Fenfluramine composition and its preparation method

Abstract

The present invention provides a method for preparing the active pharmaceutical ingredient of fenfluramine. Aspects of the present invention include (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) reacting the 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to prepare a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (c) reducing and aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with a borohydride reducing agent and ethylamine to produce a fenfluramine composition. The present invention also provides a composition and a pharmaceutical ingredient comprising a pharmaceutically acceptable salt of fenfluramine prepared according to the method and having less than a total of 0.2% by weight of trifluoromethyl regioisomers.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of priority under 35 U.S.C.§119(e) to U.S. Provisional Patent Application Serial No. 62 / 271,172, filed on December 22, 2015, the disclosure of which is incorporated herein by reference in its entirety. Summary of the Invention

[0004] Fenfluramine is an amphetamine drug that was once widely used as an appetite suppressant for treating obesity. Fenfluramine does not have the psychomotor excitation and potential for abuse of D - amphetamine and interacts with serotonin (5 - HT) receptors to release 5 - HT from neurons. The anticonvulsant activity of fenfluramine in treating Dravet syndrome or severe myoclonic epilepsy in infancy, a rare and malignant epilepsy syndrome, has been studied. This type of epilepsy occurs early in previously healthy children.

[0005] The anorectic treatment with fenfluramine has been associated with the occurrence of heart valve disease and pulmonary hypertension, including the cardiac fibrosis condition that led to the withdrawal of fenfluramine from the global market. The interaction of norfenfluramine, the main metabolite of fenfluramine, with the 5 - HT2B receptor is associated with heart valve hypertrophy. When treating epilepsy, the known cardiovascular risks of fenfluramine are weighed against its beneficial anticonvulsant activity. Summary of the Disclosure

[0006] The present disclosure provides methods for preparing active pharmaceutical ingredients of fenfluramine. Aspects of the method include: hydrolyzing a 2 - (3 - (trifluoromethyl)phenyl)acetonitrile composition to produce a 2 - (3 - (trifluoromethyl)phenyl)acetic acid composition; reacting the 2 - (3 - (trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to prepare a 1 - (3 - (trifluoromethyl)phenyl)propan - 2 - one composition; and reducing amination of the 1 - (3 - (trifluoromethyl)phenyl)propan - 2 - one composition with a borohydride reducing agent to produce a fenfluramine composition.

[0007] Also provided are fenfluramine compositions and pharmaceutical ingredients produced according to the methods of the invention, which include reduced amounts of one or more minor components such as impurities or reaction by - products. In some cases, the composition contains a pharmaceutically acceptable salt of fenfluramine that has a total of less than 0.2 wt% of trifluoromethyl regioisomers. Also provided are pharmaceutical compositions comprising the fenfluramine composition.

[0008] These and other objects, advantages, and features of the invention will become apparent to those skilled in the art upon reading the details of the metabolism - resistant fenfluramine analogs and their methods of use, as described more fully hereinafter. Brief Description of the Drawings

[0009] In conjunction with the accompanying drawings, the present invention is better understood through the following detailed description. It should be emphasized that, as a matter of convention, the various features of the drawings are not to scale. Instead, the dimensions of the various features are arbitrarily enlarged or reduced for clarity. The drawing section includes the following drawings.

[0010] Figure 1 Shows the contribution of various precursor materials to the structure of fenfluramine (1) in an exemplary retrosynthetic analysis of acid (4).

[0011] Figure 2 Shows an exemplary HPLC chromatogram (210 nm UV absorbance) of the crude fenfluramine hydrochloride.

[0012] Figure 3 Shows an exemplary HPLC chromatogram (210 nm UV absorbance) of the crystalline fenfluramine hydrochloride composition.

[0013] Figure 4 Shows various synthetic routes for preparing ketone (2). An exemplary method for the method of the present invention is to prepare ketone (2) from nitrile (5) via acid (4).

[0014] Figure 5 Shows the route for preparing ketone (2) from an aryl nitro starting material via a diazonium salt intermediate. Due to the possible formation of genotoxic intermediates (such as N-hydroxyaryl, N-nitroamine, and nitro compounds) of the compounds shown in the box, the diazotization route has disadvantages.

[0015] Definition

[0016] As used herein, the term "subject" refers to a mammal. Exemplary mammals include, but are not limited to: humans, domestic animals (such as dogs, cats, etc.), farm animals (such as cows, sheep, pigs, horses, etc.) or laboratory animals (such as monkeys, rats, mice, rabbits, guinea pigs, etc.). In some embodiments, the subject is a human. A "patient" refers to human and non-human subjects, especially mammalian subjects.

[0017] As used herein, the terms "treatment", "treating", etc. refer to obtaining the desired pharmacological and / or physiological effect. This effect can be prophylactic in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or adverse effects resulting from the disease. As used herein, the terms "treatment", "therapeutic", "therapeutically" or "therapy" do not necessarily mean the complete cure or elimination of a disease or disorder. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or disorder can be considered treatment and / or therapeutic. In addition, treatment may include actions that may worsen the overall health perception or appearance of a patient. The term "treatment" as used herein includes any treatment of a disease in mammals, and in some cases any treatment of a disease in humans, including: (a) preventing the occurrence of a disease or medical condition, such as prophylactically treating a subject; (b) ameliorating a disease or medical condition, such as eliminating a patient's disease or medical condition or causing a patient's disease or medical condition to regress; (c) inhibiting a disease or medical condition, such as by slowing or preventing the occurrence of a disease or medical condition in a patient; or (d) alleviating the symptoms of a patient's disease or medical condition.

[0018] As used herein, the term pKa refers to the negative logarithm (p) of the acid dissociation constant (Ka) of an acid, which is equal to the pH value at which equal concentrations of the acid and its conjugate base form are present in solution.

[0019] The term "salt" refers to an ionic compound produced by the neutralization reaction of an acid and a base, consisting of at least one cation (positively charged ion) and at least one anion (negatively charged ion). In some embodiments, the salt is electrically neutral (has no net charge). Where applicable, the salt is a pharmaceutically acceptable salt, but for intermediate compounds not intended to be administered to a patient, its salt is not required. By way of example, salts of the compounds of the present invention include those salts in which a basic compound is protonated by an inorganic or organic acid to form a conjugate acidic cation, and the conjugate base of the inorganic or organic acid is the anionic component of the salt. Salts of interest include, but are not limited to, hydrochloride salts. It should be understood that for any structure described herein, such a structure may also include any convenient salt form.

[0020] The term "pharmaceutically acceptable" refers to being approved by a federal or state government regulatory agency, or listed in the United States Pharmacopeia or other generally accepted pharmacopeias for use in mammals, such as humans.

[0021] The term "pharmaceutically acceptable salt" refers to an acceptable salt (e.g., a salt containing a counterion having acceptable mammalian safety for a given dosage regimen) that can be used for administration to a patient (such as a mammal). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases, or from pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound, which is derived from a variety of organic and inorganic counterions well known in the art and includes (by way of example only) sodium, etc.; and when the molecule contains a basic functional group, it is a salt of an organic or inorganic acid, such as hydrochloride, etc. Pharmaceutically acceptable related salts include, but are not limited to, hydrochloride.

[0022] The term "active pharmaceutical ingredient" (API) refers to a substance or mixture of substances intended for use in the manufacture of a pharmaceutical product and which becomes the active ingredient in the pharmaceutical product when used in the production of pharmaceuticals. These substances are intended to provide pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

[0023] "Solvate" refers to a complex formed by the combination of solvent molecules with the molecules or ions of a solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to: methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.

[0024] "Stereoisomer" refers to a compound having the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0025] "Tautomer" refers to alternative forms of a molecule that differ only in the electronic bonding of atoms and / or the position of protons, such as keto-enol and imine-enamine tautomers, or tautomeric forms of heteroaryl containing -N=C(H)-NH- ring atom rearrangement, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Those of ordinary skill in the art will understand that other tautomeric arrangements of the groups described in the present invention are possible.

[0026] It is to be understood that the term "or a salt or solvate or stereoisomer thereof" is intended to include all permutations of salts, solvates, and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of the subject compound. It is to be understood that the term "or a salt thereof" is intended to include all permutations of salts. It is to be understood that the term "or a pharmaceutically acceptable salt thereof" is intended to include all permutations of salts. It is to be understood that the term "or a solvate thereof" is intended to include all permutations of solvates. It is to be understood that the term "or a stereoisomer thereof" is intended to include all permutations of stereoisomers. It is to be understood that the term "or a tautomer thereof" is intended to include all permutations of tautomers. Thus, for example, it is intended to include a solvate of a pharmaceutically acceptable salt of a tautomer of a stereoisomer of the said compound.

[0027] "A pharmaceutically effective amount" and "a therapeutically effective amount" mean an amount of a compound sufficient to treat a particular disorder or disease or one or more symptoms thereof and / or to prevent the occurrence of a disease or disorder. With respect to a neoplastic proliferative disorder, a pharmaceutically or therapeutically effective amount includes an amount sufficient to cause tumor shrinkage or to reduce the rate of tumor growth.

[0028] The term "carrier" means a diluent, adjuvant, excipient, or vehicle with which the compounds of the invention are formulated for administration to a mammal.

[0029] When a numerical range is provided, it is also to be specifically disclosed all intermediate values therebetween in increments of one tenth of the lower limit between the upper and lower limits of the range, unless the context clearly dictates otherwise. The present invention also encompasses all smaller ranges between any of the set values or intermediate values within the set range and any other set value or intermediate value within the set range. The ranges may independently include or exclude the upper and lower limits of these smaller ranges, and the present invention also encompasses ranges that do not include the limits, include either or both of the limits, as specifically excluded for any limit within the set range. When the set range includes one or both of the limits, the present invention also encompasses ranges excluding one or both of the said limits.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used to implement or test the present invention, some potential and preferred methods and materials are described herein. All publications mentioned herein are incorporated herein by reference to disclose and describe these methods and / or materials in connection with the publications cited. It is to be understood that, in case of conflict, the present disclosure shall control over any disclosure of the incorporated publications herein.

[0031] It must be noted that the singular forms "a", "an", and "the" as used in this specification and the appended claims include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the method" includes one or more methods known to those skilled in the art and their equivalents, and so forth.

[0032] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publications by virtue of prior invention. Further, the provided publication dates may be different from the actual publication dates, which may require independent verification.

[0033] Before describing the compounds and methods of the present invention, it is to be understood that the invention is not limited to the specific compounds and methods described, as they may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the invention is defined solely by the appended claims. Detailed Description

[0034] As described above, the present disclosure provides methods for preparing fenfluramine active pharmaceutical ingredients. Aspects of the present disclosure include fenfluramine compositions and pharmaceutical ingredients produced according to the methods, wherein particularly undesirable trace components of interest are substantially removed from the composition. The methods of the present invention provide a combined process for producing a crude composition that achieves a desired minimum threshold of undesirable minor components (e.g., difficult-to-purify regioisomers, reaction by-products, and reagents). The active pharmaceutical ingredient for a pharmaceutical formulation is prepared by a controlled and reproducible process to obtain a high purity active agent composition that provides a high level of safety, efficacy, and quality in the resulting pharmaceutical formulation. In some cases, impurities or undesirable minor components in a pharmaceutical composition may result in loss of stability, potency, and toxicity of the drug product. Substantially eliminating these minor components from the fenfluramine composition provides a composition suitable for use as an active pharmaceutical ingredient (API) in a pharmaceutical composition. The compositions of the present invention can be produced effectively, reducing the need for purification, eliminating purification steps, or improving the results of method steps, such as those involving removal of regioisomers of fenfluramine that are difficult to remove.

[0035] When used in the context of the method, the term "composition" describes a material that is an ingredient or product of one or more steps of the method and can comprise a mixture of components. The composition can be referred to by its main or target component, such as a fenfluramine composition. Generally, in addition to the main target component, the composition can also comprise a mixture of other components, such as target isomers (e.g., stereoisomers or regioisomers), impurities, reaction by-products, starting materials, carry-over components from previous steps, reagents, solvents, etc. As used herein, the term "crude composition" refers to a material produced during the course of a chemical reaction that has not undergone additional purification steps, such as separate post-reaction procedural steps, such as chromatography or recrystallization steps. In the preparation of a crude composition, simple steps can be carried out on the material, such as aqueous washes, solvent extractions, and / or filtration that are considered part of the reaction process, as these steps are commonly used to terminate a chemical reaction and / or "work-up" the reaction product. As noted above, such post-reaction work-up steps are not considered additional purification steps but merely part of the preparation of the crude composition.

[0036] Method for the preparation of a fenfluramine composition

[0037] Aspects of the method include the preparation of a fenfluramine composition (Scheme 1) from a 1-(3-(trifluoromethyl)phenyl)-propan-2-one precursor composition via reductive amination.

