Method for the preparation of lisdexamfetamine

Abstract

The present disclosure provides a method for producing di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate, a key intermediate in the synthesis of lisdexamfetamine. The present disclosure also provides a method for producing lisdexamfetamine dismesylate using di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate obtainable by the method of the present disclosure. The present disclosure also provides methods for producing other intermediates useful for the synthesis of lisdexamfetamine and lisdexamfetamine dismesylate, namely (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride, (S)-1-phenylpropan-2-amine hydrochloride, crystalline (S)-1-phenylpropan-2-amine hydrochloride and crystalline (S)-1- phenylpropan-2-amine sulfate.

Description

[0001] METHOD FOR THE PREPARATION OF LISDEXAMFETAMINE FIELD OF THE INVENTION The present disclosure provides a method for producing di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate, a key intermediate in the synthesis of lisdexamfetamine. The present disclosure also provides a method for producing lisdexamfetamine dismesylate using di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate obtainable by the method of the present disclosure. The present disclosure also provides methods for producing other intermediates useful for the synthesis of lisdexamfetamine and lisdexamfetamine dismesylate, namely (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride, (S)-1- phenylpropan-2-amine hydrochloride, crystalline (S)-1-phenylpropan-2-amine hydrochloride and crystalline (S)-1-phenylpropan-2-amine sulfate. BACKGROUND OF THE INVENTION Lisdexamfetamine ((S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide) is represented by chemical formula (IVA) presented below. Lisdexamfetamine is used in the treatment of attention deficit hyperactivity disorder and binge eating disorder. Pharmacologically, lisdexamfetamine is provided as the dimesylate salt, i.e. as lisdexamfetamine dimesylate ((S)-2,6-diamino-N-((S)-1- phenylpropan-2-yl)hexanamide dimethanesulfonate), represented by the chemical formula (IV) presented below. A convenient intermediate in the synthesis of lisdexamfetamine dimesylate (S)-2,6- diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) is di-Boc- lisdexamfetamine (di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate), represented by the chemical formula (III) presented below. Methods for producing lisdexamfetamine dimesylate ((S)-2,6-diamino-N-((S)-1- phenylpropan-2-yl)hexanamide dimethanesulfonate (IV)) via di-Boc-lisdexamfetamine (di- tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) are known in the art, for instance in WO 2019 / 108542, CN 108264537, WO 2017 / 098533, WO 2017 / 003721, WO 2013 / 011526, and US 8,487,134. However, the prior art methods are disadvantageous in that they require salt liberation processes, starting material activation processes, involve difficult-to-handle starting materials, require multiple purification steps in order to achieve the required levels of purity (i.e., both for di- Boc-lisdexamfetamine intermediate and the lisdexamfetamine dimesylate product), and / or provide unacceptable overall yields. Improved methods for producing both di-Boc-lisdexamfetamine (di-tert-butyl ((S)- 6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) and lisdexamfetamine dimesylate ((S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV)) are therefore required. It is desired to provide methods for producing both di-Boc-lisdexamfetamine (di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan- 2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) and lisdexamfetamine dimesylate ((S)-2,6- diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV)) in high yields and purities in a process-efficient manner. SUMMARY OF THE INVENTION The present disclosure provides a method for producing di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III),

