Process for preparation of lysdexamphetamine

Abstract

An efficient, economical and continuous process for the preparation of L-lysine-D-amphetamine dimesylate is provided.

Description

[0001] The present invention relates to an improved, efficient and economical method for preparing L-lysine-D-amphetamine dimethanesulfonate (also known as lisdexamfetamine dimethanesulfonate). Background Art

[0002] L-Lysine-D-amphetamine dimethanesulfonate (also known as lisdexamfetamine dimethanesulfonate) is used to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD) in adults and children aged 6 years and above. This drug API is also used to treat moderate to severe binge eating disorder (BED). It belongs to the group of drugs known as central nervous system (CNS) stimulants. D-amphetamine is the active metabolite of the prodrug lisdexamfetamine dimethanesulfonate. D-amphetamine is enzymatically released from lisdexamfetamine after contact with red blood cells. This conversion is rate-limited by an enzyme that prevents high blood concentrations of D-amphetamine and reduces the potential for abuse of clinical doses of lisdexamfetamine. The IUPAC name of L-Lysine-D-amphetamine dimethanesulfonate is (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate and has the following chemical structure:

[0003]

[0004] United States Patent (USP) 7,105, No. 486, United States Patent (USP) 7,659, No. 253 and United States Patent (USP) 10,927, No. 068 disclose the method for preparing L-Methionine-D-amfetamine dimethanesulfonate by N, N'-bis-Boc-L-Ls (Boc)-OSu and D-amfetamine free alkali.For example, United States Patent (USP) 10,927, No. 068 discloses and claims to use alkyltetrahydrofuran as the solvent for preparing L-Methionine-D-amfetamine dimethanesulfonate by N, N'-bis-Boc-L-Ls (Boc)-OSu. The inventive method is more economical, because N, N'-bis-Boc-L-Lys (Boc)-OSu is commercially available, and the inventive method further avoids using alkyltetrahydrofuran as the solvent for L-Methionine-D-amfetamine dimethanesulfonate being carried out to medicine manufacturing, and allows to replace reaction solvent efficiently with another kind of solvent during the method.

[0005]

[0006] Solution 1

[0007] The inventive process outlined in Scheme 1 is a more efficient, continuous and convergent manufacturing process that avoids Class 3 solvents for the manufacture of L-Lysine-D-amphetamine dimethanesulfonate. DETAILED DESCRIPTION

[0008] definition

[0009] The term "about" or "approximately" means the acceptable error for a particular value as determined by one of ordinary skill in the art, which error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0010] The term "ambient temperature" means one or more room temperatures between about 15°C and about 30°C, such as about 15°C to about 25°C.

[0011] The term "consisting of is inclusive and excludes additional unrecited elements or method steps from the claimed invention.

[0012] The term "consisting essentially of is semi-closed and occupies a middle ground between "consisting of" and "comprising." "Consisting essentially of does not exclude the presence of additional non-recited elements or method steps that do not materially affect one or more essential characteristics of the claimed invention.

[0013] The term "comprising" is inclusive or open-ended and does not exclude additional unrecited elements or method steps from the claimed invention. The term is synonymous with "including but not limited to." The term "comprising" encompasses three alternatives, namely (i) "including," (ii) "consisting of," and (iii) "consisting essentially of."

[0014] Group " Boc " refers to the tertbutyloxycarbonyl protecting group that is used for protecting amine groups in organic synthesis.Term API refers to active pharmaceutical ingredient, and this active pharmaceutical ingredient is L-lysine-D-amphetamine free alkali or L-lysine-D-amphetamine dimethanesulfonate in the present invention.

[0015] The disclosure provides a kind of for preparing L-lysine-D-amphetamine dimethanesulfonate (dimethylsulfonic acid lisdexamfetamine) by D-amphetamine sulfate efficient, convergent and continuous method.The protected intermediate formed during the building-up process in two-phase solvent mixture (ethyl acetate and water) is by processing with sodium carbonate, sodium chloride aqueous solution, carrying out the solvent exchange of ethyl acetate with n-propyl alcohol and fine filtration before adding methylsulfonic acid to purify (therefore, eliminated the needs to the separation of expensive industrial chromatography and problematic intermediate), is dried by component distillation.Do not separate, until obtain crystallization dimethylsulfonic acid lisdexamfetamine wet cake in the following manner: add crystal seed, wash with n-propyl alcohol subsequently and heat drying under vacuum.The crystallization dimethylsulfonic acid lisdexamfetamine produced is the pure API obtained with high yield.Method as herein described has industrial applicability, further improves productive rate (for example, minimum separation) and safety (for example, eliminates 3 class solvents, such as alkyltetrahydrofuran).

