Description:
FIELD OF INVENTION
The present invention relates to the field of pharmaceuticals. More specifically the invention relates to a process for preparation of Lisdexamphetamine dimesylate [Formula I], a compound adopted for the treatment of disorders relating to the central nervous system. In particular, the present invention provides a process for preparation of Lisdexamphetamine dimesylate by reacting D- amphetamine and 2, 6-bis-tertiarybutoxycarbonylamino hexanoic acid in presence of Carbonyldiimidazole to obtain Tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate (Formula II); and obtaining dimesylate salt of Tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate (Formula II) by treating with Methane sulfonic acid in high yield and purity.
BACKGROUND OF INVENTION
Central nervous system stimulants in general work by increasing activity of neuro-transmitters in the brain, particularly dopamine and norepinephrine. These are used for various purposes including to enhance mood and cognition. Caffeine and Nicotine are commonly consumed stimulants. However certain medical conditions relating to central nervous system call for prescriptions of drugs like Amphetamines, Methylphenidate, Modafinil.
Amphetamines are stimulants that can help people with a wide array of conditions more specifically in the treatment of attention deficit hyperactivity disorder (ADHD) and obesity. Amphetamines are commonly prescribed as racemic mixtures-a combination of dextroamphetamine and levoamphetamine or as dextroamphetamine itself or as Lisdexamphetamine which needs to be metabolized by the body to become active.
Lisdexamphetamine dimesylate, is a long-acting stimulant in which the drug is released biochemically into the blood rather than mechanically in the gastrointestinal tract. Lisdexamphetamine dimesylate, chemically named (2S)-2,6-amino-N-[(1S)-1-methyl-2-phenylethyl]hexanoic acid amine dimesylate, the structure Lisdexamphetamine dimesylate [Formula I] is shown below.

FORMULA I
Lisdexamphetamine dimesylate, is used for managing ADHD in patients aged 6years and above. On oral ingestion, Lisdexamphetamine dimesylate is slowly absorbed and metabolized in the body leading to gradual release of dexamphetamine, the central nervous system stimulant, by enzymatic hydrolysis of lysine, a naturally occurring essential amino acid and D-amphetamine, chemically named (2S)-1-phenylpropan-2-amine, the active drug producing, specific pharmacologic effects and is a long acting D-amphetamine thereby beneficial to patients with ADHD.
Prior arts disclose several ways of preparation of Lisdexamphetamine dimesylate. However, the methods are cumbersome, time consuming, employ usage of expensive apparatus and reagents, and generate impurities. Also, obtaining said compound of high purity, above 99% has been a challenge.
WO2010148305 provides a process for preparation of Lisdexamphetamine by removal of chlorine from N,N-bis-trifluroacetylchlorolisdexamphetamine by hydrogenation in presence of catalyst like Pd/C (Palladium/ Carbon). The said invention involves additional steps of inserting chloro- group to further reaction and removing the chloro- group towards the end of the reaction, making the process tedious and time consuming. The invention also makes use of Palladium / Carbon which are expensive reagents. The said invention provides for 95 % yield and purity in the end product.
US7659253 includes preparation Boc-Lys-(Boc)-hydroxysuccinimide ester wherein reagents, for example N-hydroxy-succinamide and dicyclohexylcarbodimide are used. The end product is purified using a column chromatography. The process involves the usage of column chromatography, making the process cumbersome, tedious and time consuming.
US20110196173 discloses a process for the synthesis of Amphetamine Derivatives, that is preparing acylated amphetamine, methamphetamine and dexamphetamine derivatives by reacting the parent amine with the to be-coupled acid or a salt of the to-be coupled acid which acid is optionally protected, in the presence of an alkylphosphonic acid anhydride as coupling agent. The use of acid anhydrides renders the process expensive.
Indian patent application 2040/DEL/2011 discusses process for preparation of Lisdexamphetamine and salts thereof by using mixed anhydride intermediate. It also provides a process for preparation of BOC protected Lisdexamphetamine, a key intermediate in the preparation of Lisdexamphetamine and its pharmaceutically acceptable salts by using mixed anhydride intermediate and its purification by crystallization. The presence of anhydrides hinder purity of the final product.
Hence, there is a need for an efficient process for the preparation of Lisdexamphetamine and its pharmaceutically acceptable salt in high purity and high yield using easily available less expensive reagents, and generate less toxic impurities. The present invention aims to address the need.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a facile process for preparation of Lisdexamphetamine dimesylate.
Another object of the invention is to provide for pure form of Lisdexamphetamine dimesylate with a purity level above 99%.
BRIEF DESCRIPTION OF FIGURE
The features of the present invention can be understood in detail with the aid of
appended figures. It is to be noted however, that the appended figures illustrate only
typical embodiments of this invention and are therefore not to be considered limiting
of its scope for the invention.
FIGURE 1: provides the HPLC of Lisdexamphetamine dimesylate indicating purity level of more than 99%
SUMMARY OF INVENTION
The present invention provides an economical facile process or preparation of Lisdexamphetamine dimesylate.
The present invention relates to a process for preparation of Lisdexamphetamine dimesylate [ Formula I], said process comprising acts of-

