in RBF containing formamide (45 g), stirred for couple of hrs at 25-30°C to offered phenylpropan-2-formamide formamide to amide reduction carried out in presence of conc. HCl (20 g) below 40oC after workup and carbon treatment to offered a phenylpropan-2-amine (80 g, racemic mixture), in-situ by resolution using (+) tartaric acid (27.1 g) to gives desired (S)-1-phenylpropan-2-amine residue after workup, filtration and distillation (40% yield). As such residue used for amide coupling reaction in subsequent stages.

Example 2
Preparation of Bis Boc Lisdexamfetamine (Formula V)
L-Lysine HCl (100 g) and water (800 ml) were charged, stirred and cool the reaction mass to 23-30 °C. Potassium hydroxide solution (83 g potassium hydroxide in 102 ml water) was charged into above reaction mass. Tert-butyl alcohol (111.6 g) was charge. Di-tert-butyl dicarbonate (Boc anhydride) (322.5g) was added slowly in 180-240 min and stir for 4 hrs. After completion of reaction, adjust the pH of reaction mass 2.5 to 4.0 using orthophosphoric acid (OPA) (110.5 g). IPAc (720 mL) was charged and stirred for 30 min. Organic layer was separated and washed with NaCl solution (25 g in 500 ml water). The solvent was distilled out under vacuum below 45 °C up to 2.0 to 2.2 residual volume wrt L-Lysine.HCl. Strip out with 2 x 200 ml IPAc under vacuum below 45 °C up to 2.0 to 2.2 residual volume wrt L-Lysine.HCl. IPAc (1000 ml) was charged and cooled to 0-5 °C. N,N-Diisopropylethylamine (NEDIPA) (84.90 g) was added at 0-5 °C followed by addition of pivaloyl chloride (64.68 g). The reaction mass was stirred for 30 min at 8-23 °C. The solution of (S)-1-phenylpropan-2-amine (Residue 1:1 equivent) was added in NMT 45 min at 8-30 °C and stirred for 30-35 min at 5-30 °C. Aqueous OPA (9 g in 400 ml water) was charged. The organic layer was separated and washed with 10 % K2CO3 solution for two times (2 x 40 g in 400 ml). Charcoal (2.0 g) was added into organic layer and stirred for 30 min at 25-32 °C, filtered and bed washed with IPAc (50 ml). The solvent was distilled out under vacuum below 70 °C by keeping residual volume 3.0 to 4.0. Ethanol was charge (2 x 200 ml) and distilled out IPAc+ Ethanol under vacuum by keeping residual volume 3.0 to 4.0. Ethanol + water mixture (600 ml ethanol in 960 ml water) was added in 20 to 60 min at 50-60 °C and slowly cooled to 28-35 °C and stirred for 60 min. The solid was filtered to obtain wet material. The wet solid and ethanol : water 1:1 mixture (2000 ml) were charged into RBF and heated to 50-57 °C and stirred for 60-70 min followed by slowly cooling to 28-35 °C. The solid was filtered and the material was dried under vacuum. Yield: 155 to 190 g.

Example 3
Preparation of Lisdexamfetamine dimesylate (Formula I)
Bis Boc Lisdexamfetamine (Formula V) (50 g) was added in IPA (100 ml) followed by slow addition of methanesulfonic acid (MSA) (117.5 g), 4.50 eq.) for 1h at ambient temperature under nitrogen. The resulting clear solution was then agitated for 20 h at ambient temperature. The solid was filtered and washed with IPA (100 ml).
Impurity 1 and 2: 0.27 % (limit NMT: 0.5%)