[0016] The continuous process as outlined in Scheme 1 comprises: (a) converting D-amphetamine sulfate to D-amphetamine as a free base; (b) adding D-amphetamine to a two-phase reaction mixture comprising ethyl acetate, water and N,N'-bis-Boc-L-lysine succinimide or N,N'-bis-Boc-L-Lys(boc)-OSu to form an intermediate compound, which is N,N'-bis-Boc-L-lysine-D-amphetamine; and then, after step (b), reacting with one or more aqueous solutions (Na2C N'-bis--Boc-L-L-Lysine-D-amfetamine; And finally add methylsulfonic acid to form L-Lysine-D-amfetamine dimethanesulfonate, use seed crystallization to make its crystallization so that crystallization L-Lysine-D-amfetamine dimethanesulfonate is provided.

[0017] According to one embodiment of the present invention, disclose a kind of continuous process for the preparation of L-lysine-D-amphetamine dimethanesulfonate, this continuous process may further comprise the steps: (a) make the D-amphetamine free alkali with following structure

[0018]

[0019] with at least about two equivalents of N,N'-bis-Boc-L-Lys(Boc)-OSu having the structure

[0020]

[0021] The reaction was carried out in a two-phase mixture of ethyl acetate and water, which was heated from 25°C to 35°C with stirring to form N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine having the following structure as well as

[0022] (b) adding about 1 equivalent of sodium bicarbonate, then separating and removing the aqueous layer of this two-phase mixture, and using n-propyl alcohol as the ethyl acetate portion comprising this N,N'-bis-Boc-L-lysine (Boc)-D-amfetamine of this two-phase mixture of solvent replacement, then adding at least about two equivalents to about ten equivalents of methylsulfonic acid, while heating until 90 ℃ and stirring, to produce product L-lysine-D-amfetamine dimethanesulfonate.

[0023] In a separate embodiment, in step (a), D-amphetamine free alkali and approximately two equivalents of N, N '-bis--Boc-Lys (Boc)-OSu are reacted in a two-phase mixture of ethyl acetate and water.This reaction of step (a) was stirred 1 hour to 2 hours, and this mixture was heated to 35 ℃ from 25 ℃.In step (b), N, N '-bis--Boc-L-lysine-D-amphetamine and approximately two equivalents to the methylsulfonic acid of approximately 10 equivalents react in n-propyl alcohol.

[0024] In an exemplary embodiment, the solvent used according to the present invention is a two-phase mixture of water and an organic solvent with limited water solubility. Suitable solvents include ethyl acetate, butyl acetate, benzene, n-butanol, n-propanol, cyclohexane, 1,2-dichloroethane, dichloromethane, ethyl acetate, diethyl ether, heptane, hexane, methyl tert-butyl ether, methyl ethyl ketone, pentane, diisopropyl ether, toluene and xylene. In a specific embodiment, the solvent used in step (a) is ethyl acetate and water, and in step (b), ethyl acetate is replaced by n-propanol.

[0025] The amount of solvent added to the reaction mixture depends on the weight of the reactants. Generally speaking, the weight ratio of solvent to reactant in step (a) can range from about 2:1 to about 70:1. In some embodiments, the weight ratio of solvent to reactant in step (a) can range from about 3:1 to about 50:1, about 4:1 to about 20:1, about 5:1 to about 15:1, or about 6:1 to about 10:1.

[0026] In another embodiment, a continuous process for the preparation of L-lysine-D-amphetamine dimethanesulfonate is provided, the continuous process comprising the steps of: (a) making the D-amphetamine free alkali with the following structure

[0027]

[0028] With about two equivalents of N,N'-bis-Boc-Lys(Boc)-OSu having the following structure

[0029]

[0030] The reaction is carried out in a two-phase mixture of ethyl acetate and water, and the mixture is heated from 25° C. to 35° C. for 1 to 2 hours with stirring to form N,N′-bis-Boc-L-lysine (Boc)-D-amphetamine having the following structure as well as

[0031] (b) adding about 1 equivalent of sodium bicarbonate and stirring the two-phase mixture for up to 1 hour, maintaining the temperature of the stirred mixture at 20° C. to 25° C., and then separating and removing the aqueous layer of the two-phase mixture;

