Process for the preparation of lisdexamfetamine

Abstract

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

Description

Technical Field

[0001] The present invention relates to an improved, efficient and economic process for preparing L-lysine-D-amphetamine dimesylate (also referred to as lisdexamfetamine dimesylate).

Background Art

[0002] L-lysine-D-amphetamine dimesylate (also referred to as lisdexamfetamine dimesylate) is used to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD) in adults and children aged 6 years and older. This pharmaceutical API is also used to treat moderate to severe binge eating disorder (BED). It belongs to a group of drugs called central nervous system (CNS) stimulants. D-amphetamine is the active metabolite of the prodrug lisdexamfetamine dimesylate. D-amphetamine is enzymatically released from lisdexamfetamine after contact with red blood cells. This conversion is rate-limited by an enzyme, preventing high blood levels of D-amphetamine and reducing the potential for abuse of lisdexamfetamine at clinical doses. L-lysine-D-amphetamine dimesylate has the IUPAC name (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimesylate and has the following chemical structure.

[0003]

Chemical Formula

[0004] U.S. Patents 7,105,486, 7,659,253, and 10,927,068 disclose methods for preparing L-lysine-D-amphetamine dimesylate from N,N'-bis-Boc-L-Lys(Boc)-OSu and D-amphetamine free base. For example, U.S. Patent 10,927,068 discloses and claims the use of alkyltetrahydrofuran as a solvent for preparing L-lysine-D-amphetamine dimesylate from N,N'-bis-Boc-L-Lys(Boc)-OSu. The invented process is more economical because N,N'-bis-Boc-L-Lys(Boc)-OSu is commercially available, and the invented process further avoids the use of alkyltetrahydrofuran as a solvent for the pharmaceutical production of L-lysine-D-amphetamine dimesylate, and allows for the efficient replacement of the reaction solvent with another solvent during the process.

[0005] [ka]

[0006] The invented process, summarized in Scheme 1, is a more efficient, continuous, and convergent manufacturing process that avoids Class 3 solvents for the production of L-lysine-D-amphetamine dimesylate. [Modes for carrying out the invention]

[0007] definition The terms “about” or “approximately” mean an acceptable error to a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms “about” or “approximately” mean within one, two, three, or four standard deviations. In certain embodiments, the terms “about” or “approximately” mean within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0008] The term "ambient temperature" refers to one or more room temperatures between approximately 15°C and 30°C, such as approximately 15°C to approximately 25°C.

[0009] The term "consisting" is restrictive and excludes any additional, unlisted elements or process steps in the claimed invention.

[0010] The term "consisting essentially of" is semi-restrictive and occupies an intermediate position between "consisting of" and "comprising." "Consisting essentially of" does not exclude additional unlisted elements or method steps that do not materially affect the essential characteristics of the claimed invention.

[0011] The term “comprising” is either comprehensive or non-exclusive and does not exclude any additional unlisted elements or method steps in the claimed invention. This term is synonymous with “including, but not limited to.” The term “comprising” encompasses three alternatives: (i) “comprising,” (ii) “consisting,” and (iii) “consisting essentially of.”

[0012] The "Boc" group refers to the tert-butyloxycarbonyl protecting group used to protect amine groups in organic synthesis. The term API refers to an active pharmaceutical ingredient, which in this invention is L-lysine-D-amphetamine free base or L-lysine-D-amphetamine dimesylate.

[0013] This disclosure provides an efficient, convergent, and continuous process for preparing L-lysine-D-amphetamine dimesylate (lisdexamfetamine dimesylate) from D-amphetamine sulfate. The protected intermediate formed during the synthesis process in a two-phase solvent mixture of ethyl acetate and water is purified by polishing filtration before treatment with sodium carbonate, aqueous sodium chloride, solvent substitution of ethyl acetate with n-propanol, and addition of methanesulfonic acid (thus eliminating the need for expensive industrial chromatography and isolation of problematic intermediates), and dried by azeotropic distillation. Isolation is not performed until a wet cake of crystalline lisdexamfetamine dimesylate is obtained by adding seed crystals, followed by washing with n-propanol and drying under vacuum while heating. The resulting crystalline lisdexamfetamine dimesylate is a pure API obtained in high yield. The process described herein has industrial applicability, along with further improvements in yield (e.g., minimal isolation) and safety (e.g., elimination of Class 3 solvents such as alkyltetrahydrofuran).