[0038]

[0039] Scheme 1: Preparation of fenfluramine (1) from 1-(3-(trifluoromethyl)phenyl)-propan-2-one (2) via reductive amination

[0040] Any convenient reductive amination method can be used to convert the ketone (2) to fenfluramine (1) via an imine intermediate (1a), such as via a Schiff base formed between ethylamine (e.g., Et-NH2) and the ketone (2). Methods and reagents of interest include, but are not limited to, those described by Abdel-Magid et al. ("Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride, A Study of Direct and Indirect Reductive Amination Methods", J. Org. Chem., 1996, 61(11), pp. 3849-3862). In some embodiments, the reductive amination reaction is carried out under conditions including contacting a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with a solution of 70 wt% ethylamine / water and about 2.25 equivalents or more of sodium triacetoxyborohydride dissolved in methanol as a solvent. In certain cases, the reaction (e.g., Scheme 1) is carried out on an industrial scale (e.g., as described herein). In certain cases, the yield of the reaction (e.g., Scheme 1) is 80% or more, such as 85% or more, 90% or more, 95% or more, 98% or more or 99% or more.

[0041] Any convenient reducing agent can be used in the reductive amination step of the method of the present invention, for example, to reduce the Schiff base intermediate to the secondary amine product fenfluramine. In some cases, the reducing agent is a borohydride reducing agent. As used herein, the term "borohydride reducing agent" is intended to include any reducing agent containing a BH- group, such as any convenient borohydride having the formula MBR3H, a cyanoborohydride or a triacetoxyborohydride reducing agent, where each R is independently H, alkyl, cyano or acetoxy, and M is a metal such as Na, Li or K. In some cases, the reducing agent is a cyanoborohydride reducing agent. In some cases, the reducing agent is a triacetoxyborohydride reducing agent. In some cases, the reducing agent is selected from: sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium triethylborohydride, nickel borohydride, potassium borohydride and calcium borohydride. In certain cases, the borohydride reducing agent is sodium triacetoxyborohydride (STAB; Na(CH3COO)3BH).

[0042] The 1-(3-(trifluoromethyl)phenyl)propan-2-one (2) composition can be prepared from any convenient precursor composition. In some cases, for example, according to Scheme 2, 1-(3-(trifluoromethyl)phenyl)propan-2-one (2) is prepared from 2-(3-(trifluoromethyl)phenyl)acetic acid (4) via the Daikin-West reaction. Thus, aspects of the method include reacting a 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition.

[0043]

[0044] Scheme 2: Preparation of ketone (2) from acid (4) via the Daikin-West reaction

[0045] The Daikin-West reaction provides for the conversion of an enolizable carboxylic acid to the corresponding methyl ketone by reaction with an acetylating agent (such as acetic anhydride) and a catalyst. In some cases, the catalyst is a nucleophilic catalyst. Any convenient nucleophilic catalyst can be used in combination with acetic anhydride in the preparation of ketone (2) by Scheme 2. In some embodiments, the catalyst is N-methylimidazole (i.e., 1-methylimidazole). The catalyst and acetic anhydride can combine to form an acetylating agent in situ. It is understood that various other acetylating reagents and precursor reagents for in situ generation of acetylating reagents can be used in the reaction step. In some cases, the method step includes directly adding a preformed acetylating agent to acid (4). Methods and reagents of interest for the preparation of ketone (2) include, but are not limited to, those described by Buchanan in "The Dakin-West reaction", Chem. Comm. SOC. Rev., 1988, 17, 91-109. In some embodiments, the reaction is carried out under conditions including contacting a 2-(3-(trifluoromethyl)phenyl)acetic acid composition with about 0.5 equivalents of 1-methylimidazole and about 5 equivalents or more of acetic anhydride, optionally in a solvent. In certain cases, the yield of the reaction (e.g., Scheme 2) is 80% or more, such as 85% or more, 90% or more, 95% or more, 98% or more or 99% or more.

[0046] Ketone (2) can be optionally purified, if desired, by any convenient method prior to use in the steps outlined in Scheme 1. In certain cases, ketone (2) is purified by forming a bisulfite adduct. As used herein, the terms "bisulfite adduct" and "bisulfite addition compound" are used interchangeably to refer to the product of adding bisulfite ions to a ketone compound. The bisulfite adduct of ketone (2) can be a solid that is more easily purified of impurities from the adduct composition than from the corresponding parent ketone composition, where possible.

[0047]

[0048] Scheme 3: Purification of ketone (2) by forming a ketone bisulfite adduct (3).

[0049] Aspects of the method include combinations of the various steps described herein, e.g., a combination of steps as described in Scheme 4. Optional additional purification steps (e.g., crystallization steps) may be performed before or after any of the described steps. In some embodiments, the method includes reacting a 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and reductive amination of the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with an amine using a borohydride reducing agent to produce a fenfluramine composition.

[0050]

[0051] Scheme 4: Preparation of fenfluramine (1) from acid (4) via ketone (2)

[0052] The 2-(3-(trifluoromethyl)phenyl)acetic acid (4) composition can be prepared from any convenient precursor composition. In some cases, e.g., the 2-(3-(trifluoromethyl)phenyl)acetic acid composition is prepared from a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition according to the reaction of Scheme 5. Thus, the method of the invention includes hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile (5) composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid (4) composition.

[0053]

[0054] Scheme 5: Hydrolysis of nitrile (5) to form acid (4)

[0055] Hydrolysis of nitrile (5) to acid (4) can be achieved using any convenient method. In certain cases, hydrolysis of nitrile (5) is achieved by acid-catalyzed hydrolysis. In certain cases, hydrolysis of nitrile (5) is achieved by base-catalyzed hydrolysis. Under aqueous acidic conditions, hydrolysis can proceed through an amide intermediate (4a). In some embodiments of the method, hydrolysis of nitrile (5) to acid (4) is carried out under aqueous acidic conditions. In certain cases, the yield of the reaction (e.g., Scheme 5) is 80% or more, e.g., 85% or more, 90% or more, 95% or more, 98% or more or 99% or more.

[0056] In some cases, the method includes hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile (5) composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid (4) composition; and reacting the 2-(3-(trifluoromethyl)phenyl)acetic acid (4) composition with acetic anhydride and a catalyst to prepare a 1-(3-(trifluoromethyl)phenyl)propan-2-one (2) composition (see, e.g., Scheme 6).

[0057]

[0058] Scheme 6: Preparation of ketone (2) from cyanide (5) via acid (4)

[0059] Aspects of the method include combinations of the steps described herein, e.g., combinations of the steps as described in Scheme 7. Optional additional purification steps (e.g., crystallization steps) may be performed before or after any of the described steps. In some embodiments, the method comprises: hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile (5) composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid (4) composition; reacting the 2-(3-(trifluoromethyl)phenyl)acetic acid (4) composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one (2) composition; and reductive amination of the 1-(3-(trifluoromethyl)phenyl)propan-2-one (2) composition with a borohydride reducing agent and ethylamine to produce a fenfluramine (1) composition.

[0060]

[0061] Scheme 7: Preparation of fenfluramine (1) from cyanide (5) via acid (4) and ketone (2).

[0062] In some embodiments of the method, the resulting fenfluramine composition (e.g., a crude fenfluramine composition) has the following characteristics: 80 wt% or more of fenfluramine or its salt, e.g., 90 wt% or more, 95 wt% or more, 96 wt% or more, 97 wt% or more, 98 wt% or more, 99 wt% or more, 99.5 wt% and more, or even more wt of fenfluramine or its salt; 1 wt% or less of the 2-fenfluramine regioisomer or its salt, e.g., 0.5 wt% or less, 0.2 wt% or less, or 0.1 wt% or less, 0.05 wt% or less, 0.01 wt% or less, or even less wt of the 2-fenfluramine regioisomer or its salt; 1 wt% or less of the 4-fenfluramine regioisomer or its salt, e.g., 0.5 wt% or less, 0.2 wt% or less, or 0.1 wt% or less, 0.05 wt% or less, 0.01 wt% or less, or even less wt of the 4-fenfluramine regioisomer or its salt; and 10 wt% or less of the fenfluramine reduced alcohol by-product, e.g., 5 wt% or less, 2 wt% or less, or 1 wt% or less, 0.5 wt% or less, 0.1 wt% or less of the fenfluramine reduced alcohol by-product.

[0063] In some embodiments, the method is a method for preparing fenfluramine free base. Thus, the fenfluramine composition may comprise fenfluramine free base. The fenfluramine free base prepared according to the method can be converted into any suitable salt form using various methods, e.g., salts of the conjugate acid of the secondary amino group of fenfluramine (fenfluramine.H+ X - )。The formation of the fenfluramine salt can be carried out as part of the reductive amination step of Scheme 1 (e.g., in situ), or salt formation can be carried out in an optional subsequent step. In some cases, the salt form is a pharmaceutically acceptable salt of fenfluramine. Salts of interest include, but are not limited to, hydrochloride salts. In certain cases, the pharmaceutically acceptable salt form of fenfluramine is the hydrochloride salt.

[0064]

[0065] Scheme 8: Preparation of a salt of fenfluramine.

[0066] The method of the present invention provides for the substantial elimination of one or more undesired minor components from a crude fenfluramine composition or a fenfluramine salt composition, such that the final additional purification step can be readily achieved with high efficiency and / or high yield to produce a high-quality active pharmaceutical composition.

[0067] One or more additional purification steps can be performed on the crude fenfluramine composition prepared according to the method of the present invention (e.g., including fenfluramine in free base or salt form). In certain cases, the purification step includes crystallizing fenfluramine or a salt form of fenfluramine from the crude composition. The crystallized fenfluramine salt form can have a desired polymorph, high crystallinity, water solubility, and / or stability. In some cases, the method of the present invention provides crystalline fenfluramine hydrochloride, which is a single polymorph, is free-flowing, non-hygroscopic, and has a high melting point temperature.

[0068] In some embodiments of the method, the resulting composition comprises a pharmaceutically acceptable salt of fenfluramine and has the following purity characteristics: 90% by weight or more of the pharmaceutically acceptable salt of fenfluramine, such as 95% by weight or more, 96% by weight or more, 97% by weight or more, 98% by weight or more, 99% by weight or more, 99.5% by weight or more, 99.8% by weight or more, 99.9% by weight or more, or even more by weight of the pharmaceutically acceptable salt of fenfluramine; 1% by weight or less of 2-fenfluramine; 1% by weight or less of the 2-fenfluramine regioisomer or its salt, such as 0.5% by weight or less, 0.2% by weight or less, or 0.1% by weight or less, 0.05% by weight or less, 0.01% by weight or less, or even less by weight of the 2-fenfluramine regioisomer or its salt; 1% by weight or less of the 4-fenfluramine regioisomer or its salt, such as 0.5% by weight or less, 0.2% by weight or less, or 0.1% by weight or less, 0.05% by weight or less, 0.01% by weight or less, or even less by weight of the 4-fenfluramine regioisomer or its salt; 5% by weight or less of the fenfluramine reduced alcohol by-product, such as 3% by weight or less, 2% by weight or less, or 1% by weight or less, 0.5% by weight or less, 0.1% by weight or less of the fenfluramine reduced alcohol by-product. In certain embodiments, the composition prepared according to the method is an active pharmaceutical ingredient of fenfluramine comprising a pharmaceutically acceptable salt of fenfluramine and having a total of 0.2% by weight or less of the trifluoromethyl regioisomer, such as 0.1% by weight or less, 0.05% by weight or less, 0.03% by weight or less, 0.01% by weight or less, or even less by weight of the trifluoromethyl regioisomer. In certain embodiments, the active pharmaceutical ingredient of fenfluramine has the following purity characteristics, including: at least 90% by weight (e.g., at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.8% by weight, at least 99.9% by weight, or more) of the pharmaceutically acceptable salt of fenfluramine; less than 0.2% by weight (e.g., less than 0.1% by weight, less than 0.05% by weight, less than 0.03% by weight, less than 0.01% by weight) of 2-fenfluramine; less than 0.2% by weight (e.g., less than 0.1% by weight, less than 0.05% by weight, less than 0.03% by weight, less than 0.01% by weight) of 4-fenfluramine; and less than 1% by weight (e.g., less than 0.5% by weight, less than 0.3% by weight, less than 0.1% by weight, less than 0.05% by weight) of fenfluramine alcohol.

[0069] The method provides for the preparation of a racemic mixture of the enantiomers of fenfluramine. The enantiomers of fenfluramine can be referred to as: dexfenfluramine (i.e., (S)-N-ethyl-1-[3-(trifluoromethyl)phenyl]propan-2-amine, (+)-fenfluramine or (S)-fenfluramine); and levofenfluramine (i.e., (2R)-N-ethyl-1-[3-(trifluoromethyl)phenyl]-2-propanamine, (-)-fenfluramine or (R)-fenfluramine). Any convenient method can be used to separate the fenfluramine enantiomers or their salts from each other. Methods of interest for separating and purifying the fenfluramine enantiomers include, but are not limited to, chiral resolution by crystallization and chiral column chromatography. Thus, in some embodiments, the method further comprises performing a chiral separation of the racemic fenfluramine composition or its salt to produce a non-racemic fenfluramine composition comprising the major stereoisomer of fenfluramine. Non-racemic means a composition having an enantiomeric excess of at least 50%, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% of one stereoisomer (e.g., the major stereoisomer). As used herein, the term "major stereoisomer" is intended to encompass compositions that contain only one stereoisomer or compositions that contain a mixture of stereoisomers.