[0002] the method comprising a coupling step of coupling a salt of (S)-1-phenylpropan-2- amine (II) with a salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) to provide di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III). In one embodiment, the coupling step is carried out in an organic solvent and the coupling step provides a coupling step reaction mixture comprising di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, after the coupling step, the method further comprises a contacting step of contacting the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) with one or more aqueous liquids to provide a purified organic solution of di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the method is for producing solid di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), and, after the coupling step (and optional contacting step), the method further comprises a precipitating step of precipitating the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III). The present disclosure also provides a method for producing (S)-2,6-diamino-N- ((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV), the method comprising a deprotection and salt formation step of treating di-tert-butyl ((S)- 6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to: (i) the above method providing a purified organic solution of di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), or (ii) the above method producing solid di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), with methanesulfonic acid to provide lisdexamfetamine dimesylate. The present disclosure also provides methods for producing useful intermediates in the synthesis of di-Boc-lisdexamfetamine (di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan- 2-yl)amino)hexane-1,5-diyl)dicarbamate (III)). Thus, the present disclosure provides a method for producing (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I), the method comprising a reacting step of reacting, in a solvent for the chlorination, (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or a salt thereof with an electrophilic chlorinating agent to provide (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), wherein the solvent for the chlorination is selected from dichloromethane, 1,2- dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, tetrachloroethylene, and mixtures thereof. In one embodiment, the method for producing (2S)-1-chloro-1-phenylpropan-2- amine hydrochloride (I) is a method for producing crystalline (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I), wherein, after the reacting step, the method further comprises a crystallising step of crystallising the (2S)-1-chloro-1-phenylpropan-2- amine hydrochloride (I). The present disclosure also provides a method for producing (S)-1-phenylpropan-2- amine hydrochloride (IIA), the method comprising a hydrogenation reaction step of hydrogenating crystalline (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride (I) obtainable by the method for producing crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) in the presence of a hydrogenation catalyst to provide (S)-1-phenylpropan-2-amine hydrochloride (IIA). In one embodiment, the method for producing (S)-1-phenylpropan-2-amine hydrochloride (IIA) further comprises a basification step of treating the (S)-1- phenylpropan-2-amine hydrochloride (IIA) with base to provide (S)-1-phenylpropan-2- amine freebase (II). The present disclosure also provides a method for producing crystalline (S)-1- phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB), the method comprising: (a) an acidification step of treating, in a solvent for the acidification, (S)-1- phenylpropan-2-amine freebase (II) with hydrochloric acid or sulfuric acid to provide a solution of (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB); and (b) a crystallising step of crystallising the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB). DETAILED DESCRIPTION OF THE INVENTION Method for producing di-Boc-lisdexamfetamine (di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) – Phase III As described above, the present disclosure provides a method for producing di-tert- butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), the method comprising a coupling step of coupling a salt of (S)-1-phenylpropan-2- amine (II) with a salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) to provide di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III). The use of both a salt of (S)-1-phenylpropan-2-amine (II) and a salt of N2,N6- bis(tert-butoxycarbonyl)-L-lysine (II) enables more precise charging and easier handling of the reagents. In one embodiment, in order to maximise these benefits, the salt of (S)-1- phenylpropan-2-amine (II) is a solid salt of (S)-1-phenylpropan-2-amine (II) and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (II) is a solid salt of N2,N6-bis(tert- butoxycarbonyl)-L-lysine (II). The salt of (S)-1-phenylpropan-2-amine (II) may be a salt obtainable by the protonation of (S)-1-phenylpropan-2-amine by any acid that would not interfere with the coupling step above (i.e. not a carboxylic acid). In one embodiment, the acid is a strong acid such as HCl, H2SO4, HBr, HI, H3PO4, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid. In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is (S)-1-phenylpropan-2-amine hydrochloride (IIA), (S)-1-phenylpropan-2-amine sulfate (IIB), or (S)-1-phenylpropan-2-amine hydrobromide (IIC). In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is (S)-1- phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is (S)-1-phenylpropan-2- amine hydrochloride (IIA). In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is a crystalline salt. In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is crystalline (S)-1- phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA). In one embodiment, the crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB) are obtainable by a method for producing crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB) described in the section below entitled “method for producing dexamfetamine ((S)-1-phenylpropan-2-amine (II)), crystalline dexamfetamine hydrochloride ((S)-1-phenylpropan-2-amine hydrochloride (IIA)) and crystalline dexamfetamine sulfate ((S)-1-phenylpropan-2-amine sulfate (IIB))”. In one embodiment, the method for producing di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) further comprises a providing step of providing the crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, the providing step comprises a method for producing crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB) described in the section below entitled “method for producing dexamfetamine ((S)-1-phenylpropan-2- amine (II)), crystalline dexamfetamine hydrochloride ((S)-1-phenylpropan-2-amine hydrochloride (IIA)) and crystalline dexamfetamine sulfate ((S)-1-phenylpropan-2-amine sulfate (IIB))”. The salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) may be (i) a salt obtainable by the deprotonation of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) by any base that would not interfere with the coupling step above (i.e. not a primary amine base) or (ii) a salt obtainable by the deprotonation of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) by any base followed by a cation counterion swap to have a cation that is incapable of being deprotonated to provide a base that interferes with the coupling step above. In one embodiment, for the above (i), the base is a sterically congested secondary amine such as dicyclohexyl amine, N,N-diisopropylethylamine, 1,8-diazabicycloundec-7-ene, 1,5- diazabicyclo(4.3.0)non-5-ene, and 2,6-di-tert-butylpyridine. In one embodiment, for the above (ii), the cation that is incapable of being deprotonated to provide a base that interferes with the coupling step above is a tetramethylammonium cation. In one embodiment, the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is a salt according to formulae (IIIA’) or (IIIB’), (IIIA’) wherein: R1and R2are the same or different and are selected from an optionally substituted C5-C12cycloalkyl group or an optionally substituted branched C3-C10 alkyl group, and R3is selected from H or an optionally substituted C1-C6alkyl group; (IIIB’) wherein: R4to R7are the same or different and are selected from an optionally substituted C1-C12 alkyl group or an optionally substituted C5-C12 cycloalkyl group. In one embodiment, the optionally substituted C5-C12 cycloalkyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen (for example, fluoro or chloro) or C1-3 alkyl. In one embodiment, the C5-C12 cycloalkyl group is unsubstituted. In one embodiment, the C5-C12cycloalkyl group is a cyclohexyl, cyclopentyl, or cycloheptyl group. In one embodiment, the C5-C12 cycloalkyl group is a cyclohexyl group. In one embodiment, the optionally substituted branched C3-C10alkyl group is branched at the carbon adjacent to the nitrogen. Additionally or separately, the optionally substituted branched C3-C10alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen (for example, fluoro or chloro). In one embodiment, the branched C3-C10alkyl group is unsubstituted. In one embodiment, the branched C3-C10alkyl group is an iso-propyl group or a sec-butyl group. In one embodiment, the branched C3-C10alkyl group is an isopropyl group. In one embodiment, the optionally substituted C1-C6 alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen (for example, fluoro or chloro). In one embodiment, the C1-C6 alkyl group is unsubstituted. In one embodiment, the C1-C6alkyl group is ethyl, methyl or n-propyl group. In one embodiment, the C1-C6alkyl group is ethyl. In one embodiment, the optionally substituted C1-C12 alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen (for example, fluoro or chloro). In one embodiment, the C1-C12 alkyl group is unsubstituted. In one embodiment, the C1-C12alkyl group is methyl, ethyl or n-propyl. In one embodiment, the C1-C12alkyl group is methyl. In one embodiment, the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is a salt according to formulae (IIIA’) or (IIIB’), (IIIA’) wherein: R1and R2are the same or different and are selected from a cyclohexyl, cyclopentyl, or cycloheptyl group or an iso-propyl group or a sec-butyl group, and R3is selected from H or a ethyl, methyl or n-propyl group; (IIIB’) wherein: R4to R7are the same or different and are selected from a methyl, ethyl or n-propyl group or a cyclohexyl, cyclopentyl, or cycloheptyl group. In one embodiment, the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is a salt according to formulae (IIIA’), (IIIA’) wherein: R1and R2are the same or different and are selected from cyclohexyl, cyclopentyl, or cycloheptyl group or an iso-propyl group or a sec-butyl group, and R3is selected from H or ethyl, methyl or n-propyl. In one embodiment, the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is N2,N6-bis(tert-butoxycarbonyl)-L-lysine dicyclohexylamine (IIIA) (IIIA). In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is (S)-1- (S)-1-phenylpropan-2-amine sulfate (IIB), or (S)-1-phenylpropan-2-amine hydrobromide (IIC) (IIC); and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is a salt according to (IIIA’) wherein: R1and R2are the same or different and are selected from an optionally substituted C5-C12cycloalkyl group or an optionally substituted branched C3-C10 alkyl group, and R3is selected from H or an optionally substituted C1-C6 alkyl group; (IIIB’) wherein: R4to R7are the same or different and are selected from an optionally substituted C1-C12 alkyl group or an optionally substituted C5-C12cycloalkyl group. This embodiment eliminates reaction steps needed for salt liberation. In one embodiment, the salt of (S)-1-phenylpropan-2-amine (II) is (S)-1- phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB) and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is N2,N6-bis(tert- butoxycarbonyl)-L-lysine dicyclohexylamine (IIIA). In one embodiment, the salt of (S)-1- phenylpropan-2-amine (II) is (S)-1-phenylpropan-2-amine hydrochloride (IIA) and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is N2,N6-bis(tert-butoxycarbonyl)-L-lysine dicyclohexylamine (IIIA). In one embodiment, in the contacting step, the salt of (S)-1-phenylpropan-2-amine (II) and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) are present in a molar ratio of from 1:2 to 2:1, for example, from 1:1.5 to 1.5:1. In one embodiment, in the coupling step, the coupling comprises treating the salt of (S)-1-phenylpropan-2-amine (II) and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) with a coupling agent. In one embodiment, the coupling comprises treating the salt of (S)-1-phenylpropan-2-amine (II) and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) with a coupling agent and a base. In one embodiment, the coupling agent is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, ethyl-(N’,N’-dimethylamino)propylcarbodiimide hydrochloride and 1-propanephosphonic acid cyclic anhydride. In one embodiment, the coupling agent is 1-propanephosphonic acid cyclic anhydride. In one embodiment, the coupling agent is used in an amount of 1 to 4 mol per mol of the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’), for example, 1 to 3 mol per mol of the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’). The base may be selected from any non-nucleophilic base. For example, the base may be selected from 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6- di-tert-butylpyridine, and N,N-diisopropylethylamine. In one embodiment, the base is N,N- diisopropylethylamine. In one embodiment, the base is used in amount of from 1 to 15 mol per mol of the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’), for example, 2 to 10 mol per mol of the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’). In one embodiment, the coupling step is carried out in a solvent. In one embodiment, the solvent is an organic solvent, for instance, a solvent selected from dichloromethane, ethyl acetate, acetonitrile, chlorobenzene, chloroform, dichloroethane, dichlorobenzene (1,2-, 1,3- and 1,4-), diethyl ether 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, toluene and mixtures thereof. In one embodiment, the solvent is dichloromethane. In one embodiment, the solvent is present in an amount of from 2 to 20 ml per gram of the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’), for example, from 5 to 10 ml per gram of the salt. In one embodiment, the coupling step takes place at a temperature of from 0 to 50 ˚C, for example, from 5 to 30 ˚C. In one embodiment, the coupling step has a reaction time of from 10 min to 24 h, for example, from 30 min to 8 h In one embodiment, the coupling step provides a coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III). In one embodiment, after the coupling step, the method further comprises a contacting step of contacting the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) with one or more aqueous liquids to provide a purified organic solution of di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, after each contacting of the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III) with an aqueous liquid, the aqueous layer is removed and the organic layer is retained (optionally for further contacting). In one embodiment, the aqueous liquids are selected from an aqueous acid solution, an aqueous base solution, and water. In one embodiment, the contacting step comprises contacting the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) with an aqueous acid solution at least once and an aqueous base at least once. In one embodiment, the contacting step comprises contacting the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) with an aqueous acid solution at least once, an aqueous base solution at least once, and water at least once. In one embodiment, the contacting step comprises contacting the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) with an aqueous acid solution, followed by an aqueous alkaline solution, followed by an aqueous acid solution, followed by water. In one embodiment, the aqueous acid solution is a solution of a carboxylic acid in water. The carboxylic acid is selected from citric acid, malic acid, tartaric acid, succinic acid, oxalic acid, isocitric acid and quinic acid. In one embodiment, the carboxylic acid is citric acid. In one embodiment, the concentration of the carboxylic acid in the water is from 1 to 40 wt% of the carboxylic acid, for example from 2 to 30 wt%. Thus, in one embodiment, the aqueous acid solution is a 2 wt% or 30 wt% solution of citric acid in water. In one embodiment, the aqueous base solution is a solution of an inorganic base in water. The inorganic base is selected from potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. In one embodiment, the inorganic base is potassium carbonate. In one embodiment, the concentration of the inorganic base in the water is from 0.1 to 3 M, for example, from 0.2 to 2 M. Thus, in one embodiment, the base solution is a from 0.2 to 2 M potassium carbonate solution. In one embodiment, the purified organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)- 1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is concentrated to provide a concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the amount of solvent in the concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) is from 1 to 5 ml per gram of the salt of N2,N6- bis(tert-butoxycarbonyl)-L-lysine (III’) starting material used, for example, from 2 to 4 ml per gram of the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) starting material used. In one embodiment, the method is for producing solid