Example 4
Purification of Lisdexamfetamine dimesylate (Formula I)
Lisdexamfetamine dimesylate wet cake of example 3 (69.42 g) in IPA (147.82 g) and water (4.61 g) were stirred and heated to reflux. Additional IPA (32.58 g) was charged to dissolve all the solids. The solution was then cooled to below 5 °C. The solid was filtered and washed with IPA (28 g), dry the material at 65 °C for 10-15h to obtain 25.81 g (71.14% yield) of titled product.
,CLAIMS:1. A process for preparation of Lisdexamfetamine dimesylate of Formula I

comprising steps of
a) treating L-Lysine HCl of Formula II with a base and water,
(Formula II)
b) adding di-tert-butyl dicarbonate (Boc anhydride) and a suitable organic solvent,
c) isolating a solution of Bis Boc lysine of Formula III in a suitable organic solvent
(Formula III),
d) adding pivaloyl chloride and base,
e) providing a solution of (S)-1-phenylpropan-2-amine of Formula IV in a suitable organic solvent
(Formula IV),
f) adding the solution of step e) in the mixture of step d),
g) isolating Bis Boc Lisdexamfetamine of Formula V,
(Formula V), and
h) treating Bis Boc Lisdexamfetamine of Formula V with methane sulfonic acid in a suitable organic solvent to obtain Lisdexamfetamine dimesylate of Formula I,
i) optionally, crystallizing Lisdexamfetamine dimesylate of Formula I from a suitable solvent.
2. The process as claimed in claim 1 wherein the base used in step a) is an inorganic base selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate, lithium hydroxide, ammonia, or ammonium hydroxide, or an organic base selected from triethyl amine, N N-Diisopropyl amine, isopropyl amine, diethyl amine, tert butyl amine, preferably inorganic base is sodium or potassium hydroxide, and preferably organic base is tert butyl amine or triethyl amine, more preferably base is potassium hydroxide or potassium carbonate.
3. The process as claimed in claim 1 wherein the suitable organic solvent used in step b) is selected from a polar protic solvent for example tert-butyl alcohol, isobutyl alcohol, 1-butanol, 2- butanol, 2-butanone, methanol, ethanol, 1-propanol, or 2-propanol, or a polar aprotic solvent for example acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide or non-polar solvent for example toluene, diethyl ether, methyl t-butyl ether (MTBE), petroleum ether dichloromethane, chlorobenzene, chloroform, 1,2-dichloroethane, ethyl acetate, o-xylene, m-xylene, p-xylene, or a non-polar aprotic solvent for example 1,4 dioxane, tetrahydrofuran, more preferably isobutyl alcohol, tert-butyl alcohol or isopropyl alcohol.
4. The process as claimed in claim 1 wherein the suitable organic solvent used in step c) and e) is selected from acetone, acetonitrile, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, isobutyl acetate (IPAc), chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, heptane, hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyroolidionone (NMP), nitromethane, pentane, 1-propanol, 2-propanol, tetrahydrofuran (THF), toluene, o-xylene, m-xylene or p-xylene.
5. The process as claimed in claim 4 wherein the organic solvent optionally contains 1% water.
6. The process as claimed in claim 1 wherein the base used in step d) is an organic base selected from N,N-Diisopropylethylamine (NEDIPA), isoproyldiethylamine triethyl amine, methyl amine, ethyl amine, aniline, pyridine, imidazole, benzimidazole or dimethyl amino pyridine (DMAP).
7. The process as claimed in claim 1 wherein the suitable organic solvent used in step h) selected from acetone, acetonitrile, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, isobutyl acetate (IPAc), chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, heptane, hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyroolidionone (NMP), nitromethane, pentane, 1-propanol, 2-propanol, tetrahydrofuran (THF), toluene, o-xylene, m-xylene or p-xylene.
8. The process as claimed in claim 1 wherein the Lisdexamfetamine dimesylate of Formula I contain less than 5 %w/w impurity.
9. The process as claimed in claim 1 wherein the Lisdexamfetamine dimesylate of Formula I contain less than 0.5 %w/w of impurity 1 having Formula VI or impurity 2 having Formula VII
(Impurity 1; Formula VI)
(Impurity 2; Formula VII)
10. The process as claimed in claim 1 wherein the Lisdexamfetamine dimesylate of Formula I has purity of at least 95 %w/w.