Formula I
a) Preparing tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate (Formula II) comprising acts of-
i. reacting 2, 6-bis-tertiarybutoxycarbonylamino hexanoic acid with Diisopropylethylamine, Carbonyldiimidazole in an organic non-aqueous solvent at a temperature ranging from 25℃-30℃ for an hour to obtain a reaction mixture,
ii. adding a solution of (2S)-1-phenylpropan-2-amine in an organic non-aqueous solvent to the reaction mixture, and
iii. quenching the reaction mixture into water, separating the organic non-aqueous solvent layer and concentrating the organic non-aqueous solvent layer to obtain tert-butyl (1S-5-[(tertbutoxycarbonyl)amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl) pentylcarbamate [Formula II];

Formula II
b) dissolving the tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate [Formula II] in an aqueous solvent, treating the solution with charcoal and filtering,
c) treating the filtered solution with Methane sulphonic acid to obtain a white slurry, and
d) separating the slurry and treating with organic aqueous solvent to beget Lisdexamphetamine dimesylate, purified by recrystallization.

DETAILED DESCRIPTION OF INVENTION

The foregoing description of the embodiments of the invention has been presented for the purpose of illustration. It is not intended to be exhaustive or to limit the invention to the precise form disclosed as many modifications and variations are possible in light of this disclosure for a person skilled in the art in view of the figures, description and claims. It may further be noted that as used herein and in the appended claims, the singular “a” “an” and “the” include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by person skilled in the art.
The present invention relates to a preparation of Lisdexamphetamine dimesylate of formula I.

[Formula I]
The process of preparation of Lisdexamphetamine dimesylate involves condensation of 2,6-bis-tertiarybutoxycarbonylamino hexanoic acid with (S)-1-Phenylpropan-2-amine with Carbonyldiimidazole [CDI] to get tert-buty(1S-5-[(tertbutoxycarbonyl)amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl) pentylcarbamate with good purity. Said compound is reacted with Methane sulphonic acid to obtain Lisdexamphetamine dimesylate in good yield 90 to 95%and high purity.
The process of preparation of present invention involves mainly involves two steps
(Scheme A)-
i) Preparation of tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate [Formula II];

Formula II
ii) Preparation of Lisdexamphetamine dimesylate [Formula I] from tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino} carbonyl) pentylcarbamate [Formula II] by treating with Methane sulphonic acid, in a pure crystalized form.

SCHEME A
The Scheme B given below depicts the first step of the process of preparation of Lisdexamphetamine dimesylate

Scheme B

In an embodiment of present invention, the first step relating to a process for preparation of tert-butyl(1S-5-[(tertbutoxycarbonyl)amino-1-({[(1S)-1-methyl-2-phenylethyl] amino} carbonyl)pentylcarbamate [Formula II] comprises acts of -
a) condensing 2, 6-bis-tertiarvbutoxycarbonylamino hexanoic acid with Diisopropylethylamine, with coupling reagent Carbonyldiimidazole in an organic non-aqueous solvent at a temperature ranging from 25-30℃ for an hour to obtain a reaction mixture,
b) adding a solution of (2S)-1-phenylpropan-2-amine in an organic non-aqueous solvent to the reaction mixture and maintaining at 25-30℃; and
c) quenching the reaction mixture into water, separating the organic non-aqueous solvent layer and concentrating the organic non-aqueous solvent layer to obtain tert-butyl (1S-5-[(tertbutoxycarbonyl)amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl) pentylcarbamate [Formula II]