[0070] In some cases, the active pharmaceutical ingredient composition is a non-racemic composition comprising (S)-fenfluramine or a pharmaceutically acceptable salt thereof as the major stereoisomer. In some cases, the active pharmaceutical ingredient composition is a non-racemic composition comprising (R)-fenfluramine or a pharmaceutically acceptable salt thereof as the major stereoisomer. In some cases, the resulting non-racemic composition contains only one stereoisomer.

[0071] Minor component

[0072] As described above, compositions that provide the method of the present invention, such as starting material compositions, intermediate compositions, and final fenfluramine compositions, can be used to substantially eliminate one or more minor components, which are achieved by the method to produce a composition that serves as an active pharmaceutical ingredient (API) or a precursor thereof for use as a pharmaceutical composition. The method provides various ways to substantially eliminate unwanted minor components. As used herein, "substantially eliminate" means achieving the desired minimum threshold of the minor component of interest such that the minor component, if present, is present at a level equal to or below the threshold. As used herein, the term "substantially free of" means a composition in which the trace component of interest is absent or present at a level equal to or below the minimum threshold. The desired minimum threshold of the minor component of interest can vary depending on the nature of the component and whether the composition is an intermediate composition or the fenfluramine composition of interest. In some cases, the desired minimum threshold of the minor component of interest is 10% by weight or less, such as 5% by weight or less, 4% by weight or less, or 3% by weight or less, 2% by weight or less, 1% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, 0.15% or less, 0.1% by weight or less, 0.09% by weight or less, 0.08% by weight or less, 0.07% by weight or less, 0.06% by weight or less, 0.05% by weight or less, 0.03% by weight or less, or 0.01% by weight or less. In certain cases, the minor component of interest is completely removed from the composition of interest, i.e., the composition has no minor components (e.g., not detected or below the detectable limit of the component).

[0073] In some cases, a specific combination of steps used in the method can eliminate minor components of interest. In some cases, for example, purification of an intermediate composition via crystallization achieves substantial elimination of minor components, which would be difficult to remove if the minor components, such as regioisomers, were transferred to subsequent steps in the synthesis. In some cases, performance of specific method steps provides selectivity of the reaction, whereby minor components of interest are not transformed by the reaction conditions as the major components are and can thus be more easily removed, for example, as regioisomers of starting materials rather than as products of the reaction or specific method steps. In some cases, a specific combination of steps used in the method avoids the use of one or more chemical reagents, solvents, and / or reactants required via conventional methods, which result in undesired minor components in the product composition. Minor components of interest that can be substantially eliminated include, but are not limited to: product isomers, by-products, aldehydes, ketones, peroxides, metals (such as heavy metals and metal catalysts), nitrates / nitrites, trace solvents, and organic acids. Details of various minor components and their substantial elimination from the composition will be described in more detail below. Minor components of interest that can be substantially eliminated according to the method include any impurities, by-products, starting materials, and minor components described herein, including, but not limited to: acetate / ester impurities, dimer impurities, acetamide impurities, 1-((3-phenyl)phenyl)acetone, fenfluramine regioisomers, fenfluramine alcohol, N-(3-(trifluoromethyl)-benzyl)ethylamine, norfenfluramine, and any of the impurities in Table 7.

[0074] Regioisomer

[0075] In some cases, regioisomers of fenfluramine or its precursors can be present as minor components in any of the compositions of the method of the invention. Fenfluramine and its synthetic precursors can include 3-trifluoromethyl-substituted phenyls. As used herein, the terms "trifluoromethyl regioisomer" and "trifluoromethyl-phenyl regioisomer" can be used interchangeably to denote isomers of fenfluramine or any of the synthetic precursors described herein, wherein the trifluoromethyl substituent is in the 2- or 4-position of the substituted benzene ring rather than the 3-position corresponding to fenfluramine. Thus, the terms "2-trifluoromethyl regioisomer" and "4-trifluoromethyl regioisomer" can be used herein to describe specific minor components of any intermediate composition or final composition that can be used in the method of the invention.

[0076]

[0077] The raw materials of the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition of the method of the present invention may include regioisomers. In some cases, the regioisomers are from the method of preparing 2-(3-(trifluoromethyl)phenyl)acetonitrile from trifluoromethylbenzene. In some cases, the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition contains at least 0.2% by weight, such as at least 0.3% by weight, at least 0.4% by weight, at least 0.5% by weight, at least 1.0% by weight, at least 1.5% by weight, at least 2% by weight, at least 3% by weight, at least 4% by weight, at least 5% by weight, at least 10% by weight, or even more weight of the trifluoromethyl-phenyl regioisomers (for example, the total amount of 2-(2-(trifluoromethyl)phenyl)acetonitrile and 2-(4-(trifluoromethyl)phenyl)acetonitrile). In some cases, the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition contains at least 0.2% by weight, such as at least 0.3% by weight, at least 0.4% by weight, at least 0.5% by weight, at least 1.0% by weight, at least 1.5% by weight, at least 2% by weight, at least 3% by weight, at least 4% by weight, at least 5% by weight, at least 10% by weight, or even more weight of 2-(4-(trifluoromethyl)phenyl)acetonitrile. In some cases, the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition contains at least 0.2% by weight, such as at least 0.3% by weight, at least 0.4% by weight, at least 0.5% by weight, at least 1.0% by weight, at least 1.5% by weight, at least 2% by weight, at least 3% by weight, at least 4% by weight, at least 5% by weight, at least 10% by weight, or even more weight of 2-(2-(trifluoromethyl)phenyl)acetonitrile. In certain cases, the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition contains a minor regioisomer component, which is transferred to the next composition, such as the 2-(3-(trifluoromethyl)phenyl)acetic acid composition. Therefore, the 2-(3-(trifluoromethyl)phenyl)acetic acid composition produced as an intermediate in the method of the present invention may also include regioisomers (for example, 2-(2-(trifluoromethyl)phenyl)acetic acid and 2-(4-(trifluoromethyl)phenyl)acetic acid), and their contents are the same as those described for the raw materials of the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition herein.

[0078] The method of the present invention provides for removing the minor components of the intermediate composition, the 2- and / or 4-regioisomers, in various ways. In some embodiments, the method includes purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition to produce a composition substantially free of one or both of the trifluoromethyl-phenyl regioisomers. In certain cases, the composition is also substantially free of benzaldehyde present in the acetonitrile feedstock. In certain cases, the composition is also substantially free of trifluoromethyl-benzaldehyde present in the acetonitrile feedstock. In certain cases, purification of the 2-(3-(trifluoromethyl)phenyl)acetic acid composition to remove some or all of the minor regioisomer components can be achieved by crystallization of 2-(3-(trifluoromethyl)phenyl)acetic acid. As used herein, the term "substantially free of trifluoromethyl-phenyl regioisomers" means less than 0.5 wt%, such as less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt%, less than 0.1 wt%, less than 0.09 wt%, less than 0.08 wt%, less than 0.07 wt%, less than 0.06 wt%, less than 0.05 wt%, less than 0.03 wt% or even less. Any convenient crystallization or recrystallization method can be used in the method of the present invention.

[0079] After purification (e.g., crystallization) of the 2-(3-(trifluoromethyl)phenyl)acetic acid composition, the composition may contain less than 0.5 wt%, such as less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt%, less than 0.1 wt%, less than 0.09 wt%, less than 0.08 wt%, less than 0.07 wt%, less than 0.06 wt%, less than 0.05 wt%, less than 0.03 wt% or even less of 2-(2-(trifluoromethyl)phenyl)acetic acid. After purification (e.g., crystallization) of the 2-(3-(trifluoromethyl)phenyl)acetic acid composition, the composition may contain less than 0.5 wt%, such as less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt%, less than 0.1 wt%, less than 0.09 wt%, less than 0.08 wt%, less than 0.07 wt%, less than 0.06 wt%, less than 0.05 wt%, less than 0.03 wt% or even less of 2-(4-(trifluoromethyl)phenyl)acetic acid. After purification (e.g., crystallization) of the 2-(3-(trifluoromethyl)phenyl)acetic acid composition, the composition may contain less than 0.5 wt%, such as less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt%, less than 0.1 wt%, less than 0.09 wt%, less than 0.08 wt%, less than 0.07 wt%, less than 0.06 wt%, less than 0.05 wt%, less than 0.03 wt% or even less of benzaldehyde.

[0080] In some embodiments, the method comprises reacting a 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition, wherein the 2-(3-(trifluoromethyl)phenyl)acetic acid is selectively converted to the ketone in the presence of unreacted 2-(2-(trifluoromethyl)phenyl)acetic acid. The process of the present invention readily removes the 2-regioisomer present because this regioisomer does not carry through the reaction at the same rate as the target 3-trifluoromethyl compound. In some cases, the method further comprises removing the unreacted 2-(2-(trifluoromethyl)phenyl)acetic acid regioisomer from the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition. Thus, in some cases, the crude 1-(3-(trifluoromethyl)phenyl)propan-2-one composition is substantially free (e.g., contains less than 0.5 wt%, such as less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt%, less than 0.1 wt%, less than 0.09 wt%, less than 0.08 wt%, less than 0.07 wt%, less than 0.06 wt%, less than 0.05 wt%, less than 0.03 wt% or even less) of the 2-regioisomer of the ketone product.

[0081] Removal of the regioisomer minor component present in the acetonitrile feedstock can be effected in stages during the execution of the synthetic method. In some embodiments, a first portion of the regioisomer minor component present in the feedstock is removed from the 2-(3-(trifluoromethyl)phenyl)acetic acid composition, for example by crystallization. In certain cases, a second portion of the regioisomer minor component present carried through by the intermediate composition of the process of the present invention is removed by selective reaction of 2-(3-(trifluoromethyl)phenyl)acetic acid as described herein. In certain cases, a third portion of the regioisomer minor component present carried through by the intermediate composition of the process of the present invention is removed via purification of the fenfluramine composition.

[0082] Benzaldehyde and trifluorobenzaldehyde

[0083] Depending on the method for preparing 2-(3-(trifluoromethyl)phenyl)acetonitrile, the starting material composition may include benzaldehyde or trifluorobenzaldehyde as minor components. The presence of such minor components in the pharmaceutically active ingredient is undesirable. In some cases, the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition contains at least 0.2% by weight, such as at least 0.3% by weight, at least 0.4% by weight, at least 0.5% by weight, at least 1.0% by weight, at least 2% by weight, at least 5% by weight, at least 10% by weight or even more weight of benzaldehyde or trifluorobenzaldehyde as minor components. In some cases, any benzaldehyde or trifluorobenzaldehyde present as a minor component is substantially removed from the composition described herein during purification (e.g., crystallization) of 2-(3-(trifluoromethyl)phenyl)acetic acid. In certain cases, due to its preparation method, benzaldehyde is not present in the 2-(3-(trifluoromethyl)phenyl)acetonitrile starting material composition.

[0084] Method for preparing ketone (2)

[0085] The method of the present invention may include a specific combination of steps for preparing ketone (2), which provides one or more advantages over other possible methods. Figure 4 Various synthetic routes that can be used to prepare ketone (2) are shown. In certain cases, the specific method used in the method of the present invention is to prepare ketone (2) from nitrile (5) by acid (4).

[0086] In the method of the present invention, minor components (such as acetate and dimer impurities) formed during the Dakin-West reaction (e.g., as described in Scheme 2) can subsequently be substantially removed. In certain cases, a distillation process is used to remove these minor components. In certain cases, these minor components are removed by including a process for separating the product ketone (2) with bisulfite (e.g., as described herein). The acetate and dimer impurities are shown below.

[0087]

[0088] In some cases, the bisulfite separation process is used to increase the purity of the ketone by at least 30% (e.g., at least 40%, at least 50% or more) by removing these and other impurities. In some embodiments, the method of the present invention provides for substantially removing acetate impurities from the ketone (2) composition. In some embodiments, the method of the present invention provides for substantially removing dimer impurities from the ketone (2) composition.

[0089] Figure 5Shows the diazotization route for preparing ketone (2) from aryl nitro starting materials. The diazotization route has drawbacks due to the possible formation of genotoxic intermediates (such as N-hydroxyaryl, N-nitrosoamines, and nitro compounds) of the compounds shown in the box. In some cases, removing these impurities and / or demonstrating their absence is costly and time-consuming, and sometimes difficult to achieve technically. Aspects of the method of the present invention include a synthetic route that substantially eliminates the undesirable minor components that may be via Figure 5 the route shown, thus circumventing the possibility of these toxic and / or undesirable compounds being present in the compositions of the present invention.