[0032] (c) after removing the aqueous layer of the two-phase mixture in step (b), further washing the ethyl acetate portion of the two-phase mixture containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine with an aqueous sodium chloride solution, and stirring the two-phase mixture formed again for up to 1 hour, maintaining the temperature of the stirred mixture at 20°C to 25°C, and then separating and removing the aqueous layer of the two-phase mixture formed;

[0033] (d) after removing the aqueous layer of the two-phase mixture in step (c), displacing the ethyl acetate portion of the two-phase mixture containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine by concentrating the ethyl acetate under vacuum distillation and heating to 60°C, and adding n-propanol as the displacement solvent containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine;

[0034] (e) fine filtering the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in n-propanol solvent from step (d) to remove any residual inorganic salts;

[0035] (f) adding about two to ten equivalents of methanesulfonic acid to the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in n-propanol solvent from step (e) and heating the mixture from 85°C to 100°C.

[0036] Heating to 90° C. while stirring for 1 to 2 hours to produce the product L-lysine-D-amphetamine dimethanesulfonate;

[0037] (g) cooling this L-Lysine-D-amphetamine dimethanesulfonate product from step (f), and adding the crystallization L-Lysine-D-amphetamine dimethanesulfonate of 1 % by weight as crystal seed, so that this L-Lysine-D-amphetamine dimethanesulfonate product crystallization; And

[0038] (h) with at least a portion of the n-propyl alcohol solvent washing crystallized L-Methionine-D-amphetamine dimethanesulfonate product, under 50 ℃, dry the crystallized L-Methionine-D-amphetamine dimethanesulfonate product under vacuum subsequently.

[0039] In some embodiments, L-lysine-D-amphetamine dimethanesulfonate product is prepared by amphetamine salt in a continuous process.In one embodiment, amphetamine salt is D-amphetamine sulfate.The non-limitative example of suitable amphetamine salt comprises amphetamine bitartrate, amphetamine sulfate, amphetamine aspartate, amphetamine sucrose salt, amphetamine hydrochloride and amphetamine phosphate.In independent embodiment, L-lysine-D-amphetamine dimethanesulfonate product is prepared by amphetamine salt, and this amphetamine salt is first converted into free alkali by contacting with alkali, with the solvent extraction used in the method subsequently.Suitable alkali includes but not limited to the hydroxide of alkali metal and alkaline earth metal, such as sodium hydroxide, sodium carbonate, salt of wormwood or potassium hydroxide.In exemplary embodiments, use sodium carbonate to convert D-amphetamine sulfate into D-amphetamine free alkali.

[0040] In some embodiments, make N in n-propyl alcohol solvent, N'-bis-Boc-L-lysine (Boc)-D-amfetamine and about two equivalents to about ten equivalents of pharmaceutically acceptable acid reaction, and mixture is heated to 90 ℃ from 85 ℃, stirred 1 hour to 2 hours simultaneously, to produce the product L-lysine-D-amfetamine as acid addition salt.In one embodiment, acid is methylsulfonic acid and the API of production is product L-lysine-D-amfetamine mesylate.Contact with acid and remove the Boc blocking group and form the acid salt of compound from N, N'-bis-Boc-L-lysine (Boc)-D-amfetamine.The non-limitative example of suitable acid comprises methylsulfonic acid, hydrochloric acid, oxalic acid.In a particular embodiment, acid can be methylsulfonic acid.

[0041] The amount of methanesulfonic acid added to the purified mixture of N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine can be in the range of about 1:1 to about 10:1. In some embodiments, the molar ratio of acid to N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine can range from about 2:1 to about 10:1 or from about 2:1 to about 6:1.

[0042] Contacting with the acid is typically conducted at a temperature in the range of about 40° C. to about 100° C. In some embodiments, the temperature can range from about 60° C. to about 90° C., about 80° C. to about 90° C., or about 85° C. to about 90° C. The duration of contacting with the acid at the elevated temperature can be at least about 2 hours, at least about 4 hours, at least about 8 hours, at least about 12 hours, or at least about 24 hours.

[0043] The gained API L-Lysine-D-amphetamine as acid salt can be cooled to envrionment temperature or room temperature then.In one embodiment, API L-Lysine-D-amphetamine mesylate is used (by weight up to 1%) crystal as crystal seed so that the L-Lysine-D-amphetamine mesylate crystallization.By filtering, centrifugal or other suitable modes the crystallization wet cake is separated with solvent / acid mixture.Buchner funnel, filter funnel or other filter aids can be used to filter to finish.Filtering can be gravity filtration or vacuum filtration.The product of filtering can be the n-propyl alcohol solvent washing that uses in this method.The final product can be in vacuum oven or drying oven about 50 ℃ to about 80 ℃ temperature range under dry about 0.5 hour to about 12 hours.