[0014] The sequential process summarized in Scheme 1 is: (a) converting D-amphetamine sulfate to D-amphetamine as a free base; (b) adding D-amphetamine to a two-phase reaction mixture containing ethyl acetate, water, and N,N'-bis-Boc-L-lysine succinimide or N,N'-bis-Boc-L-lysine(boc)-OSu to form an intermediate compound which is N,N'-bis-Boc-L-lysine-D-amphetamine; and then, after step (b), using one or more aqueous solutions (Na2CO3, NaCl) to perform a two-phase reaction. The method comprises: phase extraction of N,N'-bis-Boc-L-lysine-D-amphetamine from the reaction mixture; solvent substitution with ethyl acetate and n-propanol; and removal by polishing filtration to remove the starting reaction products and reaction by-products, thereby forming a purified mixture containing the intermediate compound N,N'-bis-Boc-L-lysine-D-amphetamine; and finally, addition of methanesulfonic acid to form L-lysine-D-amphetamine dimesylate, which is crystallized using seed crystallization to obtain crystalline L-lysine-D-amphetamine dimesylate.

[0015] According to one embodiment of the present invention, a continuous process for preparing L-lysine-D-amphetamine dimesylate, comprising (a) a D-amphetamine free base having the following structure

[0016] [ka] This has at least about 2 equivalents of N,N'-bis-Boc-L-Lys(Boc)-OSu having the following structure.

[0017] [ka] The process involves reacting the mixture in a two-phase mixture of ethyl acetate and water, heating the mixture to 25°C to 35°C while stirring, to form N,N'-bis-Boc-L-lysine(Boc)-D-amphetamine having the following structure,

[0018] [ka] (b) Add about 1 equivalent of sodium bicarbonate, then separate and remove the aqueous layer of the biphasic mixture, then replace the ethyl acetate portion of the biphasic mixture containing N,N'-bis-Boc-L-lysine(Boc)-D-amphetamine with n-propanol as the solvent, then add at least about 2 to about 10 equivalents of methanesulfonic acid while heating to a maximum of 90 °C and stir to afford the product L-lysine-D-amphetamine dimethanesulfonate, and a continuous process is disclosed that includes the step of:

[0019] In a separate embodiment, in step (a), the D-amphetamine free base is reacted with about 2 equivalents of N,N'-bis-Boc-Lys(Boc)-OSu in a biphasic mixture of ethyl acetate and water. The reactants in step (a) are heated to 25 °C to 35 °C and stirred for 1 to 2 hours. In step (b), N,N'-bis-Boc-L-lysine-D-amphetamine is reacted with about 2 to about 10 equivalents of methanesulfonic acid in n-propanol.

[0020] In an exemplary embodiment, according to the present invention, the solvent used is a biphasic mixture of water with an organic solvent having 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-t-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 with n-propanol.

[0021] The amount of solvent added to the reaction mixture depends on the weight of the reactants. Generally, the weight ratio of the solvent to the reactants in step (a) can range from about 2:1 to about 70:1. In some embodiments, the weight ratio of the solvent to the reactants in step (a) can range from about 3:1 to about 50:1, from about 4:1 to about 20:1, from about 5:1 to about 15:1, or from about 6:1 to about 10:1.

[0022] In another embodiment, a continuous process for preparing L-lysine-D-amphetamine dimesylate, comprising: (a) D-amphetamine free base having the following structure

[0023]

Chemical formula

[0024]

Chemical formula

[0025]

Chemical formula

[0026] In some embodiments, the L-lysine-D-amphetamine dimesylate product is prepared from an amphetamine salt in a continuous process. In one embodiment, the amphetamine salt is D-amphetamine sulfate. Non-limiting examples of suitable amphetamine salts include amphetamine bitartrate, amphetamine sulfate, amphetamine aspartate, amphetamine saccharinate, amphetamine hydrochloride, and amphetamine phosphate. In another embodiment, the L-lysine-D-amphetamine dimesylate product is prepared from an amphetamine salt, which is first converted to a free base by contact with a base and then extracted with the solvent used in this process. Suitable bases include, but are not limited to, sodium hydroxide, sodium carbonate, potassium carbonate, or alkali metal and alkaline earth metal hydroxides such as potassium hydroxide. In an exemplary embodiment, D-amphetamine sulfate is converted to D-amphetamine free base using sodium carbonate.