di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), and wherein, after the coupling step (and optional contacting step and concentration), the method further comprises a precipitating step of precipitating the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the precipitating step comprises: (i) providing a solution of the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan- 2-yl)amino)hexane-1,5-diyl)dicarbamate (III), and (ii) reducing the solubility of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) in the solution so as to induce precipitation of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment of the above embodiment, - the solution of the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) of step (i) is a solution of di- tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III) in a solvent, and - the reducing the solubility of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is achieved by addition of an antisolvent; wherein, in one embodiment: (a) the solvent is dichloromethane and / or ethyl acetate and / or a C1-C6 alcohol (for example, ethanol, iso-propanol or n-propanol), for example, dichloromethane and / or ethyl acetate; and the antisolvent is a C5-C9 hydrocarbon solvent, for example, n-heptane; or (b) the solvent is a C1-C6alcohol and the antisolvent is water. In one embodiment, the solvent is dichloromethane and / or ethyl acetate and the antisolvent is n-heptane. In one embodiment, the solution of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) of step (i) is the above- described purified organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) or the above-described concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III). In one embodiment, the solution of the di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is the above-described concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the reducing the solubility of the di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is achieved by (or further achieved by) reducing the temperature of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the temperature of the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III) after the addition of the antisolvent is reduced by 10 ˚C or more, for example, 20 ˚C or more. In one embodiment, the reducing the solubility of the di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is achieved by (or further achieved by) introducing seed crystals of di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, seed crystals are added before, simultaneously with or after addition of the antisolvent. In one embodiment, the precipitation is crystallisation. In one embodiment, the precipitated material is collected. In one embodiment, the precipitated material is collected by filtration. Optionally, in the filtration, the precipitated material may be washed (for example, with antisolvent, wherein, in one embodiment, the antisolvent is chilled). In one embodiment, the precipitated material is washed with toluene. Optionally, the precipitated material is dried, for instance in vacuo. In one embodiment, the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) obtained by the process of the present disclosure has a purity of greater than 98% (by area when measured by HPLC). In one embodiment, the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III) obtained by the process of the present disclosure has a purity of greater than 99% (by area when measured by HPLC), for example, greater than 99.5% (by area when measured by HPLC), such as 99.8% (by area when measured by HPLC) or higher. The process of the present disclosure is suitable for scale up as it does not require evaporation to dryness or water removal distillations (as in, for example, US 8,487,134, WO 2019 / 108542, and WO 2013 / 011526). It provides high quality product without the need for recrystallisation. In one embodiment, the optical purity of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtained by the process of the present disclosure is 100% (by area when measured by HPLC). Method for producing lisdexamfetamine dimesylate ((S)-2,6-diamino-N-((S)-1- phenylpropan-2-yl)hexanamide dimethanesulfonate (IV)) – Phase IV As discussed above, the present disclosure also provides a method for producing (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV), the method comprising a deprotection and salt formation step of treating di-tert-butyl ((S)- 6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to: (i) the above method providing a purified organic solution of di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), or (ii) the above method producing solid di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), with methanesulfonic acid to provide lisdexamfetamine dimesylate. This method provides extremely high purity product in high yields in an operationally-straightforward manner. In one embodiment, the method further comprises a providing step of providing the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to: (i) the above method providing a purified organic solution of di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), or (ii) the above method producing solid di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), wherein, in one embodiment, the providing step comprises either: (i) the above method providing a purified organic solution of di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), or (ii) the above method producing solid di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, in the deprotection and salt formation step, the methanesulfonic acid is present in an amount of from 2 to 10 mol per mol of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), for example, from 3 to 7 mol per mol of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III), such as from 3 to 5 mol per mol of di-tert- butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), e.g., around 4 mol per mol of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the deprotection and salt formation step is carried out in a solvent. In one embodiment, the solvent is an organic solvent, for instance, a solvent selected from ethanol, dichloromethane, ethyl acetate, methanol, isopropanol, acetonitrile, chlorobenzene, chloroform, dichloroethane, dichlorobenzene (1,2-, 1,3- and 1,4-), diethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydofuran, methyl tert-butyl ether, toluene and mixtures thereof. In one embodiment, the solvent is a solvent selected from ethanol, dichloromethane, ethyl acetate, isopropanol, 1,4-dioxane, tetrahydrofuran, 2- methyl tetrahydofuran and mixtures thereof. In one embodiment, the solvent is a solvent selected from ethanol, dichloromethane, ethyl acetate and mixtures thereof. In one embodiment, the solvent is ethanol. In one embodiment, the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) is dissolved or diluted in solvent (for example, a solvent as discussed above) prior to addition of the methanesulfonic acid (optionally in a solvent, for example, a solvent as discussed above). Optionally, the solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) in solvent is filtered prior to addition of the methanesulfonic acid. In one embodiment, in the deprotection and salt formation step, the solvent is present in a total amount of from 5 to 20 ml per gram of the di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), for example, from 7 to 15 ml per gram of the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane- 1,5-diyl)dicarbamate (III). In one embodiment, the deprotection and salt formation step is carried out at a temperature of from 0 to 100 ˚C, for example, from 20 to 90 ˚C, such as from 40 to 80 ˚C. In one embodiment, the deprotection and salt formation step has a reaction time of from 10 min to 24 h, for example, from 30 min to 8 h. In one embodiment, the method is for producing crystalline (S)-2,6-diamino-N-((S)- 1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV), and wherein, after the deprotection and salt formation step, the method further comprises a crystallising step of crystallising the (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV). In one embodiment, the crystallising step comprises: (i) providing a solution of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV), and (ii) reducing the solubility of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV) in the solution so as to induce crystallisation of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV). In one embodiment of the above embodiment, - the solution of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) of step (i) is a solution of (S)-2,6-diamino-N-((S)- 1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) in a solvent, and - the reducing the solubility of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV) in the solution is achieved by addition of an antisolvent. In one embodiment, the solvent is a solvent as defined above in connection with the deprotection and salt formation step. In one embodiment, the solvent is a C1-C6 alcohol (for example, ethanol, isopropanol or n-propanol) or a mixture of a C1-C6alcohol (for example, ethanol, isopropanol or n-propanol) and ethyl acetate. In one embodiment, the solvent is a mixture of ethanol and ethyl acetate. In one embodiment, the solution of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV) is the solution resulting from the deprotection and salt formation step. The antisolvent may be selected from ethyl acetate, diethyl ether, and water. In one embodiment, the antisolvent is ethyl acetate. In one embodiment, the reducing the solubility of the (S)-2,6-diamino-N-((S)-1- phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) is achieved by (or further achieved by) reducing the temperature of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV). In one embodiment, the temperature of the (S)- 2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) after the addition of the antisolvent is reduced by 10 ˚C or more, for example, 20 ˚C or more. In one embodiment, the reducing the solubility of the (S)-2,6-diamino-N-((S)-1- phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) is achieved by (or further achieved by) introducing seed crystals (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV). In one embodiment, seed crystals are added before, simultaneously with or after addition of the antisolvent. In one embodiment, the crystalline material is collected. In one embodiment, the crystalline material is collected by filtration. Optionally, in the filtration, the crystalline material may be washed (for example, with solvent or antisolvent, wherein, in one embodiment, the solvent or antisolvent is chilled). In one embodiment, the crystalline material is washed with ethyl acetate. Optionally, the crystalline material is dried, for instance in vacuo. In one embodiment, the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) is di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method providing a purified organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the di- tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method providing a concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III). This embodiment enables the production of lisdexamfetamine dimesylate ((S)-2,6- diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV)) from a salt of (S)-1-phenylpropan-2-amine (II) and a salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) without intermediate isolation of the di-Boc-lisdexamfetamine (di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) intermediate. The process thus provides lisdexamfetamine dimesylate in high yields and extremely high purities without isolation of the di-Boc-lisdexamfetamine intermediate, thereby rendering the method of the present disclosure process-efficient. Avoiding isolation of the di-Boc- lisdexamfetamine intermediate (for instance by precipitation / crystallisation) avoids the need to collect the intermediate (for instance by filtration), which can be slow. In one embodiment, the method further comprises a providing step of providing the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method providing a purified organic solution of di- tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) or, in one embodiment, the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) is di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method providing a concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)- 1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the providing step comprises either the above method providing a purified organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) or, in one embodiment, the above method providing a concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) obtained by the process of the present disclosure without intermediate isolation of the di-Boc-lisdexamfetamine (i.e. where the tert-butyl ((S)-6-oxo- 6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is di-tert-butyl ((S)- 6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method providing a purified organic solution of di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) has a purity of greater than 98% (by area when measured by HPLC). In one embodiment, the di-(S)-2,6- diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) has a purity of greater than 99% (by area when measured by HPLC), for example, greater than 99.5% (by area when measured by HPLC), such as greater than 99.8% (by area when measured by HPLC), i.e., 99.9% (by area when measured by HPLC) or higher. No further purification of the product is therefore required (for instance by separate re-crystallisation). No mesylated by-products (for instance ethyl mesylate) are typically observed. In one embodiment, the optical purity of (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV) obtained by the process of the present disclosure is 100% (by area when measured by HPLC). Accordingly, the product of the process of the present disclosure is in a purity suitable for pharmaceutical formulation. In one embodiment, the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) is di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method producing solid di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III). This embodiment enables the production of lisdexamfetamine dimesylate ((S)-2,6- diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV)) in extremely high purity. In one embodiment, the method further comprises a providing step of providing the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method producing solid di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III). In one embodiment, the providing step comprises the above method producing solid di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III). In one embodiment, the (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) obtained by the process of the present disclosure with intermediate isolation of the di-Boc-lisdexamfetamine (i.e. where the di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to the above method producing solid di-tert-butyl ((S)-6-oxo-6-(((S)- 1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) has a purity of greater than 98% (by area when measured by HPLC). In one embodiment, the di-(S)-2,6-diamino-N- ((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) has a purity of greater than 99% (by area when measured by HPLC), for example, greater than 99.5% (by area when measured by HPLC), such as greater than 99.8% (by area when measured by HPLC), e.g., greater than 99.9% (by area when measured by HPLC), for instance, around 100 % (by area when measured by HPLC). No further purification of the product is therefore required (for instance by separate re-crystallisation). No mesylated by-products (for instance ethyl mesylate) are typically observed. In one embodiment, the optical purity of (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV) obtained by the process of the present disclosure is 100% (by area when measured by HPLC). Accordingly, the product of the process of the present disclosure is in a purity suitable for pharmaceutical formulation. Method for producing Cl-dexamfetamine ((2S)-1-chloro-1-phenylpropan-2- amine hydrochloride (I)) – Phase I As mentioned above, the present disclosure provides a method for producing (2S)- 1-chloro-1-phenylpropan-2-amine hydrochloride (I), the method comprising a reacting step of reacting, in a solvent for the chlorination, (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or a salt thereof with an electrophilic chlorinating agent to provide (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), wherein the solvent for the chlorination is selected from dichloromethane, 1,2- dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, tetrachloroethylene, and mixtures thereof. Thus, in US 7,705,184, chlorination of L-norephedrine was performed with thionyl chloride in toluene. When this procedure was repeated by the inventors, the following drawbacks were discovered: I) Cl-Dexamfetamine crashed out violently from toluene in an uncontrollable manner and was found to contain sulfur residues. These residues were noticed to poison the Pd-catalyst used in the following step. In addition, this material was found to be corrosive to Hastelloy and 316 stainless steel. II) Due to the poor solubility of the HCl-salts of the starting material and product in toluene, the isolated Cl-dexamfetamine was found to contain variable amounts of starting material as an impurity. If present in large quantities (> 1%), L-norephedrine was found to carry-over to the final product as a corresponding hydroxyl impurity (OH- lisdexamfetamine, represented by the chemical formula (IVA’) below).