[0044] The embodiments and / or optional features of the present invention have been described above. Unless the context otherwise requires, any aspect of the present invention may be combined with any other aspect of the present invention. Unless the context otherwise requires, any of the embodiments or optional features of any aspect may be combined with any aspect of the present invention, alone or in combination.

[0045] The invention will now be further described with reference to the following examples, which are intended to illustrate but not to limit the scope of the invention.

[0046] Example

[0047] abbreviation

[0048] API active pharmaceutical ingredient

[0049] EtOAc

[0050] n-PrOH n-Propanol (1-Propanol)

[0051] RT ambient temperature

[0052] Example 1

[0053] D-amphetamine free base from D-amphetamine sulfate

[0054]

[0055] D-amphetamine sulfate (100.0g, 1.0 equivalents) and ethyl acetate (500mL, 5 volumes) are added the 3L glass jacketed reactor (container 1) (it is equipped with overhead stirring, temperature probe, nitrogen inlet and addition funnel) of cleaning, to obtain white slurries.Use addition funnel in 15 minutes, aqueous sodium carbonate (31.64g, 1.1 equivalents among the 150mL, in 1.5 volumes of water) add reactor, keep 25 ℃ ± 5 ℃ of internal temperatures simultaneously.Mixture was stirred 60 minutes down at 25 ℃ ± 5 ℃, to produce the muddy two-phase mixture of D-amphetamine free alkali.In 5 minutes, deionized (DI) water (50.0ml, 0.5 volume) was added reactor.

[0056] Example 2

[0057] Conjugation of Free D-Amphetamine with N,N'-Bis-Boc-L-Lysine (Boc)-OSu

[0058]

[0059] N,N'-bis-Boc-Lys(Boc)-OSu (1263 g, 2.1 equiv) was added to a separate 1 L glass jacketed reactor (Container 2) equipped with overhead stirring, a temperature probe, a nitrogen inlet, and an addition funnel. Ethyl acetate (900 mL, 9 vol) was added to Container 2 and heated until dissolved. Dissolution of N,N'-bis-Boc-Lys(Boc)-OSu occurred at 36°C. The N,N'-bis-Boc-Lys(Boc)-OSu solution in Container 2 was quickly filtered through a preheated 250 mL fritted glass filter into a preheated 1 L 3-neck round bottom flask (Container 3). Container 2 was rinsed with ethyl acetate (100 mL, 1 vol) and the rinse was transferred to Container 3 through a preheated 250 mL fritted glass filter.

[0060] Container 3 is maintained at a temperature of 35° C. on a heating block attached to a hot plate. The N, N'-bis-Boc-Lys (Boc) -OSu solution in container 3 is transferred to container 1 via cannula over 60 minutes, maintained at 25° C. ± 5° C., to obtain a turbid two-phase mixture that becomes clear during the reaction to produce N, N'-bis-Boc-L-lysine (Boc) -D- amphetamine in the ethyl acetate portion / phase of the two-phase mixture and N-hydroxysuccinimide (NHS) as a by-product in the aqueous portion / phase of the two-phase mixture. The reaction is stirred at 25° C. ± 5° C. for 1.5 hours, and the organic layer is sampled to complete the reaction.

[0061] Example 3

[0062] Removal of NHS from N,N'-Bis-Boc-L-lysine (Boc)-D-amphetamine

[0063]

[0064] An aqueous solution of sodium carbonate (31.64 g, 1.1 equivalents in 500 mL, 5.0 volumes of water) was added to the reactor using an addition funnel over 15 minutes while maintaining 20° C. to 25° C. After stirring at 20° C. to 25° C. for 15 minutes, stirring was stopped, the layers were separated, and the bottom aqueous layer was removed. The organic layer was sampled for complete removal of N-hydroxysuccinimide (NHS).

[0065]

[0066] A 20 wt% aqueous sodium chloride solution (200 mL, 2 volumes) was added to the reactor at 20-25° C. After stirring at 20-25° C. for 15 minutes, stirring was stopped, the layers were separated, and the bottom aqueous layer was removed.