[0090] In some cases, the method of the present invention eliminates Figure 5 the isomer (e.g., regioisomer) by-products of the 3-trifluoroaniline starting material described in

[0091] These by-products can be present in the 3-trifluoroaniline composition, carried through the synthetic steps, and difficult to substantially eliminate from the downstream composition. In some cases of the method of the present invention, the crystallization of the acid (4) produced by the hydrolysis of the nitrile (5) provides the crystalline acid (4), which can easily remove these isomers early in the synthesis. Removing impurities and / or undesirable isomers early in the synthesis may be preferred, especially if such impurities are carried into the final product composition, because purification of the final product at the end of the synthesis is more expensive (e.g., loss of valuable product), and removing these minor components early in the synthesis before the raw materials enter the entire process has a greater impact on the cost of the commodity.

[0092] The method of the present invention includes a specific combination of synthetic routes and chemical reactions (e.g., as described above), which eliminates certain undesired reaction reagents and / or solvents (e.g., Class 1 or Class 2 solvents known or strongly suspected of carcinogenic activity and / or environmental hazards). Class 1 and Class 2 solvents of concern that can be removed from the fenfluramine composition by implementing the method of the present invention include, but are not limited to: any solvents listed on the International Conference on Harmonization (ICH) Q3C list and the industry guide (February 2012, Revision 2, US Department of Health and Human Services), such as acetonitrile, benzene and substituted benzenes, carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dimethoxyethane, DMF, 1,4-dioxane, methanol, methyl butyl ketone, N-methylpyrrolidone, pyridine, toluene, 1,1,1-trichloroethane, 1,1,2-trichloroethylene, and xylene. The method of the present invention can also eliminate various undesired and / or toxic reagents from the fenfluramine composition produced by implementing the method of the present invention. For example, by including a reductive amination step according to the method described in Scheme 1, an alternative synthetic route that requires the use of potentially toxic metal catalysts is avoided. By eliminating the use of such reagents and / or solvents from the synthetic route of the method of the present invention, potentially toxic minor components are eliminated from the fenfluramine composition. Thus, the fenfluramine composition of the present invention can be referred to as substantially free of the minor components of concern. In some cases, one or more potential heavy metal components, such as Pb, As, Cd, Hg, Pb, Co, Mo, Se, and V, are substantially eliminated. In certain cases, one or more Class 1 solvents are substantially removed (e.g., below the acceptable threshold adopted by ICH Q3C). In certain cases, benzene solvent is substantially removed, e.g., below a concentration limit of 2 ppm. In certain cases, carbon tetrachloride solvent is substantially eliminated, e.g., below a concentration limit of 4 ppm. In certain cases, 1,2-dichloroethane solvent is substantially removed, e.g., below a concentration limit of 5 ppm. In certain cases, 1,2-dichloroethane solvent is substantially removed, e.g., below a concentration limit of 8 ppm. In certain cases, 1,1,1-trichloroethane solvent is substantially removed, e.g., below a concentration limit of 1500 ppm. When fenfluramine is produced by a method in which minor components are not used in any synthetic step or are present in the raw materials, the minor components can be considered to be completely removed from the composition.

[0093] Fenfluramine alcohol

[0094] As used herein, the terms "fenfluramine alcohol" and "reductive alcohol byproduct" are used interchangeably and refer to the product of the reduction of a ketone to an alcohol that may occur in the reductive amination step of Scheme 1, as shown below.

[0095]

[0096] The method of the present invention can substantially eliminate fenfluramine alcohol in the composition. In some cases, the crude fenfluramine composition has less than 10% by weight of the reduced alcohol by-product, such as less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.9% by weight, less than 0.8% by weight, less than 0.7% by weight, less than 0.6% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, less than 0.05% by weight or even less. In some cases, the crude fenfluramine composition has equal to or less than 10% by weight of the reduced alcohol by-product, such as equal to or less than 9% by weight, equal to or less than 8% by weight, equal to or less than 7% by weight, equal to or less than 6% by weight, equal to or less than 5% by weight, equal to or less than 4% by weight, equal to or less than 3% by weight, equal to or less than 2% by weight, equal to or less than 1% by weight, equal to or less than 0.9% by weight, equal to or less than 0.8% by weight, equal to or less than 0.7% by weight, equal to or less than 0.6% by weight, equal to or less than 0.5% by weight, equal to or less than 0.2% by weight, equal to or less than 0.1% by weight, equal to or less than 0.05% by weight or even less.

[0097] Norfenfluramine

[0098] Norfenfluramine is a potential impurity in compositions containing fenfluramine. The method of the present invention can substantially eliminate norfenfluramine in the composition. In some cases, the crude fenfluramine composition has less than 10% by weight of norfenfluramine, such as less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.9% by weight, less than 0.8% by weight, less than 0.7% by weight, less than 0.6% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, less than 0.05% or even less. In some cases, the crude fenfluramine composition contains equal to or less than 10% by weight of norfenfluramine, such as equal to or less than 9% by weight, equal to or less than 8% by weight, equal to or less than 7% by weight, equal to or less than 6% by weight, equal to or less than 5% by weight, equal to or less than 4% by weight, equal to or less than 3% by weight, equal to or less than 2% by weight, equal to or less than 1% by weight, equal to or less than 0.9% by weight, equal to or less than 0.8% by weight, equal to or less than 0.7% by weight, equal to or less than 0.6% by weight, equal to or less than 0.5% by weight, equal to or less than 0.4% by weight, equal to or less than 0.3% by weight, equal to or less than 0.2% by weight, equal to or less than 0.1% by weight, equal to or less than 0.05% by weight or even less.

[0099] Method of Use

[0100] The fenfluramine and fenfluramine compositions described herein can be used in a variety of methods. Aspects of the present disclosure include a method that includes administering a therapeutically effective amount of a fenfluramine pharmaceutical composition (e.g., as described herein) to a subject in need thereof to treat or prevent a disease or disorder of interest. "Therapeutically effective amount" refers to the concentration of a compound sufficient to elicit the desired biological effect (e.g., treat or prevent epilepsy). Diseases and disorders of interest include, but are not limited to: epilepsy, nerve-related diseases, obesity, and obesity-related diseases.

[0101] In some embodiments, the method includes administering the composition to a subject to treat a nerve-related disease. Nerve-related diseases of interest include, but are not limited to, epilepsy and Dravet syndrome. In certain embodiments, the subject is a human. In certain cases, the patient has Dravet syndrome. In certain embodiments, the compound is administered as a pharmaceutical formulation.

[0102] Thus, according to another aspect of the present invention, there is provided a method of stimulating one or more 5-HT receptors in the brain of a patient by administering to the patient an effective dose of a fenfluramine composition, said one or more 5-HT receptors being selected from one or more of the following: 5-HT1, 5-HT 1A , 5-HT 1B , 5-HT 1C , 5-HT 1D , 5-HT 1E , 5-HT 1F , 5-HT2, 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT3, 5-HT4, 5-HT5, 5-HT 5A , 5-HT 5B , 5-HT6, and 5-HT7, etc. In some cases, the 5-HT receptor is 5-HT 2B . In certain embodiments of this aspect of the invention, the patient has been diagnosed with Dravet syndrome. In some cases, the method is a method of treating Dravet syndrome, which comprises stimulating one or more 5-HT receptors in the brain of the patient by administering to the patient an effective dose of a fenfluramine composition, said one or more 5-HT receptors being selected from one or more of 5-HT 1D , 5-HT 2A and 5-HT 2C , etc.

[0103] There are many genetic mutations indicative of Dravet syndrome. Mutations in SCN1A (such as partial or complete deletion mutations, truncating mutations and / or missense mutations, such as in the voltage or pore regions S4 to S6), SCN1B (such as the region encoding the sodium channel β1 subunit), SCN2A, SCN3A, SCN8A, SCN9A, GABRG2 (such as the region encoding the γ2 subunit), GABRD (such as the region encoding the δ subunit) and / or the PCDH19 gene are associated with Dravet syndrome.

[0104] Thus, according to another aspect of the present invention, there is provided a method of treating a patient exhibiting a mutation in one, some or all of the above genes by administering to the patient an effective dose of a fenfluramine composition. In certain embodiments of this aspect of the invention, the patient has been diagnosed with Dravet syndrome.

[0105] In an embodiment of the present invention, any effective dose of fenfluramine composition can be employed. However, the inventors unexpectedly found that low doses of fenfluramine composition are effective, particularly for suppressing or eliminating seizures in epileptic patients. Thus, in some cases, in a preferred embodiment of the present invention, the daily dose employed is less than about 10 mg / kg / day, such as less than about 9 mg / kg / day, less than about 8 mg / kg / day, less than about 7 mg / kg / day, less than about 6 mg / kg / day, less than about 5 mg / kg / day, less than about 4 mg / kg / day, less than about 3 mg / kg / day, less than about 2 mg / kg / day, less than about 1 mg / kg / day, such as about 1.0 mg / kg / day, about 0.9 mg / kg / day, about 0.8 mg / kg / day, about 0.7 mg / kg / day, about 0.6 mg / kg / day, about 0.5 mg / kg / day, about 0.45 mg / kg / day, about 0.4 mg / kg / day, about 0.3 mg / kg / day, about 0.25 mg / kg / day or from about 0.2 mg / kg / day to about 0.1 mg / kg / day, about 0.05 mg / kg / day, or about 0.01 mg / kg / day. Different, however, is that the preferred dose is less than about 10 mg / kg / day to about 0.01 mg / kg / day. In some cases, the dose is less than about 5 mg / kg / day to about 0.1 mg / kg / day, such as less than about 5 mg / kg / day to about 0.5 mg / kg / day, less than about 4 mg / kg / day to about 0.5 mg / kg / day, less than about 3 mg / kg / day to about 0.5 mg / kg / day, less than about 2 mg / kg / day to about 0.5 mg / kg / day, or less than about 1.7 mg / kg / day to about 0.9 mg / kg / day.

[0106] As described above, administration is based on the patient's body weight. However, for convenience, the dose may be, for example, an amount of 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg or 50 mg. In certain cases, the dose may be, for example, from about 0.25 mg to about 5 mg, such as about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5.0 mg. The amount of administration described herein may be administered once or multiple times per day to provide a daily dose, for example, once a day, twice a day, three times a day, or four times a day or more. In certain embodiments, the daily dose is 30 mg or less per day, such as 30 mg, about 29 mg, about 28 mg, about 27 mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg, about 22 mg, about 21 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg or about 1 mg. Generally, the minimum effective dose should be used for a particular patient. In certain cases, the dose is typically much lower than the dose for weight loss.

[0107] Administration of the pharmaceutical composition of the present invention may be systemic or local. In certain embodiments, administration to a mammal will result in systemic release of fenfluramine (e.g., into the bloodstream). Administration methods may include enteral routes, such as oral, buccal, sublingual and rectal administration; topical administration, such as transdermal and intradermal; and parenteral administration. Suitable parenteral routes include injection via a subcutaneous injection needle or catheter, such as intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarterial, intracardiac, intrathecal and intracameral injection and non-injection routes, such as intravaginal rectal administration or nasal administration. In certain embodiments, the compositions of the present disclosure are administered orally. In certain embodiments, it may be necessary to locally administer one or more of the compounds of the present invention to the area to be treated. This can be achieved, for example, by local infusion during topical administration, by catheter injection, by means of a suppository, or by an implant, which is a porous, non-porous or gel-like material, including membranes, such as silicone rubber membranes or fibers.

[0108] The dose of fenfluramine administered in the methods of the present invention can be formulated into any pharmaceutically acceptable dosage form, including but not limited to oral dosage forms, such as tablets, including orally disintegrating tablets, capsules, lozenges, oral solutions or syrups, oral emulsions, oral gels, oral films, oral liquids, powders, such as for suspensions, etc.; injectable dosage forms; transdermal dosage forms, such as transdermal patches, ointments, creams; inhalable dosage forms; and / or intranasal, rectal, vaginal dosage forms. Such dosage forms can be formulated for once-daily administration, or for multiple daily administrations (e.g., 2, 3, or 4 times daily).

[0109] In some embodiments, the method includes administering to a subject an appetite-suppressing amount of the compound to treat obesity. Any method of administration and dosage form of the compositions of the present invention can be used to treat obesity.

[0110] Combination therapies include administering a single pharmaceutical dosage formulation containing the composition of the present invention and one or more additional agents; and administering the composition of the present invention and one or more additional pharmaceuticals in their separate pharmaceutical dosage formulations. For example, the composition of the present invention and other drugs having appetite-suppressing activity (e.g., phentermine or topiramate) can be administered to a patient together in a single-dose composition (e.g., a combination formulation), or each agent can be administered in a separate dosage formulation. In the case of using separate dosage formulations, the composition of the present invention and one or more additional agents can be administered simultaneously, or at separate staggered times, e.g., sequentially.