[0003] III) Filtration of Cl-dexamfetamine was found to be extremely slow and thus unsuitable for larger scale. In addition, the inventors were concerned that excess thionyl chloride was not quenched after the reaction. IV) Additional purification (carbon treatment) was needed before isolated Cl- dexamfetamine could be used in the following step. Unlike US 7,705,184, the method of the present disclosure enables the production of (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) in an easily handled form, in high yield and in a high purity making it suitable for use in the following steps without further purification (i.e. without carbon treatment). Thus, the method provides (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride (I) containing minimal or no impurities corresponding to the L-norephedrine (i.e., (1R,2S)-2-amino-1-phenylpropan-1-ol (I’)) starting material and / or residues from the chlorinating agent. These benefits are attained through use of the solvent for the chlorination as defined above. The use of the solvent for the chlorination as defined above better dissolves L-norephedrine HCl and Cl- dexamfetamine HCl than toluene, which allowed for lower reaction temperature to be used. The use of the solvent for the chlorination as defined above also makes the reactions faster and more selective than in toluene. In one embodiment, the solvent for the chlorination is selected from dichloromethane, 1,2-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, tetrachloroethylene, and mixtures thereof. In one embodiment, the solvent for the chlorination is dichloromethane. In one embodiment, in the reacting step, the solvent for the chlorination is present in an amount of from 2 to 20 ml per gram of the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or the salt thereof, for example, from 3 to 15 ml per gram of the (1R,2S)-2-amino-1- phenylpropan-1-ol (I’) or the salt thereof, such as from 4 to 10 ml per gram of the (1R,2S)- 2-amino-1-phenylpropan-1-ol (I’) or the salt thereof. The electrophilic chlorinating agent is selected from oxalyl chloride, phosphorous pentachloride, phosphorous trichloride, phosphorous oxychloride, trichloroisocyanuric acid, and thionyl chloride. In one embodiment, the electrophilic chlorinating agent is thionyl chloride. In one embodiment, the electrophilic chlorinating agent is used in an amount of from 1 to 10 mol per mol of the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or the salt thereof, for example, from 1.5 to 5 mol per mol of the (1R,2S)-2-amino-1-phenylpropan-1- ol (I’) or the salt thereof. The (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or a salt thereof may be the (1R,2S)- 2-amino-1-phenylpropan-1-ol freebase (I’) or any suitable salt. In one embodiment, the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or salt thereof is (1R,2S)-2-amino-1- phenylpropan-1-ol hydrochloride (IA’) or (1R,2S)-2-amino-1-phenylpropan-1-ol freebase (I’). In one embodiment, the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or salt thereof is (1R,2S)-2-amino-1-phenylpropan-1-ol hydrochloride (IA’). This reactant is stable. In one embodiment, the reacting step takes place at a temperature of from -78 to 40 ˚C, for example, from 0 to 30 ˚C. In one embodiment, the electrophilic chlorinating agent is added to the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or salt thereof at a temperature of from -78 to 20 ˚C, for example, from 0 to 5 ˚C before heating to a temperature of from 20 to 40 ˚C, for example, around 30 ˚C for further reacting. In one embodiment, the reacting step has a reaction time of from 10 min to 24 h, for example, from 30 min to 8 h. In one embodiment, the reacting step provides a reacting step reaction mixture comprising (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, after the reacting step, the method further comprises a quenching step of quenching residual electrophilic chlorinating agent with a quenching agent. The quenching agent may be any chemical compound capable of reacting with the residual electrophilic chlorinating agent. In one embodiment, the quenching agent is a C1- C6 alcohol, for example, n-propanol, methanol, ethanol or iso-propanol. In one embodiment, the quenching agent is n-propanol. In one embodiment, the quenching agent is used in an amount of from 1 to 10 ml per gram of the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or the salt thereof, for example, from 2 to 8 ml per gram of the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or the salt thereof. In one embodiment, the quenching step takes place at a temperature of from 0 to 20 ˚C, for example, from 5 to 10 ˚C. In one embodiment, the quenching step provides a quenching step reaction mixture comprising (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, the reaction step reaction mixture comprising (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I) or quenching step reaction mixture comprising (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) (for example, the quenching step reaction mixture comprising (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I)) is concentrated to provide a concentrated solution of (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, the amount of solvent in the concentrated solution of (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) is from 1 to 5 ml per gram of the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or salt thereof starting material used, for example, from 2 to 4 ml per gram of the (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or salt thereof starting material. In one embodiment, the method is for producing crystalline (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I), and wherein, after the reacting step (and optional quenching step and / or concentration), the method further comprises a crystallising step of crystallising the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). (ii) In one embodiment, the crystallising step comprises: providing a solution of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), and (ii) reducing the solubility of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) in the solution so as to induce crystallisation of the (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, the solution of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) is a solution in the solvent for the chlorination and / or the quenching agent. In one embodiment, the solution of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) is a solution in a solution in the quenching agent. In one embodiment, the reducing the solubility of the (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I) is achieved by addition of an antisolvent. In one embodiment, the antisolvent is a C5-C9 hydrocarbon solvent, for example, n-heptane. In one embodiment of the above embodiment, - the solution of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) of step (i) is a solution of (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) in the quenching agent, and - the reducing the solubility of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) is achieved by addition of an antisolvent, for example, a C5-C9 hydrocarbon solvent, such as n-heptane. In one embodiment, the reducing the solubility of the (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I) is achieved by (or further achieved by) reducing the temperature of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, the temperature of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) after the addition of the antisolvent is reduced by 10 ˚C or more, for example, 20 ˚C or more. In one embodiment, the reducing the solubility of the (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I) is achieved by (or further achieved by) introducing seed crystals of (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, seed crystals are added before, simultaneously with or after addition of the antisolvent. In one embodiment, the crystalline material is collected. In one embodiment, the crystalline material is collected by filtration. Optionally, in the filtration, the crystalline material may be washed (for example, with solvent or antisolvent, wherein, in one embodiment, the solvent or antisolvent is chilled). In one embodiment, the crystalline material is washed with ethyl acetate. Optionally, the crystalline material is dried, for instance in vacuo. In one embodiment, the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) obtained by the process of the present disclosure has a purity of greater than 98% (by area when measured by HPLC). In one embodiment, the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) obtained by the process of the present disclosure has a purity of greater than 99% (by area when measured by HPLC), for example, greater than 99.5% (by area when measured by HPLC). In one embodiment, the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) obtained by the process of the present disclosure is free from residues from the electrophilic chlorinating agent. It may therefore be used in the following step directly without further purification. Method for producing dexamfetamine ((S)-1-phenylpropan-2-amine (II)), crystalline dexamfetamine hydrochloride ((S)-1-phenylpropan-2-amine hydrochloride (IIA)) and crystalline dexamfetamine sulfate ((S)-1-phenylpropan-2-amine sulfate (IIB)) – Phase II As discussed above, the present disclosure also provides a method for producing (S)-1-phenylpropan-2-amine hydrochloride (IIA), the method comprising a hydrogenation reaction step of hydrogenating crystalline (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride (I) obtainable by the above method for producing crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) in the presence of a hydrogenation catalyst to provide (S)-1-phenylpropan-2-amine hydrochloride (IIA). The crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) obtainable by the above method for producing crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) contains minimal or no residues from the electrophilic chlorinating agent which can poison the hydrogenation catalyst. Accordingly, the crystalline (2S)-1-chloro-1- phenylpropan-2-amine hydrochloride (I) obtainable by the above method for producing crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) enables the efficient production of (S)-1-phenylpropan-2-amine hydrochloride (IIA), for instance using lower catalyst loadings (for instance less than 7% wt) and / or reaction temperatures. In one embodiment, the method further comprises a providing step of providing the crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) obtainable by the above method for producing crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, the providing step comprises the above method for producing crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, the hydrogenation reaction step is carried out in a solvent. In one embodiment, the solvent is a protic solvent, for instance, a solvent selected from water, methanol, ethanol, n-propanol, iso-propanol and mixtures thereof. In one embodiment, the solvent is water or ethanol. In one embodiment, the solvent is water. In one embodiment, the solvent is present in an amount of from 5 to 40 ml per gram of the crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), for example, from 10 to 30 ml per gram of the crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). The hydrogenation catalyst may be any catalyst capable of catalysing the conversion of a carbon-chlorine bond to a carbon-hydrogen