[0067] Example 4

[0068] N,N'-Bis-Boc-L-lysine (Boc)-D-amphetamine: Solvent exchange of ethyl acetate with n-propanol

[0069]

[0070] By vacuum distillation with the ethyl acetate (organic phase) of N, N'-bis-Boc-L-lysine (Boc)-D-amfetamine from embodiment 4, be concentrated into 1000mL (10.0 volumes), maintaining the temperature is 60 ℃.Solvent n-propyl alcohol (1000mL, 10 volumes) is added in reactor, keeps 40 ℃ ± 5 ℃, and is concentrated into 500mL (10.0 volumes) by vacuum distillation, maintaining the temperature is 60 ℃.N-propyl alcohol (1000mL, 10 volumes) is further packed into reactor, keeps 40 ℃ ± 5 ℃, and is concentrated into 1000mL (10.0 volumes) by vacuum distillation, maintaining the temperature is 60 ℃.Mixture is sampled to obtain residual ethyl acetate and water.

[0071] Example 5

[0072] Fine Filtration of N,N'-Bis-Boc-L-Lysine (Boc)-D-Amphetamine

[0073]

[0074] The n-propanol solution of N,N′-bis-Boc-L-lysine (Boc)-D-amphetamine from Example 4 was finely filtered (0.2 μm) through a fritted funnel under vacuum to remove inorganic salts.

[0075] Example 6

[0076] Addition of Methanesulfonic Acid to N,N'-Bis-Boc-L-Lysine (Boc)-D-Amphetamine

[0077]

[0078] With from embodiment 5 N, N '-bis--Boc-L-lysine (Boc)-D-amfetamine n-propyl alcohol solution through fine filtration with propyl alcohol flushing (300mL, 3 volumes) be transferred to the 2L jacketed reactor (Temperature Setting is 40 ℃) of cleaning (it is equipped with overhead stirring (PTFE, 4 blade spacings), temperature probe, condenser, nitrogen inlet and addition funnel), to obtain settled solution.Solvent n-propyl alcohol (700mL, 7 volumes) is added reactor.Solution is sampled to obtain purity.Solution is heated to 90 ℃ ± 3 ℃ (T j =97 ℃). In 60 minutes, methylsulfonic acid (260.8g, 176.1mL, 10.0 equivalents) was added drop-wise to the reaction via addition funnel (slight heat release).Observe CO and the outgassing of isobutylene.To react at 90 ℃ ± 3 ℃ and kept 60 minutes, to produce API L-lysine-D-amphetamine dimethanesulfonate, and it is sampled to complete the reaction.

[0079] Example 7

[0080] Seeded crystallization of API L-lysine-D-amphetamine dimethanesulfonate

[0081]

[0082] To be cooled to 85 ℃ and stirred 10 minutes from the reaction of embodiment 6.Add crystallization dimesylic acid lisdexamfetamine (12.50g, 1 % by weight) as crystal seed for crystallization.If crystal seed continues the crystallization of API, then by mixture stirring one hour, then cool off as described in step 23.

[0083] If the seed crystals do not continue to crystallize, the mixture is cooled to 80°C and stirred for 10 minutes. Further lisdexamfetamine dimesylate (2.50 g, 1 wt %) is added as a seed crystal for crystallization. The mixture is cooled and seed crystals are added in increments of 5°C until the seed crystals continue to crystallize. The mixture is then cooled as described. The slurry is cooled to 60°C ± 2°C over 10 hours and then cooled to 20°C over 4 hours. The slurry of API is stirred at 20°C for 8 hours. The slurry is filtered (rapid filtration), washed twice with n-propanol (2×300 mL, 2×3 volumes), and dried under vacuum. During vacuum drying, a nitrogen flow is maintained due to the hygroscopicity of the solid. Yield: 226.3 g, 91.5%

Claims

1. a method for the preparation of L-lysine-D-amphetamine dimethanesulfonate, said method comprising the steps of: (a) making the D-amphetamine free base with the following structure With about two equivalents of N,N'-bis-Boc-L-Lys(Boc)-OSu having the following structure The reaction was carried out in a two-phase mixture of ethyl acetate and water, which was heated from 25° C. to 35° C. with stirring to form N,N′-bis-Boc-L-lysine (Boc)-D-amphetamine having the structure (b) adding about 1 equivalent of sodium bicarbonate, then separating and removing the aqueous layer of the two-phase mixture, and using n-propyl alcohol as the ethyl acetate portion comprising the N,N'-bis-Boc-L-lysine (Boc)-D-amfetamine of the two-phase mixture for solvent replacement, then adding about two equivalents to about 10 equivalents of methylsulfonic acid, while heating until 90°C and stirring, to produce the product L-lysine-D-amfetamine dimethanesulfonate.