[0111] In some embodiments, the methods of the present invention are in vitro methods that include contacting a sample with the composition of the present invention. There are many protocols that can be used in these methods, including but not limited to serotonin release assays from neuronal cells, cell-free assays, binding assays (e.g., 5HT2B receptor binding assays); cell assays in which cell phenotypes are measured, such as gene expression assays; and assays involving specific animal models for the disorder of interest (e.g., Dravet syndrome).

[0112] Pharmaceutical formulations

[0113] Also provided are pharmaceutical formulations comprising a fenfluramine active pharmaceutical ingredient composition prepared according to the methods of the present invention. A pharmaceutical formulation is a composition comprising a compound (alone or in the presence of one or more additional active agents) present in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a fenfluramine composition formulated in a pharmaceutically acceptable excipient (e.g., as described herein).

[0114] The choice of excipient can be determined in part by the specific compound, as well as by the specific method of administering the composition. Thus, there are a variety of suitable formulations of the pharmaceutical compositions of the present invention.

[0115] The dosage form of fenfluramine used in the method of the present invention can be prepared by combining a fenfluramine composition with one or more pharmaceutically acceptable diluents, carriers, adjuvants, etc. in a manner known to those skilled in the art of pharmaceutical formulations.

[0116] The composition of the present invention can be dissolved, suspended or emulsified in an aqueous or non-aqueous solvent, such as vegetable oil or other similar oils, synthetic fatty acid glycerides, esters of higher fatty acids or propylene glycol; if necessary, conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives are added, and then formulated into an injection.

[0117] In some embodiments, the formulations suitable for oral administration can include (a) liquid solutions, such as an effective amount of the compound dissolved in a diluent such as water or saline; (b) capsules, sachets or tablets, each containing a predetermined amount of the solid or particulate active ingredient (fenfluramine); (c) suspensions in a suitable liquid; and (d) suitable emulsions. Tablet forms can contain one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, gum arabic, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid and other excipients, coloring agents, diluents, buffering agents, wetting agents, preservatives, flavoring agents and pharmaceutically compatible excipients. Troche forms can contain the active ingredient in a flavoring agent (usually sucrose and gum arabic or tragacanth), as well as soft troches containing an inert base (such as gelatin and glycerin) or the active ingredient in sucrose, and gum arabic, emulsions, gels, etc., which contain the excipients described herein in addition to the active ingredient.

[0118] The formulations can be made into aerosol formulations for administration by inhalation. These aerosol formulations can be placed in a pressurized acceptable propellant, such as dichlorodifluoromethane, propane, nitrogen, etc. It can also be formulated as a non-pressurized drug formulation, such as for use in a nebulizer or atomizer.

[0119] In some embodiments, the formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostatic agents and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions containing suspending agents, solubilizers, thickening agents, stabilizers and preservatives. The formulations can be provided in unit dose or multi-dose sealed containers, such as ampoules and vials, and can also be stored under lyophilized (freeze-dried) conditions, and only need to add a sterile liquid excipient such as water for injection before use. The temporary injection solutions and suspensions can be prepared from the aforementioned sterile powders, granules and tablets.

[0120] Formulations suitable for topical administration can be made into creams, gels, pastes or foams, which contain, in addition to the active ingredient, for example, a suitable carrier. In some embodiments, the topical formulation contains one or more components selected from structurants, thickeners or gelling agents, as well as emollients or lubricants. Commonly used structurants include long-chain alcohols such as stearyl alcohol, and glycerol ethers or esters and oligo(ethylene oxide) ethers or their esters. Thickeners and gelling agents include, for example, polymers of acrylic acid or methacrylic acid and their esters, polyacrylamide, and naturally occurring thickeners such as agar, carrageenan, gelatin and guar gum. Examples of emollients include triglycerides, fatty acid esters and amides, waxes such as beeswax, cetyl wax or carnauba wax, phospholipids such as lecithin, and sterols and their fatty acid esters. The topical formulation may also contain other components, such as astringents, fragrances, pigments, skin penetration enhancers, sunscreens (e.g., sunscreens), etc.

[0121] For oral solid pharmaceutical formulations, suitable excipients include pharmaceutical-grade carriers such as mannitol, lactose, glucose, sucrose, starch, cellulose, gelatin, magnesium stearate, sodium saccharin, and / or magnesium carbonate. For use in oral liquid formulations, the composition can be prepared as a solution, suspension, emulsion or syrup, provided in solid or liquid form, which is suitable for hydration in an aqueous carrier, such as saline, aqueous dextrose, glycerol or ethanol, preferably water or normal saline. If desired, the composition may also contain small amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents or buffering agents.

[0122] By way of illustration, the fenfluramine composition can be mixed with conventional pharmaceutically acceptable carriers and excipients (i.e., carriers) and used in the form of aqueous solutions, tablets, capsules, elixirs, suspensions, syrups, films, etc. In certain embodiments, the pharmaceutical composition contains from about \(0.1\%\) to about \(90\%\) by weight of the active compound, and more typically, from about \(1\%\) to about \(30\%\) by weight of the active compound. The pharmaceutical composition may contain common carriers and excipients, such as, for example, corn starch or gelatin, lactose, dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid. Disintegrants commonly used in the formulations of the present invention include cross-linked carboxymethyl cellulose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

[0123] A particular formulation of the present invention is in liquid form. The liquid can be a solution or a suspension, and can be an oral solution or syrup, which is contained in a bottle with a dropper scale, measured in milligram amounts, which will be obtained in a given volume of solution. The liquid solution allows for adjustment of the solution for pediatric use, any dose from \(0.5\) mg to \(15\) mg can be given, and it can be administered in any amount in half-milligram increments between \(0.5\) mg, \(1.0\) mg, \(1.5\) mg, \(2.0\) mg, etc.).

[0124] The liquid composition will generally consist of a suspension or solution of the compound or a pharmaceutically acceptable salt in a suitable liquid carrier, such as ethanol, glycerol, sorbitol, a non-aqueous solvent such as polyethylene glycol, an oil or water, along with suspending agents, preservatives, surfactants, wetting agents, flavoring agents or coloring agents. Alternatively, the liquid formulation can be prepared from a reconstitutable powder.

[0125] Examples

[0126] The following examples are provided to fully disclose and describe to those of ordinary skill in the art how to make and use the present invention. These examples are not intended to limit the scope of the invention as perceived by the inventors, nor do they represent that the following experiments are all or the only experiments conducted. Efforts have been made to ensure the accuracy of the values used (such as amounts, temperatures, etc.), but some experimental errors and deviations are allowed. Unless otherwise indicated, parts are parts by weight, molecular weights are weight-average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. "Average" means arithmetic mean. Standard abbreviations can be used, such as s or sec for seconds; min for minutes; h or hr for hours; aa for amino acid; i.m. for intramuscular; i.p. for intraperitoneal; s.c. for subcutaneous; and so on.

[0127] General synthesis process

[0128] Many general references are available which provide known chemical synthetic schemes and conditions for synthesizing the disclosed compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, Wiley-Interscience, 2001); or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, 4th Edition, New York: Longman, 1978).

[0129] The compounds described herein can be purified by any purification method known in the art, including chromatographic methods such as HPLC, preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal phase and reverse phase as well as ionic resins. In certain embodiments, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, edited by L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edited by E. Stahl, Springer-Verlag, New York, 1969.

[0130] During the preparation of any target compound, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved by conventional protecting groups as described in standard works, such as J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999, "The Peptides"; Volume 3 (Eds.: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden der organischen Chemie", Houben-Weyl, Fourth Edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982, and / or Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate", Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed in a convenient subsequent stage using methods known in the art.

[0131] The compounds of the present invention can be synthesized using commercially available starting materials and / or starting materials prepared by conventional synthetic methods via a variety of different synthetic routes. Various examples of synthetic routes that can be used to synthesize the compounds disclosed herein are described in the following schemes.

[0132] Example 1

[0133] 1. Naming and structure of fenfluramine

[0134] Chemical Abstracts Service (CAS) Registry Number (RN): 404-82-0 (hydrochloride), 458-24-2 (parent free base)

[0135] Chemical Name: N-Ethyl-α-methyl-3-(trifluoromethyl)phenethylamine hydrochloride (1:1). Other Names: Fenfluramine Hydrochloride, DL-Fenfluramine, (±)-Fenfluramine

[0136] Structure of the hydrochloride:

[0137]

[0138] Stereochemistry: Fenfluramine hydrochloride has one chiral center and is developed as a racemate and contains dexfenfluramine and levofenfluramine

[0139] Molecular formula of the hydrochloride: C12H16F3N·HCl

[0140] Molecular weight / Weight: 267.72 g / mol

[0141] 2. General properties

[0142] Table 1 summarizes the chemical and physical properties of fenfluramine hydrochloride.

[0143] Table 1: General characteristics of fenfluramine hydrochloride drug

[0144]

[0145]

[0146] 3. Synthesis of fenfluramine drug

[0147] Scheme 3.1 shows a two-step synthetic route for manufacturing the initial clinical supply of fenfluramine hydrochloride from ketone (2). The batch size is 4 kg in laboratory glassware (kilogram laboratory). Chromatography is not required and the process steps can be scaled up. In Method 1, starting from commercially available 1-(3-(trifluoromethyl)phenyl)acetone (ketone 2), there is an isolated intermediate fenfluramine free base (1). All steps are carried out under cGMP starting from ketone (2).

[0148] Scheme 3.1 Synthetic process scheme of fenfluramine hydrochloride (Route 1)

[0149]

[0150] MTBE = Methyl-tert-butyl ether, EtOAc = Ethyl acetate.

[0151] Scheme 3.2 shows a four-step synthetic route for phentermine hydrochloride that can be used for commercial supply. Route 2 converts ketone (2) to phentermine hydrochloride using the same two-step method as Route 1, except that ketone (2) is synthesized starting from 3-(trifluoromethyl)phenylacetic acid (acid 4) under cGMP conditions. The bisulfite complex (3) is a separable solid that can be purified before being broken down into ketone (2). The in situ intermediates shown in parentheses are oily. The batch size is 10 kg. The commercial batch of 20 kg was carried out in a fixed pilot plant facility. Steps 1-2 of preparing ketone (2) in Scheme 3.2 have been demonstrated to provide a high purity ketone (2) of >99.8% (GC and HPLC) on a 100 g scale. Converting ketone (2) to phentermine using Route 1 or Route 2 provides similar purity profiles.

[0152] Scheme 3.2 Phentermine Hydrochloride Synthesis Process Scheme (Route 2)

[0153]

[0154] The starting materials are shown in the enclosed boxes. The compounds in parentheses and without parentheses represent the proposed in situ and isolated intermediates, respectively. NMI = N-methylimidazole.

[0155] 4.1. Narrative description (Route 1)

[0156] Step 1: Reductive amination (Preparation of fenfluramine free base 1)

[0157] A solution of ethylamine, water, methanol, and 1-(3-(trifluoromethyl)phenyl)acetone (ketone 2) was treated with sodium triacetoxyborohydride and stirred at 25 °C for 16 hours. At this time, HPLC analysis (IPC-1; Process Control No. 1) showed that the reaction was complete, and sodium hydroxide solution was added until pH > 10. Toluene was added and the phases were separated. The remaining phentermine and phentermine alcohol in the aqueous phase (IPC-2) and organic phase (IPC-3) were checked, and the organic phase decreased. Purified water was added and the pH was adjusted to <2 using concentrated hydrochloric acid, and the phases were separated. The aqueous phase was washed with toluene, and the phentermine and phentermine alcohol contents in the toluene phase (IPC-4) and aqueous phase (IPC-5) were checked. The pH of the aqueous phase containing the product was adjusted to >10 using sodium hydroxide solution. The basic aqueous phase was extracted with MTBE until phentermine was observed to be removed from the aqueous phase by HPLC (<0.5 mg / ml) (IPC-6). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the intermediate phentermine free base 1 as a pale yellow oil, which was tested according to the instructions described herein. NMR showed that the material contained 2.93% toluene, providing an 88.3% active yield and a purity of 98.23% (0.67% phentermine alcohol) by HPLC.

[0158] Step 2: Salt formation (Preparation of fenfluramine hydrochloride)

[0159] Add ethanol and acetyl chloride to the flask. Stir the solution slowly overnight, then add ethyl acetate. Filter the HCl in the formed ethyl acetate solution through fine filtration into a clean glass bottle for later use. Add fenfluramine free base 1 and MTBE to the container. Collect the fenfluramine solution in MTBE into two glass bottles, then clean the container and check for particulate residues. Filter the fenfluramine solution through fine filtration into the container and cool it. Add HCl in the ethyl acetate solution to obtain a final pH of 6 - 7. Stir the batch for 1 hour and filter. The product is dried under vacuum at 40 °C. Test the product according to IPC - 7 (96.52% yield), the purity measured by HPLC is 99.75%, and GC headspace analysis shows the presence of MTBE (800 ppm) and EtOAc (150 ppm). Then test the product according to the instructions described herein.