bond. The hydrogenation catalyst may be, for example, a palladium catalyst, an iridium catalyst, a nickel catalyst, a platinum catalyst, a rhodium catalyst, or a ruthenium catalyst. In one embodiment, the catalyst is a palladium catalyst, for example, palladium on carbon (Pd / C). In one embodiment, the palladium on carbon (Pd / C) catalyst contains palladium in an amount of from 1 to 20 wt%, for example, from 5 to 10 wt%. In one embodiment, the hydrogenation catalyst is used in a sub-stoichiometric amount relative to the amount of crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, when the hydrogenation catalyst is a metal catalyst, the hydrogenation catalyst is used in an amount of from 0.05 to 1.0 mol% metal based on the amount of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I). In one embodiment, the catalyst is used in an amount of from 0.1 to 0.5 mol% metal based on the amount of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), for example, 0.1 to 0.3 mol% metal, such as around 0.2 mol% metal. In one embodiment, when the hydrogenation catalyst is palladium on carbon, the hydrogenation catalyst is present in an amount of from 0.1 to 0.5 mol% palladium based on the amount of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), for example, from 0.1 to 0.3 mol% palladium, such as around 0.2 mol% palladium. In one embodiment, the hydrogenation reaction step is carried out under a hydrogen atmosphere. Optionally, however, the hydrogenation reaction step is carried out using transfer hydrogenation. In one embodiment, the hydrogenation reaction step takes place at a temperature of from 5 to 40 ˚C, for example, from 10 to 30 ˚C. This low hydrogenation reaction temperature minimises the backwards reaction from Cl- dexamfetamine to L-norephedrine In one embodiment, the hydrogenation reaction step has a reaction time of from 10 min to 24 h, for example, from 30 min to 8 h. In one embodiment, after the hydrogen reaction, the catalyst is removed, for instance by filtration. In one embodiment, the hydrogenation reaction step provides a hydrogenation reaction mixture comprising (S)-1-phenylpropan-2-amine hydrochloride (IIA). In one embodiment, the method further comprises a basification step of treating the (S)-1-phenylpropan-2-amine hydrochloride (IIA) with base to provide (S)-1-phenylpropan- 2-amine freebase (II). The base may be any base capable of neutralising the hydrogenation reaction mixture comprising (S)-1-phenylpropan-2-amine hydrochloride (IIA) and releasing the (S)- 1-phenylpropan-2-amine freebase (II). The base may be, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. In one embodiment, the base is sodium hydroxide or potassium hydroxide, for example, sodium hydroxide. In one embodiment, the base is in an aqueous solution. For example, when the base is sodium hydroxide, the sodium hydroxide is an aqueous solution of sodium hydroxide. In one embodiment, the aqueous solution of sodium hydroxide may have a concentration of around 50% sodium hydroxide. In one embodiment, following basification, the (S)-1-phenylpropan-2-amine freebase (II) is separated from the aqueous layer by extraction to provide an organic solution of (S)-1-phenylpropan-2-amine freebase (II). In one embodiment, the organic solvent for extraction is a solvent selected from toluene, diethyl ether and mixtures thereof. In one embodiment, the organic solvent for extraction is toluene. As discussed above, the present disclosure also provides a method for producing crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB), the method comprising: (ii) an acidification step of treating, in a solvent for the acidification, (S)-1-phenylpropan-2-amine freebase (II) with hydrochloric acid or sulfuric acid to provide a solution of (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB); and (b) a crystallising step of crystallising the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, the method further comprises a providing step of providing the (S)-1-phenylpropan-2-amine freebase (II), wherein, in one embodiment, the providing step comprises the above method for providing (S)-1-phenylpropan-2-amine freebase (II). In one embodiment, the solvent for the acidification is an organic solvent, and may be, for example, a solvent selected from toluene, diethyl ether, 1,4-dioxane, methanol iso- propanol, n-butanol and mixtures thereof. In one embodiment, when the method further comprises a providing step of providing the (S)-1-phenylpropan-2-amine freebase (II), wherein the providing step comprises the above method for providing (S)-1-phenylpropan- 2-amine freebase (II), the solvent for the acidification is the same as the organic solvent for extraction. In one embodiment, therefore, the solvent for the acidification is toluene. In one embodiment (particularly where the solvent for the acidification is not toluene), the hydrochloric acid or sulfuric acid are hydrochloric acid or sulfuric acid in organic solvent. In one embodiment, the hydrochloric acid is hydrochloric acid in diethyl ether, 1,4-dioxane, iso-propanol or n-butanol. Similarly, in one embodiment, the sulfuric acid is sulfuric acid in methanol. In one embodiment (particularly where the solvent for the acidification is toluene), the hydrochloric acid or sulfuric acid are aqueous hydrochloric acid or sulfuric acid. In one embodiment, the aqueous hydrochloric acid has a concentration of from 5 to 37 wt%, for example, from 20 to 35 wt%. In one embodiment, the sulfuric acid has a concentration of from 5 to 50 wt%, for example, from 20 to 35 wt%. In one embodiment, in the acidification step, the (S)-1-phenylpropan-2-amine freebase (II) is treated with hydrochloric acid or sulfuric acid in an amount of from 1 to 4 mol hydrochloric acid or sulfuric acid per mol (S)-1-phenylpropan-2-amine freebase (II), for example, from 1.1 to 3 mol hydrochloric acid or sulfuric acid per mol (S)-1- phenylpropan-2-amine freebase (II). (ii) In one embodiment, the crystallising step comprises: providing a solution of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)- 1-phenylpropan-2-amine sulfate (IIB), and (ii) reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) in the solution so as to induce crystallisation of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, the solution of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) is the solution of (S)-1- phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB) of the above step (a). Accordingly, in one embodiment, the solution of the (S)-1- phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) is a solution of (S)-1-phenylpropan-2-amine hydrochloride (IIA) in the solvent for the acidification and the solvent of the hydrochloric acid. In one embodiment, therefore, the solution of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan- 2-amine sulfate (IIB) of step (i) is a solution of (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB) in a mixture of toluene and water. The reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) in the solution so as to induce crystallisation of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1- phenylpropan-2-amine sulfate (IIB) may be carried out by any means, such as addition of an antisolvent, by concentration, or by addition of seed crystals of (S)-1-phenylpropan-2- amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, - the solution of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) of step (i) is a solution of (S)-1- phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB) in a mixture of toluene and water, and - the reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) is achieved by azeotropic removal of water. Optionally, the reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) is further achieved by concentration of the toluene. In one embodiment, the reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) is achieved by (or further achieved by) reducing the temperature of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, the temperature of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1- phenylpropan-2-amine sulfate (IIB) after the azeotropic removal of water and optional concentration of the toluene is reduced by 20 ˚C or more, for example, 40 ˚C or more, such as 60 ˚C or more, e.g., 80 ˚C or more. In one embodiment, the reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) is achieved by (or further achieved by) introducing seed crystals of (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB). In one embodiment, seed crystals are added after the azeotropic removal of water and optional concentration of the toluene. In one embodiment, the crystalline material is collected. In one embodiment, the crystalline material is collected by filtration. Optionally, in the filtration, the crystalline material may be washed (for example, with solvent or antisolvent, wherein, in one embodiment, the solvent or antisolvent is chilled). In one embodiment, the crystalline material is washed with toluene. Optionally, the crystalline material is dried, for instance in vacuo. In one embodiment, the crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the crystalline (S)-1-phenylpropan-2-amine sulfate (IIB) obtained by the process of the present disclosure has a purity of greater than 98% (by area when measured by HPLC). In one embodiment, the crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the crystalline (S)-1-phenylpropan-2-amine sulfate (IIB) obtained by the process of the present disclosure has a purity of greater than 99% (by area when measured by HPLC), for example, greater than 99.5% (by area when measured by HPLC). In one embodiment, the optical purity of the crystalline (S)-1-phenylpropan-2- amine hydrochloride (IIA) or the crystalline (S)-1-phenylpropan-2-amine sulfate (IIB) obtained by the process of the present disclosure is 100% (by area when measured by HPLC). In one embodiment, the crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the crystalline (S)-1-phenylpropan-2-amine sulfate (IIB) obtained by the process of the present disclosure is used in the following step (i.e., the method for producing di- tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III)) directly without further purification. When describing the embodiments of the present disclosure, the combinations and permutations of all possible embodiments have not been explicitly described. Nevertheless, the mere fact that certain measures are described in different embodiments does not indicate that a combination of these measures cannot be used to advantage. The present disclosure envisages all possible combinations and permutations of the described embodiments. The present disclosure is explained in more detail by the following examples. The examples are meant for illustrating purposes only and do not limit the scope of the invention defined in the claims. The abbreviations have the meanings indicated below. DCM dichloromethane DIPEA N,N-diisopropyl-N-ethylamine EtOAc ethyl acetate EtOH ethanol HPLC high-performance liquid chromatography rt room temperature EXAMPLES Example 1 –- Synthesis of lisdexamfetamine dimesylate via isolated di-Boc- lisdexamfetamine intermediate (2S)-1-Chloro-1-phenylpropan-2-amine hydrochloride (Cl-dexamfetamine HCl) L-Norephedrine hydrochloride (60 g, 320 mmol, 100 mol-%) was charged to a multi-neck round-bottom flask. DCM (360 ml, 6 vol) was added in two parts so that the 150-ml (2.5 vol) level could be marked on the reaction flask. The reaction mixture was cooled to 0-5 °C and thionyl chloride (47 ml, 644 