[0027] In some embodiments, N,N'-bis-Boc-L-lysine(Boc)-D-amphetamine in n-propanol solvent is reacted with about 2 to about 10 equivalents of a pharmaceutically acceptable acid, and the mixture is heated to 85°C to 90°C with stirring for 1 to 2 hours to yield the product L-lysine-D-amphetamine as an acid addition salt. In one embodiment, the acid is methanesulfonic acid, and the resulting API is the product L-lysine-D-amphetamine mesylate. Contact with the acid removes the Boc protecting group from N,N'-bis-Boc-L-lysine(Boc)-D-amphetamine, forming an acid salt of the compound. Non-limiting examples of suitable acids include methanesulfonic acid, hydrochloric acid, and oxalic acid. In specific embodiments, the acid may be methanesulfonic acid.

[0028] The amount of methanesulfonic acid added to the purified mixture of N,N'-bis-Boc-L-lysine(Boc)-D-amphetamine may range from 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 may range from about 2:1 to about 10:1, or from about 2:1 to about 6:1.

[0029] Contact with the acid is generally carried out at temperatures in the range of about 40°C to about 100°C. In some embodiments, the temperature may be in the range of 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 contact with the acid at high temperatures may proceed for 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.

[0030] The resulting API L-lysine-D-amphetamine as an acid addition salt can then be cooled to ambient temperature or room temperature. In one embodiment, the API L-lysine-D-amphetamine mesylate is subjected to seed crystal addition (up to 1% by weight) of crystals to crystallize the L-lysine-D-amphetamine mesylate. The crystalline wet cake is isolated from the solvent / acid mixture by filtration, centrifugation, or other suitable means. Filtration can be achieved using a Buchner funnel, a filtration funnel, or other filtration aids. Filtration can be gravity filtration or vacuum filtration. The filtered product can be washed with the n-propanol solvent used in this process. The final product can be dried in a vacuum oven or drying oven at a temperature in the range of about 50°C to about 80°C for about 0.5 to about 12 hours.

[0031] Embodiments and / or optional features of the present invention are described above. Any aspect of the present invention may be combined with any other aspect of the present invention unless otherwise required by context. Any embodiment or optional feature of any aspect may be combined with any aspect of the present invention, individually or in combination, unless otherwise required by context.

[0032] The present invention will be further described with reference to the following examples, which are intended to illustrate rather than limit the invention. [Examples]

[0033] Abbreviation API Active Pharmaceutical Ingredients HCl ethyl acetate n-PrOH n-propanol (1-propanol) RT ambient temperature

[0034] Example 1 D-amphetamine free base from D-amphetamine sulfate

[0035] [ka]

[0036] D-amphetamine sulfate (100.0 g, 1.0 equivalent) and ethyl acetate (500 mL, 5 volumes) were added to a clean 3 L glass-coated reactor (Vessel 1) equipped with overhead stirring, a temperature probe, a nitrogen inlet, and an addition funnel to produce a white slurry. While maintaining an internal temperature of 25 ± 5 °C, aqueous sodium carbonate (31.64 g, 1.1 equivalents in 150 mL of water, 1.5 volumes) was added to the reactor over 15 minutes using the addition funnel. The mixture was stirred at 25 ± 5 °C for 60 minutes to produce a turbid two-phase mixture of free D-amphetamine base. Deionized (DI) water (50.0 mL, 0.5 volumes) was added to the reactor over 5 minutes.

[0037] Example 2 D-amphetamine release and coupling with N,N'-bis-Boc-L-lysine (Boc)-OSu

[0038] [ka]

[0039] N,N'-bis-Boc-Lys(Boc)-OSu (1263 g, 2.1 equivalents) was added to a separate 1 L glass-coated reactor (Vessel 2) equipped with overhead stirring, a temperature probe, a nitrogen inlet, and an addition funnel. Ethyl acetate (900 mL, 9 vol) was added to Vessel 2 and heated until dissolution occurred. Dissolution of N,N'-bis-Boc-Lys(Boc)-OSu occurred at 36°C. The N,N'-bis-Boc-Lys(Boc)-OSu solution in Vessel 2 was rapidly filtered through a preheated 250 mL frit glass filter into a preheated 1 L three-necked round-bottom flask (Vessel 3). Vessel 2 was rinsed with ethyl acetate (100 mL, 1 vol), and the rinse solution was transferred to Vessel 3 through a preheated 250 mL frit glass filter.