FORMULA II

The second step comprises acts of -
a) dissolving the crystalized tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate in an aqueous solvent, treating with charcoal and filtering to obtain clear solution,
b) the clear solution is treated with Methane sulphonic acid to obtain a white slurry,
c) the slurry is separated and treated with aqueous solvent to beget Lidexamphetamine dimesylate, purified by recrystallization.

In an embodiment of the invention, the organic non- aqueous solvent is Toluene and organic aqueous solvent is methyl ethyl ketone.
In an embodiment of present invention, the solvent mixture for recrystallization is alcohol and ester, more specifically the mixture is Ethanol and Ethyl acetate in ratio 1v/v:15 v/v.

In a typical embodiment of present invention, the first step relating to a process for preparation of tert-butyl (1S-5-[(tertbutoxycarbonyl)amino-1-({[(1S)-1-methyl-2-phenylethyl]amino} carbonyl)pentylcarbamate [Formula II] comprises acts of -
a) reacting 2, 6-bis-tertiarvbutoxycarbonylamino hexanoic acid with Diisopropylethylamine, with coupling reagent Carbonyldiimidazole in Toluene at a temperature ranging from 25-30℃ for an hour to obtain a reaction mixture;
b) adding a solution of (2S)-1-phenylpropan-2-amine in Toluene to the reaction mixture of 2, 6-bis-terbutoxycarbonylamino hexanoic acid, Diisopropylethylamine and coupling reagent Carbonyldiimidazole in Toluene and maintaining said reaction mixture at 25-30℃ for 20-40hr; and
c) quenching the reaction mixture into water, separating the Toluene layer and concentrating the Toluene layer to obtain tert-butyl (1S-5-[(tertbutoxycarbonyl)amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate [Formula II]

The second step comprises acts of -
a) dissolving the crystalized tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate in Methyl ethyl ketone at 40-45℃, charcolized and filtered at 40-45℃, and filtered to obtain clear solution,
b) the clear solution is treated with methane sulphonic acid for two hours to obtain a white slurry,
c) the slurry is separated and treated with Isopropylalcohol at 60-65℃ for one hour to beget Lidexamphetamine dimesylate, purified by recrystallization with a solvent mixture to obtain Lisdexamphetmine dimesylate.

In yet another embodiment of the invention the purity of Lisdexamphetamine dimesylate is about 99.90% when measured by HPLC method.
Experimental
The examples described below illustrates the process of preparation of Lisdexamphetamine dimesylate, however they do not limit the scope of the invention.
All the reagents are obtained from commercial sources and used without any further purification.

Example 1.
Step 1 -Preparation of tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate
About 600ml of Toluene is taken in a 2L three -neck flask equipped with mechanical stirrer, followed by about 160g (0.46 mole) of 2, 6-bis-tertiarvbutoxycarbonylamino hexanoic acid: and 196g (1.51 mole) of DIPEA (Diisopropylethylamine) is further added under nitrogen atmosphere. The temperature is maintained between 25°C- 30 °C. Further 137 g (0.84 mole) of coupling reagent Carbonyldiimidazole is added for over a period of 1 hr at 25-30°C, The reaction mass obtained is further maintained for 1hr at a temperature ranging from about 25°C-30°C. A solution of about 100g (0.74 mole) (2S)-1-phenylpropan-2-amine in 120ml Toluene is prepared separately and is added into reaction mass for over a period of 30mins to 1 hr at 25°C- 30 °C. The reaction mass is again maintained at 25°C-30°C for about 20hrs to 40 hrs. Progress of reaction is monitored using TLC. As per reading on TLC, after completion of the reaction, reaction mass is rapidly cooled with 200ml Demineralised water. On quenching, the Toluene layer gets separated, which is then washed with dil HCl solution The layer is then dried over sodium sulphate and concentrated over vacuum yielding a residue, which is then crystallized using ter-butyl methyl ether to get about 140g titled compound with a purity of 98.90% as measured on HPLC.