mmol, 200 mol-%) was added dropwise so that the reaction temperature did not rise above 20 °C. After the addition, the reaction was heated to 30 °C and the mixture was stirred for 3 h. After reaction monitoring showed that the reaction was complete (did not proceed any further, usually < 1.0 a-% of starting material), it was cooled to 5-10 °C and excess thionyl chloride was quenched with dropwise addition of n-propanol (240 ml, 4 vol). After this, the reaction mixture was concentrated in a normal pressure distillation until the temperate in the distillation flask reached 60 °C. Then, the solution was cooled to 30 °C, 200 mbar vacuum was applied, and the solution was concentrated to 2.5 vol by vacuum distillation. After the concentration, the solution was left to cool to rt, after which n-heptane (600 ml, 10 vol) was added dropwise. Finally, the mixture was cooled to 0 °C and stirred for at least 30 min. The solids were filtered, washed with EtOAc (2 x 120 ml, 2 x 2 vol) and dried under vacuum at 50 °C overnight.62.7 g (95 %) of light brown solid was obtained (purity 99.57 a-% by HPLC). (S)-1-Phenylpropan-2-amine hydrochloride (dexamfetamine HCl): Cl-Dexamfetamine HCl (30 g, 146 mmol, 100 mol-%) was dissolved in water (500 ml, 5 vol) in a bottle. A 1-l hydrogenation reactor was charged with Pd / C catalyst (5 % Pd, Noblyst®P1080, 50 % H2O, 1.5 g, 5 w-%, 0,24 mol-%) followed by the preformed Cl-dexamfetamine solution. Slow stirring was turned on. The reactor was evacuated and nitrogen atmosphere was applied 3-4 times. The nitrogen atmosphere was changed to hydrogen atmosphere (3-4 times) and the pressure was set to 2.0 bar. Temperature was set to 20 °C and stirring to 800-900 rpm. The reaction mixture was stirred for 3 h, after which nitrogen atmosphere was reapplied. The catalyst was filtered off using pressure filtration and a T950 cardboard. The catalyst cake was washed with water (2 x 25ml) and the filtrate was mixed with the filtered reaction mixture. The filtered reaction mixture was charged into a multi-neck round-bottom flask and cooled to 10 °C.50 % NaOH solution was added until the solution was alkaline (pH > 12, consumption about l7 ml). The aqueous phase was extracted with toluene (2 x 165 ml). The pH of the aqueous phase was checked again after the first extraction. The combined organic phases were washed with water (l x 85 ml) and charged to a fresh multi-neck round-bottom flask.30 % HCl solution (20 ml, 189 mmol, 130 mol- %) was added dropwise, after which water was removed by an azeotropic water removal distillation until no more water was separating in the Dean-Stark apparatus (about 14 ml of water was removed). Then, the distillation was continued as a normal distillation until the vapor temperature was no longer rising (110 ml of toluene was removed). Heating was removed and seed crystals were added as soon as possible. The solution was left to cool to rt and kept at rt for 1 h. The solids were filtered, washed with toluene (2 x 75 ml) and dried overnight in an oven at 50 °C under vacuum.23.12 g (92 %) of white shiny solids was obtained (purity 99.68 a-% by HPLC, optical purity 100.0 %). Di-tert-butyl ((S)-6-oxo-6-(((S)-1 -phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (di-Boc-lisdexamfetamine): Di-N-Boc-L-lysine dicyclohexylamine (22 g), dexamphetamine hydrochloride, (1.04 eq) and DCM (6.8 vol) were charged to a reaction vessel and stirred at rt for about 5-10 min. DIPEA (5.5 eq) was added and the reaction mixture was stirred at rt for about 5 min. The mixture was cooled to about 15 °C and 50 % 1-propanephosphonic acid cyclic anhydride (T3P) in EtOAc (1.5 eq) was added gradually at about 20 °C. The reaction mixture was stirred at rt for about 2 h. When the reaction was complete, the reaction was quenched with about 10 % citric acid solution. First, citric acid (7.5 g) was added to the reaction mixture followed by water (68 ml) at rt. The reaction mixture was stirred for about 10 min at rt before the phase separation. The lower, organic phase including the product was stirred for about 10 min with 0.5 M K2CO3-solution (3.1 vol) followed by phase separation. The separated organic phase was washed once more with about 10 % citric acid solution as before. The last extraction was with water (3.1 vol). All extractions were done at rt. The organic phase was concentrated by distilling off the solvents and water residues (about 3 vol) at normal pressure. n-Heptane (12.5 vol) was added gradually at elevated temperature while stirring vigorously. The distillation was continued to distill off solvents (about 2.3 vol). Seed crystals were added at about 50-55 °C. The mixture was cooled slowly to rt over about 8 h and kept at rt for at least 1-2 h. The precipitation was collected by filtration and washed twice with n-heptane (2 x 1.37 vol) and dried under vacuum at 45 °C overnight to obtain di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate. (Yield 18.13 g / 93.81 %, purity 99.82 a-% by HPLC, optical purity 100 %). (S)-2,6-Diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (lisdexamfetamine dimesylate): Di-Boc-lisdexamfetamine (14 g) and EtOH (8.6 vol) were charged to a reaction vessel. The mixture was stirred for a while to obtain a solution. The solution was filtered to remove possible trashes. The filtrate was heated to about 65 °C. Methanesulfonic acid (4 eq) was added gradually to the reaction vessel at 65 °C. The bottle with methanesulfonic acid was rinsed with EtOAc (0.5 vol) and the EtOAc was added to the reaction mixture. The mixture was stirred at 65 °C for about 1-2 h. Seed crystals were added. EtOAc (4 vol) was added gradually at about 60-65 °C. The product precipitated during the addition. The mixture was cooled slowly to 10-15 °C and kept at 10-15 °C about 4-5 h. The precipitation was collected by filtration and washed twice with a mixture of EtOH and EtOAc (1:1) (2 x 1.1 vol) and finally dried under vacuum at 50 °C overnight to obtain the final drug substance, lisdexamfetamine dimesylate, with good yield and purity. (Yield 12.63 g / 91.81 %, purity 100 a-% by HPLC). Example 2 – Synthesis of lisdexamfetamine dimesylate via unisolated di-Boc- lisdexamfetamine intermediate (2S)-1-Chloro-1-phenylpropan-2-amine hydrochloride (Cl-dexamfetamine HCl) L-Norephedrine hydrochloride (20 g, 107 mmol, 100 mol-%) was charged to a multi-neck round bottom-flask. DCM (120 ml, 6 vol) was added in two parts so that the 50 ml (2.5 vol) level could be marked on the reaction flask. The reaction mixture was cooled to 0-5 °C and thionyl chloride (23.3 ml, 320 mmol, 300 mol-%) was added dropwise so that the reaction temperature did not rise above 20 °C. After the addition, the reaction was heated to 30 °C and stirred for 3 h. After reaction monitoring showed that the reaction was complete, the mixture was cooled to 5-10 °C and excess thionyl chloride was quenched with dropwise addition of n-propanol (100 ml, 5 vol). After this, the reaction mixture was concentrated in a normal pressure distillation until the temperature in the distillation flask reached 60 °C. Then, the solution was cooled to 30 °C, 200 mbar vacuum was applied and the solution was concentrated to 2.5 vol by vacuum distillation. After the concentration, the solution was left to cool to rt, after which n-heptane (140 ml, 7 vol) was added dropwise. Finally, the mixture was cooled to 0 °C and stirred at 0 °C for at least 30 min. The solids were filtered, washed with EtOAc (3 x 40 ml, 3 x 2 vol) and dried under vacuum at 50 °C overnight.21.2 g (96.7 %) of light brown solid was obtained (purity 99.76 a-% by HPLC). (S)-1-Phenylpropan-2-amine hydrochloride (dexamfetamine HCl) Cl-Dexamfetamine HCl (30 g, 146 mmol, 100 mol-%) was dissolved in water (500 ml, 5 vol), treated with activated charcoal (Norit®SX Ultra) and the mixture was filtered. A 1-l hydrogenation reactor was charged with Pd / C catalyst (5 % Pd, Noblyst®P1080, 50 % H2O, 1.5 g, 5 w-%, 0,24 mol-%) followed by the preformed Cl-dexamfetamine solution. Slow stirring was turned on. The reactor was evacuated and nitrogen atmosphere was applied 3-4 times. The nitrogen atmosphere was changed to hydrogen atmosphere (3-4 times) and the pressure was set to 2.0 bar. The temperature was set to 20 °C and stirring to 800-900 rpm. The reaction was stirred for 3 h, after which nitrogen atmosphere was reapplied. The catalyst was filtered off using pressure filtration and a T950 cardboard. The catalyst cake was washed with water (2 x 25ml) and the filtrate was mixed with the filtered reaction mixture. The filtered reaction mixture was charged into a multi-neck round-bottom flask and cooled to 10 °C.50 % NaOH solution was added until the solution was alkaline (pH > 12, consumption about 17 ml). The aqueous phase was extracted with toluene (2 x 150 ml). The pH of the aqueous phase was checked again after the first extraction. The combined organic phase was washed with water (1 x 75 ml), charged to a fresh multi-neck round- bottom flask and 30 % HCl solution (20 ml, 189 mmol, 130 mol-%) was added dropwise, after which water was removed by an azeotropic water removal distillation until no more water was separating in the Dean- Stark apparatus (about 14 ml of water removed). Then the distillation was continued as a normal distillation until the vapor temperature was no longer rising (110 ml of toluene was removed). Heating was removed and seed crystals were added as soon as possible. The solution was left to cool to rt and kept at rt for 1 h. The solids were filtered, washed with toluene (2 x 75 ml) and dried overnight in an oven at 50 °C under vacuum.23.27 g (93.0 %) of white shiny solids were obtained (purity 99.87 a- % by HPLC, optical purity 100.0 %). (S)-2,6-Diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (lisdexamfetamine dimesylate) Di-N-Boc-L-lysine dicyclohexylamine (22 g, 41.7 mmol, 100 mol-%), dexamphetamine hydrochloride, (7.44 g, 43.3 mmol, 104 mol-%) and DCM (150 ml, 6.8 vol) were charged to a reaction vessel and stirred at rt for about 5-10 min. DIPEA, (47.2 ml, 271 mmol, 650 mol-%) was added and the reaction mixture was stirred at rt for about 5 min. The mixture was cooled to about 15 °C and 50 % 1-propanephosphonic acid cyclic anhydride (T3P) in DCM (29.4 ml, 60.5 mmol, 145 mol-%) was added gradually at about 20 °C. The reaction mixture was stirred at rt for about 2 h. When the reaction was complete, the reaction was quenched with 15 % citric acid solution (100 ml). The mixture was stirred at rt and the phases separated. The organic phase was then sequentially washed with 1 M K2CO3(100 ml), 15 % citric acid (100 ml) and water (100 ml). The organic phase was concentrated by distilling off solvents under atmospheric pressuse until roughly 2.5 volumes remained. EtOH (200 ml) was added and solvents were distilled off until roughly 6 volumes remain. The solution was cooled and then polish filtered and the filter sheet was rinsed with EtOH. The filtered solution was heated to 65 °C and methanesulfonic acid (10.8 ml, 167 mmol, 400 mol-%) was added dropwise. The mixture was stirred for 2 h at 65 °C, upon which the reaction was complete. The mixture was seeded with lisdexamfetamine dimesylate, followed by addition of EtOAc (100 ml, 4.5 vol) at 60-65°C. Upon complete addition, the mixture was gradually cooled to rt and stirring was continued at this temperature. The product was filtered, washed with chilled EtOAc (2 x 40 ml) and dried under vacuum at 50 °C to give lisdexamfetamine dimesylate as a white powder. (Yield 17.0 g / 89.7 %, purity 99.93 a-% HPLC).