[0160] 4.2. Narrative description (Route 2)

[0161] Step 1: Preparation of ketone bisulfite adduct

[0162]

[0163] Procedure: Add acetic anhydride (2.8 volumes, 3.0 weights, 5.0 equivalents) to a container and start stirring. Cool the solution to -5 to 5 °C, aiming for -4 °C. Add 1-methylimidazole (0.2 volumes, 0.21 weights, 0.5 equivalents) to the mixture at -5 to 5 °C. Caution: Substantial heat release. If necessary, adjust the temperature to 0 to 5 °C. Add ZX008 acid (1.00 weight, 1.0 equivalent) to the mixture at 0 to 5 °C. Caution: Heat release. Stir the mixture at 0 to 5 °C until the ZX008 acid area by HPLC analysis is ≤ 2.1%, typically 7 to 9 hours. Add 15% w / w sodium chloride solution (2.0 volumes) to the mixture at 0 - 5 °C, 60 - 90 minutes. Caution: Substantial heat release, with a slight delay. Warm the mixture to 18 to 23 °C within 45 to 60 minutes and continue stirring at 18 to 23 °C for 30 to 45 minutes. Add TBME (5.0 volumes, 3.7 weights) to the mixture and stir at 18 to 23 °C for 10 to 15 minutes. Separate the aqueous layer and retain the organic layer. Back-extract the aqueous layer with TBME (2 x 3.0 volumes, 2 x 2.2 weights) at 18 to 23 °C, retaining each organic layer. Adjust the pH of the combined organic layers to pH 6.5 to 9.0 by adding 20% w / w sodium hydroxide solution (5.3 to 8.3 volumes) at 18 to 23 °C. Caution: Heat release. Separate the aqueous layer and retain the organic layer. Wash the organic layer with 4% w / w sodium bicarbonate solution (2 × 3.0 volumes) at 18 to 23 °C. Determine the residual ZX008 acid content in the organic layer by HPLC analysis, with an area of ZX008 acid ≤ 0.10% as the passing standard. Wash the organic layer with purified water (2 × 3.0 volumes) at 18 to 23 °C. Concentrate the organic layer under reduced pressure to approximately 2 volumes at 40 to 45 °C, aiming for 43 °C.

[0164] Determine the w / w assay of ZX008 ketone (WIP) in the mixture by 1H-NMR analysis for reference only and calculate the yield of ZX008 ketone (WIP) contained in the mixture. Note: This step can be omitted from the procedure as the procedure provides a stable and consistent yield of 80% to 90%. The yield achieved is factored into the cost of subsequent steps.

[0165] At 40 - 45 °C, target 43 °C, n - heptane (4.0 volumes, 2.7 weights) was added to the mixture. At 40 - 45 °C, target 43 °C, the mixture was concentrated to approximately 2 volumes. The TBME content in the mixture was determined by 1H - NMR analysis (TBME ≤ 5.0% w / w compared to ZX008 ketone is the passing standard). At 40 to 45 °C, target 43 °C, n - heptane (2.4 volumes, 1.6 weights) was added to vessel A. At 18 - 23 °C, sodium metabisulfite (0.82 weights, 0.88 equivalents) was added to vessel B. Under the condition of 18 - 23 °C, a solution of sodium bicarbonate (0.16 weights, 0.4 equivalents) in purified water (code RM0120 (2.0 volumes)) was added to vessel B, and then rinsed with purified water, code RM0120 (0.4 volumes) at 18 - 23 °C. Caution: Gas evolution. The content of vessel B was heated to 40 to 45 °C, target 43 °C. The content of vessel A was added to vessel B, and then rinsed with n - heptane (0.8 volumes, 0.5 weights) at 40 - 45 °C, target 43 °C. At 40 to 45 °C, target 43 °C, the mixture was stirred for 1 to 1.5 hours. n - heptane, code RM0174 (3.2 volumes, 2.2 weights) was added to the mixture, and the temperature was cooled to 18 - 45 °C at the end of the addition. The mixture was cooled to 18 to 23 °C at a substantially constant rate within about 45 to 60 minutes. The mixture was stirred at 18 to 23 °C for 1.5 to 2 hours.

[0166] Sample determination of the mixture was carried out by 1H - NMR analysis to determine the residual ZX008 ketone content (ZX008 ketone ≤ 10.0% mol relative to the ZX008 ketone bisulfite adduct, target 5.0% mol, passing standard). The mixture was filtered and the filter cake was slurried with n - heptane (2×2.0 volumes, 2×1.4 weights) at 18 to 23 °C. The solid was dried at up to 23 °C until the water content by KF analysis according to AKX reagent ≤ 10.0% weight. For at least 16 hours. The w / w determination of the separated ZX008 ketone bisulfite adduct was carried out by 1H - NMR analysis and the yield of the contained ZX008 ketone bisulfite adduct was calculated.

[0167] Yield and characteristics: The yields of the first - stage demonstration batches are summarized in the following table. According to the preparation method, input: 1700.0 g uncorrected, acid, 99.50 area% (QC, HPLC), 2 - isomer not detected, 4 - isomer 0.02 area%, RRT 1.58 (not observed in the past) 0.48 area%. Table 1A below summarizes the analytical data:

[0168] Table 1A: Table of the isolated yields of the step 1 demonstration batches

[0169]

[0170] Step 2: Preparation of ketone

[0171]

[0172] Procedure: Add toluene (5.0 volumes, 4.3 weights) and purified water (5.0 volumes) into a container and start stirring. If necessary, adjust the temperature to 18 - 23 °C, and add ZX008 ketone bisulfite adduct (1.00 weight, corrected for % w / w determination) to the mixture at 18 - 23 °C. Add 20% w / w sodium hydroxide solution to the mixture at 18 - 23 °C, and adjust the pH of the mixture to pH 8.0 - 12.0, with a target of 9.0 (0.5 - 1.0 volumes).

[0173] Separate the lower aqueous layer and retain the top organic layer. Wash the organic layer with purified water (3.0 volumes) at 18 to 23 °C. Concentrate the organic layer to approximately 2 volumes under reduced pressure at 45 to 50 °C, with a target of 48 °C. Add methanol (5.0 volumes, 4.0 weights) to the mixture at 45 - 50 °C, with a target of 48 °C. Concentrate the mixture to approximately 2 volumes again under reduced pressure at 45 - 50 °C, with a target of 48 °C. Repeat steps 7 and 8 once, then continue with step 9. Cool the mixture to 18 - 23 °C. Decant the mixture into a tared, appropriately sized drum, and then rinse it with methanol (1.0 volume, 0.8 weight) at 18 - 23 °C. Determine the w / w determination of ZX008 ketone (WIP) in the mixture by 1H-NMR analysis, and calculate the yield of ZX008 ketone (WIP) contained in the mixture. Determine the toluene content in the mixture by 1H-NMR analysis.

[0174] Yield and Characterization: The yields of the Phase 2 demonstration batches are summarized in Table 1B below. Input: 1200.0 g of corrected ketone bisulfite adduct, 76.0% w / w determination (NMR, using DMB as internal standard, d6-DMSO), (1.00 equivalent, 1.00 weight corrected for w / w determination), for input calculation.

[0175] Table 1B: Table of Isolated Yields for Step 2 Demonstration Batches

[0176]

[0177] Step 3: Preparation of crude fenfluramine hydrochloride

[0178]

[0179] Procedure: Add ZX008 ketone (corrected for analysis, 1.00 weight, 1.00 equivalent, separated as a solution in MEOH in Stage 2) to a container. At 18 - 23 °C, add methanol, code RM0036 (5.0 volumes, 4.0 weights) to the mixture. Cool the solution to 0 - 5 °C. At 0 - 10 °C, add 70 wt% aqueous ethylamine solution (1.3 volumes, 1.6 weights, 4.0 equivalents) to the mixture over a period of 15 - 30 minutes, then rinse with methanol (1.0 volume, 0.8 weight). Warm the mixture to 15 - 20 °C and stir the mixture at 15 - 20 °C for an additional 60 - 70 minutes. If necessary, adjust the mixture to 15 - 18 °C, target 15 °C. Add sodium triacetoxyborohydride (2.4 weights, 2.25 equivalents) to the mixture in approximately 10 portions, keeping the mixture at 15 - 20 °C, target 17 °C. The addition time is 1.5 - 2 hours. Caution: Exothermic. Stir the mixture at 15 - 20 °C until HPLC detection is complete, with a passing criterion of ZX008 ketone area ≤ 3.0%, typically 2 - 3 hours. Adjust the pH of the mixture to pH > 12 by adding 20 wt% aqueous sodium hydroxide solution (5.0 - 6.0 volumes) to the mixture at 15 - 40 °C. The addition time is 10 - 30 minutes. Caution: Exothermic. If necessary, adjust the temperature to 18 - 23 °C. Extract the mixture with toluene (3 x 3.0 volumes, 3 x 2.6 weights) at 18 - 23 °C, retaining and combining the top organic layer after each extraction. Wash the combined organic layer with purified water (1.0 volume) at 18 - 23 °C. Heat the mixture to 40 - 50 °C, target 48 °C. At 40 - 50 °C, target 48 °C, add the organic layer at a rate approximately the same as the distillation rate, and concentrate the mixture under reduced pressure while maintaining a constant volume of approximately 5 volumes. Cool the mixture to 18 - 23 °C. Add purified water (10.0 volumes) to the mixture at 18 - 23 °C. Adjust the pH of the mixture to 0.1 ≤ pH ≤ 1.5 by adding concentrated hydrochloric acid 0.5 volume at 18 - 23 °C. Do not delay from this step until neutralization.

[0180] Separate the layers at 18 - 23 °C and retain the aqueous layer at the bottom. Wash the aqueous layer with toluene (3.0 volumes, 2.6 weights) at 18 - 23 °C and retain the aqueous layer. Adjust the pH of the aqueous layer to pH > 12 by adding 0.8 - 0.9 volumes of 20 wt% aqueous sodium hydroxide solution at 18 - 23 °C. Caution: Exothermic. Add TBME, code RM0002 (2.0 volumes, 1.5 weights) to the alkaline aqueous layer. Separate the layers at 18 - 23 °C and retain the organic layer. Back - extract the aqueous layer with TBME (2 x 2.0 volumes, 2 x 1.5 weights) at 18 to 23 °C and retain the organic layer. Wash the combined organic layer with purified water (2 × 1.0 volume) at 18 to 23 °C. Concentrate the combined organic layer under reduced pressure to approximately 3 volumes at 40 to 50 °C, target 48 °C. Determine the residual toluene content in the mixture by 1H - NMR analysis. Determine the residual water content of the sample by KF analysis, AKX reagent. Add TBME (8.7 volumes, 6.4 weights) to the mixture at 40 - 50 °C. Cool the solution to 0 - 5 °C, target 2 °C. Add concentrated hydrochloric acid (0.54 volume, 0.46 weight), keeping the temperature < 15 °C. Caution: Exothermic. Rinse with TBME (1.0 volume, 0.7 weight). If necessary, adjust the temperature to 0 - 10 °C and stir the mixture at 0 - 10 °C for 2 - 3 hours. Filter the mixture at 0 - 10 °C and wash the filter cake with TBME (2 x 4.4 volumes, 2 x 3.3 weights). Dry the solid at up to 40 °C until the TBME content determined by 1H - NMR is ≤ 0.5% w / w TBME. 4 - 8 hours.

[0181] Yield and characteristics: The yields of the Phase 3 demonstration batches are summarized in Table 1C below. Input: 856.8 g of corrected ketone, 44.2% w / w determined (NMR, using TCNB as internal standard, in CDCl3), (1.00 equivalent, 1.00 weight corrected for w / w determination), for input calculation. Figure 2 And Table 1D shows an exemplary HPLC chromatogram (210 nm UV absorbance) of crude fenfluramine hydrochloride. <*

[0182] Table 1C: Table of isolated yields for the Step 3 demonstration batches.

