JP-2026514203-A - Process for the preparation of lisdexamfetamine

Abstract

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

Inventors

• コフリン、ダニエル
• メルカダンテ、マイケル
• ウェザリー、ケイル
• ガットマン、ユージン

Assignees

• ベラノバ・リミテッド・パートナーシップ

Dates

Publication Date

20260507

Application Date

20231027

Priority Date

20221028

Claims (9)

1. A process for preparing L-lysine-D-amphetamine dimesylate, comprising (a) a D-amphetamine free base having the following structure This is a mixture of approximately two equivalents of N,N'-bis-Boc-L-Lys(Boc)-OSu having the following structure. 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. (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 in 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, 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 undergoes 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 are 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 while stirring for 1 to 2 hours to yield the product L-lysine-D-amphetamine dimesylate.
7. The process according to claim 1, further comprising the step of (c) adding a 1% by weight seed crystal of L-lysine-D-amphetamine dimesylate while cooling the mixture from step (b), thereby assisting 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 subsequently 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 This is a mixture of approximately two equivalents of N,N'-bis-Boc-Lys(Boc)-OSu having the following structure. 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, (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.

Description

This invention relates to an improved, efficient, and economical process for preparing L-lysine-D-amphetamine dimesylate (also known as lisdexamfetamine dimesylate). L-lysine-D-amphetamine dimesylate (also known 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 drug 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 enzymatically rate-limited, preventing high blood concentrations 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]hexaneamide dimesylate and has the following chemical structure. 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. Furthermore, the invented process 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. The invented process, summarized in Scheme 1, is a more efficient, continuous, and convergent manufacturing process for the production of L-lysine-D-amphetamine dimesylate, avoiding Class 3 solvents. Definitions 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. 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. The term "consisting" is limiting and excludes any additional, unlisted elements or method steps in the claimed invention. The term "consisting essentially of" is semi-restrictive, occupying an intermediate position between "consisting of" and "comprising." "Consisting essentially of" does not exclude additional, unlisted elements or process steps that do not materially affect the essential characteristics of the claimed invention. The term “comprising” is either comprehensive or non-exclusive and does not exclude 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.” The "Boc" group refers to the tert-butyloxycarbonyl protecting group used to protect amine groups in organic synthesis. In this invention, the term API refers to the active pharmaceutical ingredient, which is either L-lysine-D-amphetamine free base or L-lysine-D-amphetamine dimesylate. 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). The sequential process summarized in Scheme 1 is: (a) converting D-amphetamine sulfate to D-amphetamine as a free base; (b) addin