Claims

CLAIMS 1. A method for producing (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I),the method comprising a reacting step of reacting, in a solvent for the chlorination, (1R,2S)-2-amino-1-phenylpropan-1-ol (I’) or a salt thereofwith an electrophilic chlorinating agent to provide (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), wherein the solvent for the chlorination is selected from dichloromethane, 1,2- dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, tetrachloroethylene, and mixtures thereof.

2. The method according to claim 1, wherein the solvent for the chlorination is selected from dichloromethane, 1,2-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, tetrachloroethylene, and mixtures thereof, for example, dichloromethane.

3. The method according to claim 1 or 2, wherein the electrophilic chlorinating agent is selected from oxalyl chloride, phosphorous pentachloride, phosphorous trichloride, phosphorous oxychloride, trichloroisocyanuric acid, and thionyl chloride, for example, thionyl chloride.

4. The method according to any one of claims 1 to 3, wherein the (1R,2S)-2-amino-1- phenylpropan-1-ol (I’) or a salt thereof is (1R,2S)-2-amino-1-phenylpropan-1-ol hydrochloride (IA’)or (1R,2S)-2-amino-1-phenylpropan-1-ol freebase (I’),for example, (1R,2S)-2-amino-1-phenylpropan-1-ol hydrochloride (IA’).

5. The method according to any one of claims 1 to 4, wherein, after the reacting step, the method further comprises a quenching step of quenching residual electrophilic chlorinating agent with a quenching agent, for example, a C1-C6 alcohol, such as n- propanol.

6. The method according to any one of claims 1 to 5, wherein the method is for producing crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), and wherein, after the reacting step and optional quenching step, the method further comprises a crystallising step of crystallising the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I).

7. The method according to claim 6, wherein the crystallising step comprises: (i) providing a solution of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), and(ii) reducing the solubility of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) in the solution so as to induce crystallisation of the (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride (I).

8. The method according to claim 7, wherein - the solution of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) of step (i) is a solution of (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) in the quenching agent, and - the reducing the solubility of the (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) is achieved by addition of an antisolvent, for example, a C5-C9hydrocarbon solvent, such as n-heptane.

9. A method for producing (S)-1-phenylpropan-2-amine hydrochloride (IIA),the method comprising a hydrogenation reaction step of hydrogenating crystalline (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride (I) obtainable by the method of any one of claims 6 to 8 in the presence of a hydrogenation catalyst to provide (S)-1-phenylpropan-2- amine hydrochloride (IIA).

10. The method according to claim 9, wherein the method further comprises a providing step of providing the crystalline (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I) obtainable by the method of any one of claims 6 to 8, wherein, for example, the providing step comprises a method according to any one of claims 6 to 8.

11. The method according to claim 9 or 10, wherein, in the hydrogenation reaction step, the hydrogenation catalyst is palladium on carbon, and the hydrogenation catalyst is present in an amount of from 0.1 to 0.5 mol% palladium based on the amount of the (2S)- 1-chloro-1-phenylpropan-2-amine hydrochloride (I).

12. The method according to any one of claims 9 to 11, wherein the method further comprises a basification step of treating the (S)-1-phenylpropan-2-amine hydrochloride (IIA) with base to provide (S)-1-phenylpropan-2-amine freebase (II).

13. A method for producing crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA)or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB),the method comprising: (a) an acidification step of treating, in a solvent for the acidification, (S)-1- phenylpropan-2-amine freebase (II) with hydrochloric acid or sulfuric acid to provide a solution of (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB); and (b) a crystallising step of crystallising the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB).

14. The method according to claim 13, wherein the method further comprises a providing step of providing the (S)-1-phenylpropan-2-amine freebase (II), wherein, for example, the providing step comprises a method according to claim 12.

15. The method according to claim 13 or 14, wherein, in the acidification step, the solvent for the acidification is toluene and the hydrochloric acid or sulfuric acid are aqueous hydrochloric acid or aqueous sulfuric acid.

16. The method according to any one of claim 13 to 15, wherein the crystallising step comprises: (i) providing a solution of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB), and (ii) reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) in the solution so as to induce crystallisation of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB).