[0040] Container 3 was maintained at a temperature of 35°C on a heating block attached to a hot plate. The solution of N,N'-bis-Boc-Lys(Boc)-OSu in container 3 was transferred to container 1 via a cannula over 60 minutes while maintaining a temperature of 25±5°C, producing a turbid two-phase mixture, which became clear throughout the reaction. N,N'-bis-Boc-L-lysine(Boc)-D-amphetamine was produced in the ethyl acetate portion / phase of the two-phase mixture, and N-hydroxysuccinimide (NHS) was produced as a byproduct in the aqueous portion / phase of the two-phase mixture. The reaction mixture was stirred at 25±5°C for 1.5 hours, and the organic layer was sampled for completion.

[0041] Example 3 Removal of NHS from N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine

[0042] [ka]

[0043] While maintaining a temperature of 20-25°C, aqueous sodium carbonate (31.64 g, 1.1 equivalents in 500 mL, 5.0 volumes of water) was added to the reactor over 15 minutes using an addition funnel. After stirring for 15 minutes at 20-25°C, stirring was stopped, the layers were separated, and the aqueous layer at the bottom was removed. The organic layer was sampled to ensure complete removal of N-hydroxysuccinimide (NHS).

[0044] [ka]

[0045] A 20% by weight aqueous solution of sodium chloride (200 mL, 2 volumes) was added to the reactor at 20-25°C. After stirring for 15 minutes at 20-25°C, stirring was stopped, the layers were separated, and the aqueous layer at the bottom was removed.

[0046] Example 4 N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine: Solvent replacement of ethyl acetate with n-propanol

[0047] [ka]

[0048] The ethyl acetate (organic phase) of N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine from Example 4 was concentrated to 1000 mL (10.0 vol) by vacuum distillation while maintaining a temperature of 60°C. The solvent n-propanol (1000 mL, 10 vol) was added to the reactor while maintaining a temperature of 40±5°C and concentrated to 500 mL (10.0 vol) by vacuum distillation while maintaining a temperature of 60°C. Another 1000 mL (10 vol) of n-propanol was added to the reactor while maintaining a temperature of 40±5°C and concentrated to 1000 mL (10.0 vol) by vacuum distillation while maintaining a temperature of 60°C. The mixture was sampled for residual ethyl acetate and water.

[0049] Example 5 Polished filtration of N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine

[0050] [ka]

[0051] The n-propanol solution of N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine from Example 4 was polished and filtered (0.2 μm) under vacuum through a frit funnel to remove the inorganic salts.

[0052] Example 6 Addition of methanesulfonic acid with N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine

[0053] [ka]

[0054] The polished and filtered n-propanol solution of N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine from Example 5 was transferred, along with propanol rinse solution (300 mL, 3 volumes), to a clean 2 L coated reactor (set to 40°C) equipped with overhead stirring (PTFE, 4-blade pitch), temperature probe, condenser, nitrogen inlet, and addition funnel, yielding a clear solution. Solvent n-propanol (700 mL, 7 volumes) was added to the reactor. The solution was sampled for purity. The solution was then heated to 90±3°C (T j The mixture was heated to 97°C. Methanesulfonic acid (260.8 g, 176.1 mL, 10.0 equivalents) was added dropwise to the reaction mixture via an addition funnel (slightly exothermic) over 60 minutes. The release of CO2 and isobutylene gases was observed. The reaction mixture was maintained at 90±3°C for 60 minutes to produce API L-lysine-D-amphetamine dimesylate, and a sample was taken for completion.

[0055] Example 7 Seed crystallization of API L-lysine-D-amphetamine dimesylate

[0056] [ka]

[0057] The reaction mixture from Example 6 was cooled to 85°C and stirred for 10 minutes. Crystalline lisdexamfetamine dimesylate (12.50 g, 1 wt%) was added as a seed crystal for crystallization. If the seed crystal continued to crystallize the API, the mixture was stirred for 1 hour and then cooled as described in step 23.

[0058] If the seed crystal did not sustain crystallization, the mixture was cooled to 80°C and stirred for 10 minutes. Lisdexamfetamine dimesylate (2.50 g, 1 wt%) was further added as a seed crystal for crystallization. The mixture was cooled and seed crystals were added in 5°C increments until the seed crystal sustained crystallization. The mixture was then cooled as described. The slurry was cooled to 60±2°C over 10 hours, and then to 20°C over 4 hours. The API slurry was stirred at 20°C for 8 hours. The slurry was filtered (fast filtration), washed twice with n-propanol (2 × 300 mL, 2 × 3 vol), and dried under vacuum. During vacuum drying, a nitrogen stream was maintained due to the hygroscopic nature of the solid. Yield: 226.3 g, 91.5%