[0183]

[0184]

[0185] Table 1D: HPLC determination of the purity of crude fenfluramine hydrochloride (see Figure 2 )

[0186] -------- Process channel description DAD AU Ch1 Sample 210, Bw4 Peak results

[0187]

[0188] Step 4.2: Crystallization of fenfluramine hydrochloride

[0189]

[0190] Procedure: Add fenfluramine hydrochloride (crude) (1.00 weight, 1.0 equivalent) and TBME (10.0 volumes, 7.4 weight) to a container and start stirring. Heat the suspension to reflux (50 - 58 °C). Add ethanol (5.0 volumes, 3.9 weight), maintaining the temperature at 50 - 58 °C. The addition time is 20 minutes. Stir for 5 - 10 minutes at 50 - 58 °C and check for dissolution. Stir the solution for 5 - 10 minutes at 50 - 58 °C, aiming for 54 - 58 °C. Filter the reaction mixture through a 0.1 μm tandem filter at 54 - 58 °C, then rinse with TBME (1 volume, 0.7 weight). Cool the solution to 48 - 50 °C. Add fenfluramine hydrochloride, code FP0188 (0.01 weight). Check for crystallization. Cool the suspension to 15 - 20 °C at a roughly constant rate over 5 - 5.5 hours, aiming for 17 °C. Stir the mixture for 2 - 3 hours at 15 - 20 °C, aiming for 17 °C. Filter the mixture at 5 - 15 °C and wash the filter cake with TBME (2 x 3 volumes, 2 x 2.2 weight). Dry the solid at up to 40 °C until the 1H-NMR determination shows that the TBME content is ≤ 0.5% w / w TBME and the ethanol content is < 0.5% w / w EtOH. 4 - 8 hours. Determine the w / w of the isolated fenfluramine hydrochloride by 1H-NMR analysis.

[0191] Yield and Characteristics: The yields of the Phase 4 demonstration batches are summarized in Table 1E below. Input: 750.0 g of uncorrected crude fenfluramine hydrochloride (1.00 equivalent, 1.00 weight uncorrected) was used for input calculations. [[ID= An exemplary HPLC chromatogram (210 nm UV absorbance) of a crystalline fenfluramine hydrochloride sample is shown.

[0192] Table 1E: Table of Isolated Yields for Phase 4 Demonstration Batches

[0193]

[0194] ​

[0195] Table 2 summarizes the process controls (IPCs) by the IPC numbers cited in the narrative process used in Process 1 above.

[0196] Table 2: Process Controls Conducted in Process 1

[0197]

[0198] ​

[0199] This section provides information and specification controls for the raw materials used in the production of clinical supplies of fenfluramine according to the routes shown herein.

[0200] Table 3: Raw materials for Route 1.

[0201]

[0202] Table 4: Raw materials for Route 2.

[0203]

[0204] Table 5 provides a list of intermediates for the synthesis of Route 2. The two routes share the same intermediate fenfluramine free base (1). Fenfluramine free base (1) is treated as a separated intermediate during Route 1. However, in Route 2, fixed equipment is used where both the ketone (2) and fenfluramine free base 1 (two inseparable oils) are combined as a solution and controlled as an in-situ intermediate. The bisulfite complex (3) is separated as a solid and is thus suitable for treatment as a separated intermediate and is released as such. Before recrystallization, the crude fenfluramine hydrochloride can be separated as an intermediate.

[0205] Specifications and test strategies for the use of intermediates. Based on the evaluation of the primary stability batch data and the study of the critical parameters of process validation, additional tests and acceptance criteria are added. Analytical reference standards are used for the comprehensive characterization of each intermediate. The HPLC methods used for the determination of assays and impurities are the same as those for the drug substance release method and are validated for accuracy, precision, repeatability, intermediate precision, selectivity / specificity, detection limit, quantitation limit, linearity, range, and robustness.

[0206] Table 5: In-situ and separated intermediates

[0207]

[0208]

[0209] ​

[0210] Physicochemical properties of the drug.

[0211] Fenfluramine hydrochloride is developed as a single polymorphic form 1. Polymorphism and pre-formulation studies have been conducted. Over a wide range of solvents and conditions, crystal materials are produced from the same polymorph 1 based on well-defined XRPD patterns and consistent reproducible endotherms analyzed by DSC. The following provides a summary of the physicochemical properties of fenfluramine hydrochloride from this study. The tabulated data includes example diffraction patterns, DSC, and micrographs.

[0212] The characteristics of the input phentermine hydrochloride (from precipitation separation) provide reference data and also determine whether the salt has the same form as the previously determined salt formed. The XRPD pattern of the salt reveals a crystalline solid that visually matches the reflection pattern obtained from the official crystallization of phentermine hydrochloride and has been arbitrarily designated as polymorph 1. Comparison of the μATR-FTIR data of the salt from each batch gives a 99.95% match.

[0213] The thermal data analysis matches the previous data obtained with only one major endothermic peak on the DSC temperature recorder, which peaks at 172.3 °C and matches the onset of potential decomposition shown in the TGA temperature plot. This also corresponds to the melting point reported in the reference standard.

[0214] The isolation of the amorphous form has proven difficult, and attempts using three common methods (rapid solvent evaporation, anti-solvent precipitation, and lyophilization) all produced highly crystalline solids that very closely share the same XRPD pattern of the input form 1.

[0215] The stability analysis of the salt at 40 °C / 0% RH for one week, at 40 °C / 75% RH for three weeks, and under photostability conditions shows that the input form 1 is maintained and no new impurities are observed at the 0.1% threshold.

[0216] The results of the DSC thermal cycling analysis of phentermine hydrochloride are comparable to those obtained when the material is maintained at 170 °C. No crystallization events are noted and no amorphous form is produced, but instead form 1 is returned.

[0217] Maintaining phentermine hydrochloride at approximately 170 °C for several hours results in melting and evaporation events, followed by recrystallization and cooling to provide a white solid. Analysis of the white solid by XRPD, DSC, and 1 H NMR shows no change in chemical or physical form, purity, or decomposition.

[0218] The forced degradation studies conducted have demonstrated that phentermine hydrochloride is stable under a range of conditions. Thermal conditioning of phentermine hydrochloride repeatedly produces the input form 1.

[0219] ​

[0220] Impurities in the drug can be organic impurities (process impurities or drug-related degradants), inorganic impurities (salt residues or metals), and residual solvents; it is necessary to evaluate whether some of these impurities are genotoxic agents. These impurities are taken into account and controlled during the preparation of phentermine hydrochloride, either by using brief or validated analytical methods according to the instructions, or by separate "for reference only" tests. The following sections describe the actual and potential impurities of phentermine hydrochloride.

[0221] ​

[0222] There are no impurities reported in batches of cGMP drugs for human use that exceed the ICH Q3A defined threshold of 0.15% (Table 8). All impurities >0.1% are identified and handled as described in ICH Q3A, unless they are genotoxic impurities.

[0223] ​

[0224] Table 6 lists the known potential impurities resulting from the synthetic route. By process changes and / or controlling the input purity of raw materials, all these impurities are controlled below the ICH Q3A defined threshold of 0.15%.

[0225] Table 6: Known potential process impurities of fenfluramine hydrochloride (Route 1)

[0226]

[0227]

[0228] 1) ICH Q3A defined threshold. The reporting threshold (LOQ) of the HPLC method is 0.05%.

[0229] ​

[0230] Based on forced degradation studies under thermal (solid, solution), acid, base, oxidation conditions of ICH Q1A(R2) and photostability conditions of ICH Q1B (solid, solution), no change in impurity profile was observed during long-term storage. Fenfluramine hydrochloride was stable for 7 days as a solid at 150 °C (99.90% parent area), as a solution in water - acetonitrile at 70 °C (99.73% parent area), and as a solution under acidic, basic or photosensitive conditions under ambient conditions. Only the oxidation condition (peroxide condition) degraded fenfluramine hydrochloride to 94.42% after 1 day, producing approximately 1% of several new related substances, each of which was found to be consistent with the +16 oxidation by-product by LC-MS analysis.

[0231] ​

[0232] Table 11 in the batch analysis section summarizes the amounts found in the solvents used in the process and the drug. All solvents used in the GMP steps are controlled within the ICH Q3A limits using a suitable Head-Space (HS) GC method.

[0233] ​

[0234] Heavy metals comply with USP <231> or ICP method USP <233> and ICH Q3D.

[0235] ​

[0236] The ICH guidelines Q3A and Q3B are not sufficient to provide guidance on DNA reactive impurities. The European Medicines Agency (EMA) guideline (2006) "Guideline on the Limits of Genotoxic Impurities" (EMA 2006) and the ICH guideline M7 (2014) "Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk" (ICH guideline M7) are taken into account when controlling potential genotoxic impurities. Due to the possible formation of genotoxic intermediates (such as N-hydroxyaryl, N-nitroamine, and nitro compounds) that give rise to the compounds shown in the box, ​ The diazotization route shown for the preparation of ketone (2) has drawbacks. Muller et al. (Regulatory Toxicology and Pharmacology 44(2006)198-211) listed potential functional alert groups that may be genotoxic. Safety guidelines and regulations indicate that the analysis of the handling and identification of potential genotoxic substances and the control of these impurities below 10 parts per million are crucial for safety. Generally, the removal of these impurities and / or the demonstration of their absence is costly and time-consuming, and sometimes difficult to achieve technically. For these reasons, it is important to select a possible synthetic route that avoids such toxic intermediates. Due to the potential problems with the diazo route discussed above, as well as the potential safety issues with the use of diazo (shock-sensitive) intermediates and the lower purity profile of this route, this route is less preferred compared to the preferred route for the synthesis of ketone (2) starting from nitrile (5). This route does not produce potential genotoxic agents and yields high-purity ketone (2) after sequential separation by distillation or by hydrolysis of the bisulfite adduct.

[0237] In addition, attempts to remove the isomeric by-products present in the commercial supply of aniline were unsuccessful, while crystallization of the acid (4) produced from the hydrolysis of nitrile (5) yielded crystalline acid (4), which can be purified at the early stage of the synthesis to remove the isomers. If it is known that such impurities will trace to the final product, then it is preferred to remove these impurities and / or isomers early in the synthesis because the loss required for crystallizing the final product at the end of the synthesis is higher and affects the product cost to a much greater extent than the removal at an early stage of the synthesis before the raw materials are introduced throughout the process.

[0238] Table 7: Potential Impurities in the Synthesis of Fenfluramine

[0239]

[0240] Table 8: Batch Analysis of Phentermine Hydrochloride Drug

[0241]

[0242]

[0243] a) These tests have recently been added to the specification, so only the most recent batches have been tested using this test.

[0244] b) These tests have been removed from the specification, so only historical batches that used this test have been tested.

[0245] ​

[0246] ​

[0247]

[0248] Table 9

[0249]

[0250]

[0251] Expected yield: varies from 60 - 90%. Uncorrected 68 - 103% w / w

[0252] Expected purity: 93.00 - 99 area % by HPLC assay

[0253] ​

[0254] ​

[0255] The impurities formed in the Dakin - West chemical process and subsequently removed by distillation or by separating the product ketone as a bisulfite are described. The two main impurities found are shown below.

[0256]

[0257] Table 10 shows the analytical data tables of the crude ketone (2) isolated from the Dakin-West reaction before and after bisulfite purification. In entry 1, the crude ketone (pre-bisulfite treatment) directly isolated from the Dakin-West step was 61.66% pure (e.g., about 62%) and contained 1.98% (e.g., about 2%) and 4.64% (e.g., about 5%) of impurities with RRT 1.20 and 1.34, respectively, which were considered acetate and dimer impurities (e.g., as described above). In entry 2 after bisulfite treatment, other impurities were removed, resulting in an overall purity of 95.55% (e.g., about 96%). The other entries shown in Table 10 provide other examples of such impurity enhancement of the crude Dakin-West ketone by bisulfite treatment. The last two entries used pure Fluorchem ketone as the input for the salt formation step and re-isolation of the ketone, thereby demonstrating that salt formation and re-isolation themselves do not produce any impurities. Additionally, the additional use of a bicarbonate extraction process during the work-up of the reaction provided an improvement in the purity of the resulting composition for removing any unreacted acid. The crude ketone (2) prepared by the diazotization method showed a similar improvement in purity when treated with bisulfite and isolated.

[0258] Table 10: Analytical purity data of the crude ketone (2) isolated from the Dakin-West reaction before and after bisulfite purification. RRT is the relative retention time (minutes) in chromatography.

[0259]

[0260] Entry 1 (crude ketone from Route 1); Entry 2 (ketone from Route 1 after bisulfite release); Entry 3 (crude ketone using crude acid); Entry 4 (ketone using crude acid after bisulfite); Entry 5 (crude ketone using crystalline acid); Entry 6 (crude ketone using crystalline acid after bisulfite); Entry 7 (crude ketone using crystalline acid); Entry 8 (Fluorochem ketone); Entry 9 (Fluorochem ketone after bisulfite).

[0261] ​

[0262]

[0263] ​

[0264] 35 mL of water and 45 g of a 37% (w / w) aqueous hydrochloric acid solution were added to a flask equipped with a stirrer and a dropping funnel. After cooling to 10 °C with an ice bath, 24.25 g (0.151 mol) of m-trifluoromethylaniline was added, and then an aqueous solution containing 12.43 g (0.180 mol) of sodium nitrite in 150 mL of water was slowly added at 5 °C. The reaction mixture was stirred for 30 minutes and then poured within 30 minutes into a mixture consisting of 90 mL of water, 1.35 g (0.014 mol) of copper(I) chloride, 2.30 g (0.013 mol) of copper(II) chloride dihydrate, 50 mL of acetone, 40.8 g (0.300 mol) of sodium acetate trihydrate, and 23 g (0.230 mol) of isopropenyl acetate, while maintaining the reaction temperature at 30 °C. After stirring for another 30 minutes, the reaction mixture was brought to 20 °C, 50 mL of dichloromethane was added, and the two layers were separated.