2. The method according to claim 1, wherein the reaction of step (a) is stirred for 1 to 2 hours while the mixture is heated from 25°C to 35°C.

3. The process of claim 1, wherein in step (b), after the addition of sodium bicarbonate, the two-phase mixture is stirred for up to 1 hour, maintaining the temperature of the stirred mixture at 20°C to 25°C.

4. The method of claim 3 , wherein in step (b), after removing the aqueous layer of the two-phase mixture, the ethyl acetate portion of the two-phase mixture comprising the N,N′-bis-Boc-L-lysine (Boc)-D-amphetamine is further washed with aqueous sodium chloride solution, and the two-phase mixture formed is stirred for up to 1 hour, the temperature of the stirred mixture is maintained at 20° C. to 25° C., the aqueous layer of the formed two-phase mixture is then separated and removed, and the ethyl acetate portion of the two-phase mixture comprising the N,N′-bis-Boc-L-lysine (Boc)-D-amphetamine is subsequently replaced with n-propyl alcohol as the solvent.

5. method according to claim 4, wherein in step (b), before adding described methylsulfonic acid, make described N, N'-bis-Boc-L-lysine (Boc)-D-amfetamine experience fine filtration in n-propyl alcohol to remove any inorganic salt.

6. method according to claim 5, wherein in step (b), about two equivalents to about ten equivalents of methylsulfonic acid are added to the described N in n-propyl alcohol solvent, N'-bis-Boc-L-Methionine (Boc)-D-amfetamine, described mixture is heated to 90 ℃ from 85 ℃, stirred simultaneously 1 hour to 2 hours, to produce described product L-Methionine-D-amfetamine dimethanesulfonate.

7. The method according to claim 1, further comprising the steps of: (c) add the L-Lysine-D-amphetamine dimethanesulfonate crystal seed of 1 % by weight, the described mixture of cooling step (b) simultaneously, to help make the described L-Lysine-D-amphetamine dimethanesulfonate product crystallization.

8. The method according to claim 7, further comprising: With at least a portion of the n-propyl alcohol solvent washing crystallized L-Methionine-D-amphetamine dimethanesulfonate product, under 50 ℃, dry the crystallized L-Methionine-D-amphetamine dimethanesulfonate product under vacuum subsequently.

9. a method for the preparation of L-lysine-D-amphetamine dimethanesulfonate, said method comprising the steps of: (a) making the D-amphetamine free base with the following structure With about two equivalents of N,N'-bis-Boc-Lys(Boc)-OSu having the following structure The reaction is carried out in a two-phase mixture of ethyl acetate and water, which is heated from 25° C. to 35° C. with stirring for 1 to 2 hours to form N,N′-bis-Boc-L-lysine (Boc)-D-amphetamine having the following structure (b) adding about 1 equivalent of sodium bicarbonate and stirring the two-phase mixture for up to 1 hour, maintaining the temperature of the stirred mixture at 20° C. to 25° C., and then separating and removing the aqueous layer of the two-phase mixture; (c) after removing the aqueous layer of the two-phase mixture in step (b), further washing the ethyl acetate portion of the two-phase mixture containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine with an aqueous sodium chloride solution, and stirring the two-phase mixture formed again for up to 1 hour, maintaining the temperature of the stirred mixture at 20°C to 25°C, and then separating and removing the aqueous layer of the two-phase mixture formed; (d) after removing the aqueous layer of the two-phase mixture in step (c), displacing the ethyl acetate portion of the two-phase mixture containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine by concentrating the ethyl acetate under vacuum distillation and heating to 60°C, and adding n-propanol as the displacement solvent containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine; (e) fine filtering the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in n-propanol solvent from step (d) to remove any residual inorganic salts; (f) adding about two equivalents to about ten equivalents of methanesulfonic acid to the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in n-propanol solvent from step (e), and heating the mixture from 85°C to 90°C while stirring for 1 to 2 hours to produce the product, L-lysine-D-amphetamine dimethanesulfonate; (g) cooling the described L-Lysine-D-amphetamine dimethanesulfonate product from step (f), and adding the crystallization L-Lysine-D-amphetamine dimethanesulfonate of 1 % by weight as crystal seed, so that the described L-Lysine-D-amphetamine dimethanesulfonate product crystallization; And (h) with at least a portion of the n-propyl alcohol solvent washing crystallized L-Methionine-D-amphetamine dimethanesulfonate product, under 50 ℃, dry the crystallized L-Methionine-D-amphetamine dimethanesulfonate product under vacuum subsequently.

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