Claims

1. A process for preparing L-lysine-D-amphetamine dimesylate, comprising (a) a D-amphetamine free base having the following structure 【Chemistry 1】 This is a mixture of approximately two equivalents of N,N'-bis-Boc-L-Lys(Boc)-OSu having the following structure. 【Chemistry 2】 The process involves reacting the mixture in a two-phase mixture of ethyl acetate and water, and heating the mixture to 25°C to 35°C while stirring to form N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine having the following structure. 【Transformation 3】 (b) A process comprising adding about 1 equivalent of sodium bicarbonate, then separating and removing the aqueous layer of the two-phase mixture, then replacing the ethyl acetate portion of the two-phase mixture containing N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine with n-propanol as a solvent, then adding about 2 to 10 equivalents of methanesulfonic acid while heating to a maximum of 90°C and stirring to yield the product L-lysine-D-amphetamine dimesylate.

2. The process according to claim 1, wherein the reactant of step (a) is stirred for 1 to 2 hours while heating the mixture to 25°C to 35°C.

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

4. The process according to 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 containing N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine is further washed with an aqueous solution of sodium chloride, and the newly formed two-phase mixture is stirred for a maximum of 1 hour while maintaining the temperature of the stirred mixture at 20°C to 25°C, and then the aqueous layer of the formed two-phase mixture is separated and removed before replacing the ethyl acetate portion of the two-phase mixture containing N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine with n-propanol as a solvent.

5. The process according to claim 4, wherein in step (b), the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in n-propanol is subjected to abrasive filtration to remove any inorganic salts before the addition of the methanesulfonic acid.

6. The process according to claim 5, wherein in step (b), about 2 to about 10 equivalents of methanesulfonic acid is added to the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in n-propanol solvent, and the mixture is heated to 85°C to 90°C with stirring for 1 to 2 hours to yield the product L-lysine-D-amphetamine dimesylate.

7. The process according to claim 1, further comprising (c) adding a 1% by weight seed crystal of L-lysine-D-amphetamine dimesylate while cooling the mixture from step (b) to assist in the crystallization of the L-lysine-D-amphetamine dimesylate product.

8. The process according to claim 7, further comprising washing the crystallized L-lysine-D-amphetamine dimesylate product with at least one fraction of n-propanol solvent, and then drying the crystallized L-lysine-D-amphetamine dimesylate product under vacuum at 50°C.

9. A process for preparing L-lysine-D-amphetamine dimesylate, comprising (a) a D-amphetamine free base having the following structure 【Chemistry 4】 This is a mixture of approximately two equivalents of N,N'-bis-Boc-Lys(Boc)-OSu having the following structure. 【Transformation 5】 The process involves reacting the mixture in a two-phase mixture of ethyl acetate and water, and heating the mixture to 25°C to 35°C for 1 to 2 hours while stirring to form N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine having the following structure, 【Transformation 6】 (b) Adding approximately 1 equivalent of sodium bicarbonate, stirring the two-phase mixture for a maximum of 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), the ethyl acetate portion of the two-phase mixture containing N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine is further washed with an aqueous solution of sodium chloride, and the newly formed two-phase mixture is stirred for a maximum of 1 hour while maintaining the temperature of the stirred mixture at 20°C to 25°C, and then the aqueous layer of the formed two-phase mixture is separated and removed. (d) After removing the aqueous layer of the two-phase mixture in step (c), the ethyl acetate is concentrated under vacuum distillation and heated to 60°C, and n-propanol is added as a substitution solvent containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine, thereby replacing the ethyl acetate portion of the two-phase mixture containing the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine. (e) A step of removing any residual inorganic salts by polishing and filtering the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in the n-propanol solvent from step (d), (f) Adding approximately 2 to 10 equivalents of methanesulfonic acid to the N,N'-bis-Boc-L-lysine (Boc)-D-amphetamine in the n-propanol solvent from step (e), and heating the mixture to 85°C to 90°C while stirring for 1 to 2 hours to obtain the product L-lysine-D-amphetamine dimesylate, (g) A step of cooling the L-lysine-D-amphetamine dimesylate product from step (f), adding 1% by weight of crystalline L-lysine-D-amphetamine dimesylate as a seed crystal to crystallize the L-lysine-D-amphetamine dimesylate product, (h) A process comprising washing the crystallized L-lysine-D-amphetamine dimesylate product with at least one fraction of n-propanol solvent, and then drying the crystallized L-lysine-D-amphetamine dimesylate product under vacuum at 50°C.

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