17. The method according to claim 16, wherein - the solution of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) of step (i) is a solution of (S)-1- phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB) in a mixture of toluene and water, and - the reducing the solubility of the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB)is achieved by azeotropic removal of water and optionally concentration of the toluene.

18. The method according to claim 17, wherein the solution of (S)-1-phenylpropan-2- amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB) in a mixture of toluene and water results from the acidification step.

19. A method for producing di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III),the method comprising a coupling step of coupling a salt of (S)-1-phenylpropan-2- amine (II)with a salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’)to provide di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III).

20. The method according to claim 19, wherein the salt of (S)-1-phenylpropan-2-amine (II) is (S)-1-phenylpropan-2-amine hydrochloride (IIA),(S)-1-phenylpropan-2-amine sulfate (IIB),or (S)-1-phenylpropan-2-amine hydrobromide (IIC),for example, (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2- amine sulfate (IIB), such as (S)-1-phenylpropan-2-amine hydrochloride (IIA).

21. The method according to claim 20, wherein the salt of (S)-1-phenylpropan-2-amine (II) is crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1- phenylpropan-2-amine sulfate (IIB) obtainable by the method of any one of claims 13 to 18, for example, crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) obtainable by the method of any one of claims 13 to 18.

22. The method according to claim 21, wherein the method further comprises a providing step of providing the crystalline (S)-1-phenylpropan-2-amine hydrochloride (IIA) or crystalline (S)-1-phenylpropan-2-amine sulfate (IIB), wherein, for example, the providing step comprises a method according to any one of claims 13 to 18.

23. The method according to any one of claims 19 to 22, wherein the salt of N2,N6- bis(tert-butoxycarbonyl)-L-lysine (III’) is a salt according to formulae (IIIA’) or (IIIB’),(IIIA’) wherein:R1and R2are the same or different and are selected from an optionally substituted C5-C12 cycloalkyl group or an optionally substituted branched C3-C10 alkyl group, and R3is selected from H or an optionally substituted C1-C6alkyl group;(IIIB’) wherein: R4to R7are the same or different and are selected from an optionally substituted C1-C12 alkyl group or an optionally substituted C5-C12cycloalkyl group; and wherein the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) is, for example, N2,N6-bis(tert-butoxycarbonyl)-L-lysine dicyclohexylamine (IIIA)(IIIA).

24. The method according to any one of claims 19 to 23, wherein, in the coupling step, the coupling comprises treating the salt of (S)-1-phenylpropan-2-amine (II) and the salt of N2,N6-bis(tert-butoxycarbonyl)-L-lysine (III’) with a coupling agent and a base.

25. The method according to claim 24, wherein the coupling agent is a selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, ethyl-(N’,N’- dimethylamino)propylcarbodiimide hydrochloride and 1-propanephosphonic acid cyclic anhydride, for example, 1-propanephosphonic acid cyclic anhydride.

26. The method according to claim 24 or 25, wherein the base is selected from 1,8- diazabicycloundec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6-di-tert-butylpyridine, and N,N-diisopropylethylamine, for example, N,N-diisopropylethylamine.

27. The method according to any one of claims 19 to 26, wherein the coupling step is carried out in an organic solvent and the coupling step provides a coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane- 1,5-diyl)dicarbamate (III).

28. The method according to claim 27, wherein, after the coupling step, the method further comprises a contacting step of contacting the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III) with one or more aqueous liquids to provide a purified organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III).

29. The method according to claim 28, wherein the purified organic solution of di-tert- butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is concentrated to provide a concentrated organic solution of di-tert-butyl ((S)-6-oxo-6-(((S)- 1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III).

30. The method according to any one of claims 19 to 29, wherein the method is for producing solid di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III), and wherein, after the coupling step, the method further comprises a precipitating step of precipitating the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III).

31. The method according to claim 30, wherein the precipitating step comprises: (i) providing a solution of the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan- 2-yl)amino)hexane-1,5-diyl)dicarbamate (III), and (ii) reducing the solubility of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) in the solution so as to induce precipitation of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III).

32. The method according to claim 31, wherein- the solution of the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) of step (i) is a solution of di- tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III) in a solvent, and - the reducing the solubility of the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) is achieved by addition of an antisolvent; wherein, for example: (a) the solvent is dichloromethane and / or ethyl acetate and / or a C1-C6 alcohol, and the antisolvent is a C5-C9hydrocarbon solvent, for example, n-heptane; or (b) the solvent is a C1-C6alcohol and the antisolvent is water.

33. The method according to any one of claims 30 to 32, wherein the precipitation is crystallisation.

34. A method for producing (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV),the method comprising a deprotection and salt formation step of treating di-tert-butyl ((S)- 6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to any one of claims 28 to 33 with methanesulfonic acid to provide lisdexamfetamine dimesylate.

35. The method according to claim 34, wherein the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to any one of claims 28 to 33 is di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to claim 28 or 29.

36. The method according to claim 34, wherein the di-tert-butyl ((S)-6-oxo-6-(((S)-1- phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to any one of claims 28 to 33 is di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to any one of claims 30 to 33.

37. The method according to claim 34, wherein the method further comprises a providing step of providing the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to any one of claims 28 to 33, wherein, for example, the providing step comprises a method according to any one of claims 28 to 33.

38. The method according to claim 37, wherein the method further comprises a providing step of providing the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to claim 28 or 29, wherein, for example, the providing step comprises a method according to claim 28 or 29.

39. The method according to claim 37, wherein the method further comprises a providing step of providing the di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) obtainable according to any one of claims 30 to 33, wherein, for example, the providing step comprises a method according to any one of claims 30 to 33.

40. The method according to any one of claims 34 to 39, wherein the method is for producing crystalline (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV), and wherein, after the deprotection and salt formation step, the method further comprises a crystallising step of crystallising the (S)-2,6-diamino-N-((S)-1- phenylpropan-2-yl)hexanamide dimethanesulfonate (IV).

41. The method according to claim 40, wherein the crystallising step comprises: (i) providing a solution of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV), and (ii) reducing the solubility of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV) in the solution so as to induce crystallisation of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV).

42. The method according to claim 41, wherein - the solution of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) of step (i) is a solution of (S)-2,6-diamino-N-((S)- 1-phenylpropan-2-yl)hexanamide dimethanesulfonate (IV) in a solvent, wherein the solvent is, for example, a C1-C6 alcohol or a mixture of a C1-C6 alcohol and ethyl acetate, and - the reducing the solubility of the (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV) in the solution is achieved by addition of an antisolvent, for example, ethyl acetate.

43. A method according to claim 34, the method comprising: (a) a reacting step of reacting, in a solvent for the chlorination, (1R,2S)-2- amino-1-phenylpropan-1-ol (I’) or a salt thereof with an electrophilic chlorinating agent to provide (2S)-1-chloro-1-phenylpropan-2-amine hydrochloride (I), wherein the solvent for the chlorination is selected from dichloromethane, 1,2- dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, tetrachloroethylene, and mixtures thereof; (b) a crystallising step of crystallising the (2S)-1-chloro-1-phenylpropan-2- amine hydrochloride (I); (c) a hydrogenation reaction step of hydrogenating the crystalline (2S)-1- chloro-1-phenylpropan-2-amine hydrochloride (I) in the presence of ahydrogenation catalyst to provide (S)-1-phenylpropan-2-amine hydrochloride (IIA); (d) a basification step of treating the (S)-1-phenylpropan-2-amine hydrochloride (IIA) with base to provide (S)-1-phenylpropan-2-amine freebase (II); (e) an acidification step of treating, in a solvent for the acidification, the (S)-1- phenylpropan-2-amine freebase (II) with hydrochloric acid or sulfuric acid to provide a solution of (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB); (f) a crystallising step of crystallising the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or (S)-1-phenylpropan-2-amine sulfate (IIB); (g) a coupling step of coupling the (S)-1-phenylpropan-2-amine hydrochloride (IIA) or the (S)-1-phenylpropan-2-amine sulfate (IIB) with a salt of N2,N6- bis(tert-butoxycarbonyl)-L-lysine (III’) to provide di-tert-butyl ((S)-6-oxo- 6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III), wherein the coupling step is carried out in an organic solvent and the coupling step provides a coupling step reaction mixture comprising di-tert- butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5- diyl)dicarbamate (III); (h) a contacting step of contacting the coupling step reaction mixture comprising di-tert-butyl ((S)-6-oxo-6-(((S)-1-phenylpropan-2- yl)amino)hexane-1,5-diyl)dicarbamate (III) with one or more aqueous liquids to provide a purified organic solution of di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III); (i) an optional precipitating step of precipitating the di-tert-butyl ((S)-6-oxo-6- (((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate (III); and (j) a deprotection and salt formation step of treating the di-tert-butyl ((S)-6- oxo-6-(((S)-1-phenylpropan-2-yl)amino)hexane-1,5-diyl)dicarbamate with methanesulfonic acid to provide (S)-2,6-diamino-N-((S)-1-phenylpropan-2- yl)hexanamide dimethanesulfonate (IV).

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