Step 2: Preparation of Lisdexamphetaminedimesylate
140 gm of pure tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate is dissolved in 500ml of Methyl ethyl ketone. The temperature is maintained at a range of about 40°C to about 45°C to yield a clear solution The clear solution is then passed through a charcoal filter. The filtered solution is then transferred into a clean flask. 100.8g (0.74 mole) Methane sulphonic acid is then added dropwise into the flask and the solution is stirred. As this is an exothermic reaction, the reaction mixture is stirred for about 2 hr at room temperature (25℃-30℃) during which time the solution in the flask turns into a thick white slurry. The white solids formed are then collected by suction filtration method. The solid thus obtained is then treated with 500ml of Isopropyl alcohol at a temperature ranging between 60°C-65°C and maintained at the same temperature for about an hour. The solids-Isopropyl alcohol solution are then allowed to cool down for about an hour and then suction filtered to obtain 175g of crude Lisdexamphetamine dimesylate, thus obtained crude form is purified using a combination of solvents - alcohol and ketone or alcohol and ester to procure about 150g of pure Lisdexamphetamine dimesylate with a purity of about 99.88% as when measured using HPLC.

The present invention thus addresses the need with ease of preparation, the process being continuous for bulk production, following constant parameters vis a vis temperature and flow of supplies yielding consistent quality and purity in the yield.

The aforesaid description is enabled to capture the nature of the invention. It is to be noted however that the aforesaid description and the appended figure illustrate only a typical embodiment of the invention and therefore not to be considered limiting of its scope for the invention may admit other equally effective embodiments. It is an object of the appended claims to cover all such variations and modifications as can come within the true spirit and scope of the invention
, Claims:WE CLAIM
1. A process for preparation of Lisdexamphetamine dimesylate of formula I, said process comprising acts of-

Formula I
a) Preparing tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate of Formula II comprising acts of-
i. reacting 2, 6-bis-tertiarybutoxycarbonylamino hexanoic acid with Diisopropylethylamine, Carbonyldiimidazole in an organic non-aqueous solvent at a temperature ranging from 25℃-30℃ for an hour to obtain a reaction mixture,
ii. adding a solution of (2S)-1-phenylpropan-2-amine in an organic non-aqueous solvent to the reaction mixture, and
iii. quenching the reaction mixture into water, separating the organic non-aqueous solvent layer and concentrating the organic non-aqueous solvent layer to obtain tert-butyl (1S-5-[(tertbutoxycarbonyl)amino-1-({[(1S)-1-methyl-2-phenylethyl] amino} carbonyl) pentylcarbamate of Formula II;

Formula II
b) dissolving the tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino}carbonyl)pentylcarbamate of Formula II in an aqueous solvent, treating the solution with charcoal and filtering,
c) treating the filtered solution with Methane sulphonic acid to obtain a white slurry, and
d) separating the slurry and treating with organic aqueous solvent to beget Lisdexamphetamine dimesylate, purified by recrystallization.
2. The process as claimed in Claim1, wherein the organic non- aqueous solvent is Toluene and organic aqueous solvent is selected from methyl ethyl ketone, isopropyl alcohol.
3. The process as claimed in Claim 1, wherein the solvent mixture for recrystallization is Ethanol- Ethyl acetate in ratio 1v/v :15 v/v.
4. The process as claimed in claim 1, wherein the solution of tert-butyl (1S-5-[(tertbutoxycarbonyl) amino-1-({[(1S)-1-methyl-2-phenylethyl]amino} carbonyl)pentylcarbamate of Formula II is treated with charcoal at a temperature ranging from 40°C to 45 °C.
5. The process as claimed in Claim 1, wherein the slurry is treated with organic nonaqueous solvent- Isopropyl alcohol at a temperature ranging from 60°C to 65°C.
6. The process as claimed in Claim 1, wherein the Lisdexamphetamine dimesylate of Formula I is of purity 99.88%.
7. The process as claimed in claim 1, wherein the Lisdexamphetamine dimesylate is 90 to 95% yield.