[0265] The aqueous layer was discarded, and the organic layer was concentrated in vacuo until an oil was obtained. The oil was stirred for 12 hours at room temperature and treated with 35 g of sodium metabisulfite, 70 mL of water, and 150 mL of heptane. The suspension was filtered, and the bisulfite complex was washed on the filter with 50 mL of heptane and then suspended in a two-phase mixture consisting of 100 mL of dichloromethane and 150 mL of a 10% (w / v) aqueous sodium hydroxide solution. After stirring for 1 hour at room temperature, the layers were separated, the aqueous phase was discarded, and the organic layer was washed with water and evaporated in vacuo to give the pure ketone.

[0266] Notwithstanding the appended claims, the disclosure set forth herein is also defined by the following clauses:

[0267] Clause 1: A method for preparing a fenfluramine active pharmaceutical ingredient, the method comprising:

[0268] (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition;

[0269] (b) reacting the 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to prepare a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and

[0270] (c) reductively aminating the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with a borohydride reducing agent and ethylamine to produce a fenfluramine composition.

[0271] Clause 2: The method according to Clause 1, wherein the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition comprises at least 0.2% by weight of trifluoromethyl-phenyl regioisomers.

[0272] Clause 3: The method according to any one of Clauses 1 and 2, wherein the 2-(3-(trifluoromethyl)phenyl)acetonitrile composition is prepared from trifluoromethylbenzene.

[0273] Clause 4: The method according to any one of Clauses 1-3, further comprising purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition prior to step (b) to produce a composition substantially free of one or more trifluoromethylphenyl regioisomers and substantially free of trifluoromethylbenzaldehyde and benzaldehyde.

[0274] Clause 5: The method according to Clause 4, wherein the purification comprises crystallizing 2-(3-(trifluoromethyl)phenyl)acetic acid from the composition.

[0275] Clause 6: The method according to any one of Clauses 1-5, wherein step (b) comprises purifying the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition by a ketone bisulfite adduct.

[0276] Clause 7: The method according to any one of Clauses 1-6, wherein step (b) comprises selectively reacting 2-(3-(trifluoromethyl)phenyl)acetic acid in the presence of unreacted 2-(2-(trifluoromethyl)phenyl)acetic acid.

[0277] Clause 8: The method according to any one of Clauses 1-7, wherein step (b) further comprises removing unreacted 2-(2-(trifluoromethyl)phenyl)acetic acid regioisomers from the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition.

[0278] Clause 9: The method according to any one of Clauses 1-8, wherein the fenfluramine composition is crude and substantially free of: trifluoromethyl-phenyl regioisomers of florfenfluramine or its salts; metal catalysts; Class I and / or Class II solvents (ICH Q3C) (e.g., benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, and / or 1,1,1-trichloroethane); and reduced alcohol by-products.

[0279] Clause 10: The method according to any one of Clauses 1-9, wherein the fenfluramine composition is crude and has less than a total of 1% by weight of trifluoromethyl-phenyl regioisomers of fenfluramine or its salts.

[0280] Clause 11: The method according to any one of Clauses 1-10, wherein the borohydride reducing agent is sodium triacetoxyborohydride.

[0281] Clause 12: The method according to any one of Clauses 1-11, wherein the fenfluramine composition is crude and has less than 10% by weight of reduced alcohol by-products.

[0282] Clause 13: The method as described in any one of Clauses 1 - 12 further includes crystallizing fenfluramine or its salt from a fenfluramine composition.

[0283] Clause 14: The method as described in Clause 1, wherein step (a) is carried out under aqueous acid conditions.

[0284] Clause 15: The method as described in Clause 14, wherein the yield of step (a) is 80% or higher.

[0285] Clause 16: The method as described in Clause 1, wherein step (b) is carried out under conditions including contacting a 2-(3-(trifluoromethyl)phenyl)acetic acid composition with about 0.5 equivalents of 1-methylimidazole and about 5 equivalents or more of acetic anhydride in an optional solvent.

[0286] Clause 17: The method as described in Clause 16, wherein the yield of step (b) is 80% or higher.

[0287] Clause 18: The method as described in Clause 1, wherein step (c) is carried out under conditions including contacting a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with a 70 wt% aqueous solution of ethylamine and a solution of about 2.25 equivalents or more of triacetoxyborohydride dissolved in a methanol solvent.

[0288] Clause 19: The method as described in Clause 18, wherein the yield of step (c) is 80% or higher.

[0289] Clause 20: The method as described in Clause 1, wherein the fenfluramine composition has the following characteristics: at least 80 wt% of fenfluramine or its salt; less than 1 wt% of 2-fenfluramine or its salt; less than 1 wt% of 4-fenfluramine or its salt; and less than 10 wt% of a fenfluramine reduced alcohol by-product.

[0290] Clause 21: The method as described in any one of Clauses 1 - 20 further includes converting the fenfluramine in the fenfluramine composition into a pharmaceutically acceptable salt of fenfluramine.

[0291] Clause 22: The method as described in Clause 21 further includes crystallizing the pharmaceutically acceptable salt of fenfluramine from the fenfluramine composition.

[0292] Clause 23: The method as described in Clause 22, wherein the pharmaceutically acceptable salt of fenfluramine has the following purity characteristics: at least 90% or more of the pharmaceutically acceptable salt of fenfluramine; less than 1 wt% of 2-fenfluramine; less than 5 wt% of 4-fenfluramine; and less than 5 wt% of a fenfluramine reduced alcohol by-product.

[0293] Clause 24: A method as described in any one of Clauses 20 - 22, wherein the pharmaceutically acceptable salt of fenfluramine is fenfluramine hydrochloride.

[0294] Clause 25: A method as described in any one of Clauses 1 - 20, further comprising purifying the fenfluramine free base from a fenfluramine composition.

[0295] Clause 26: A method as described in any one of Clauses 1 - 25, further comprising performing a chiral separation of a racemic fenfluramine composition to produce a non - racemic fenfluramine composition comprising the major stereoisomer of fenfluramine.

[0296] Clause 27: A method as described in Clause 26, wherein the major stereoisomer of fenfluramine is (S)-N - ethyl - 1 - [3 - (trifluoromethyl)phenyl] - propan - 2 - amine.

[0297] Clause 28: A method as described in Clause 26, wherein the major stereoisomer of fenfluramine is (R)-N - ethyl - 1 - [3 - (trifluoromethyl)phenyl] - propan - 2 - amine.

[0298] Clause 29: A fenfluramine composition produced by the method according to any one of Clauses 1 - 28.

[0299] Clause 30: A fenfluramine active pharmaceutical ingredient comprising a pharmaceutically acceptable salt of fenfluramine and having less than a total of 0.2% by weight of trifluoromethyl regioisomers.

[0300] Clause 31: The fenfluramine active pharmaceutical ingredient as described in Clause 30, having the following characteristics: at least 90% by weight of the pharmaceutically acceptable salt of fenfluramine; less than 0.2% by weight of 2 - fenfluramine; less than 0.2% by weight of 4 - fenfluramine; and less than 1% by weight of fenfluramine alcohol.

[0301] Clause 32: The fenfluramine active pharmaceutical ingredient as described in any one of Clauses 30 - 31, wherein heavy metal components are substantially or completely removed from the composition.

[0302] Clause 33: The fenfluramine active pharmaceutical ingredient as described in any one of Clauses 30 - 31, wherein Class 1 and / or Class 2 solvents are substantially or completely removed from the composition (e.g., the fenfluramine active pharmaceutical ingredient as described in any one of Clauses 30 - 31 is substantially free of Class 1 and / or Class 2 solvents).

[0303] Clause 34: The fenfluramine active pharmaceutical ingredient as described in any one of Clauses 30 - 33, wherein fenfluramine alcohol is completely removed from the composition.

[0304] Clause 35: A fenfluramine active pharmaceutical ingredient as described in any one of Clauses 30 - 34, wherein benzaldehyde and trifluorobenzaldehyde are substantially or completely removed from the composition.

[0305] Clause 36: A fenfluramine active pharmaceutical ingredient as described in any one of Clauses 30 - 35, wherein the composition is not purified.

[0306] Clause 37: A pharmaceutical composition comprising a fenfluramine active pharmaceutical ingredient as described in any one of Clauses 30 - 36 and a pharmaceutically acceptable excipient.

[0307] The foregoing merely illustrates the principles of the present invention. It is to be understood that those skilled in the art can devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within the spirit and scope of the invention. Moreover, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the contribution the invention makes to the advancement of the art, and are not to be construed as limitations to these specifically recited examples and conditions. Also, all statements herein regarding the principles, aspects, embodiments, and specific examples of the invention are to include their structural and functional equivalents. Additionally, these equivalents are to include both currently known equivalents and equivalents developed in the future, i.e., any newly developed elements having the same function regardless of their structure. Therefore, the scope of the present invention is not limited to the exemplary embodiments shown and described herein. Appropriately, the scope and spirit of the present invention are defined by the appended claims.

Claims

1. Use of a preparation comprising fenfluramine as an active pharmaceutical ingredient in the preparation of a medicament for treating a neurological disease, wherein the fenfluramine as an active pharmaceutical ingredient is prepared by a method comprising the following steps: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition by crystallization to produce purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% total trifluoromethyl-phenyl regioisomer; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminated the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition using a borohydride reducing agent and ethylamine to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount; The fenfluramine active pharmaceutical ingredient has less than 0.2% by weight of 4-fenfluramine or a salt thereof.

2. The use according to claim 1, wherein The 2-(3-(trifluoromethyl)phenyl)acetonitrile composition is prepared from trifluoromethylbenzene.

3. The use according to claim 1, wherein In the method for preparing the fenfluramine active pharmaceutical ingredient, step (c) comprises purifying the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition via a ketone bisulfite adduct.

4. The use according to claim 1, wherein The fenfluramine active pharmaceutical ingredient: Containing at least 0.01% by weight of the trifluoromethyl-phenyl regioisomer of fenfluramine or a salt thereof and free of: Metal catalysts; a solvent selected from the group consisting of acetonitrile, benzene and substituted benzenes, carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dimethoxyethane, DMF, 1,4-dioxane, methanol, methyl butyl ketone, N-methylpyrrolidone, pyridine, toluene, 1,1,1-trichloroethane, 1,1,2-trichloroethylene, and xylene; and Having less than 5% by weight of reduced alcohol by-product.

5. The use according to claim 1, wherein In the method for preparing the fenfluramine active pharmaceutical ingredient, step (c) is carried out under conditions comprising contacting the 2-(3-(trifluoromethyl)phenyl)acetic acid composition with about 0.5 equivalents of 1-methylimidazole and about 5 equivalents or more of acetic anhydride in an optional solvent.

6. The use according to claim 1, wherein In the method for preparing the fenfluramine active pharmaceutical ingredient, step (d) is carried out under conditions comprising contacting the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition with a 70 wt% aqueous solution of ethylamine and a solution of about 2.25 equivalents or more of triacetoxyborohydride dissolved in a methanol solvent.

7. The use according to claim 1, wherein The fenfluramine active pharmaceutical ingredient has the following characteristics: At least 80% by weight of fenfluramine or a salt thereof at least 0.01% by weight of 2-fenfluramine or a salt thereof; at least 0.01% by weight of 4-fenfluramine or a salt thereof; and Less than 10% by weight of fenfluramine reduced alcohol by-product.

8. The use according to claim 1, wherein: The method for preparing the fenfluramine active pharmaceutical ingredient further comprises the step of purifying fenfluramine free base.

9. The use according to claim 1, wherein: The method for preparing the fenfluramine active pharmaceutical ingredient further comprises performing chiral separation of the racemic fenfluramine composition to produce a non-racemic fenfluramine composition comprising a major stereoisomer of fenfluramine.

10. The use according to claim 1, wherein: In the method for preparing the fenfluramine active pharmaceutical ingredient, the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.1% by weight of 4-trifluoromethyl-phenyl regioisomer.

11. The use according to claim 1, wherein: In the method for preparing the fenfluramine active pharmaceutical ingredient, the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition of step (b) has less than 0.1% by weight of 2-trifluoromethyl-phenyl regioisomer.

12. The use according to claim 1, wherein: The fenfluramine active pharmaceutical ingredient comprises at least 0.01% by weight of 4-fenfluramine or a salt thereof.

13. The use according to claim 1, wherein: The fenfluramine active pharmaceutical ingredient comprises at least 0.01% by weight of 2-fenfluramine or a salt thereof.

14. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.3% by weight of the fenfluramine active pharmaceutical ingredient.

15. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.4% by weight of the fenfluramine active pharmaceutical ingredient.

16. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.5% by weight of the fenfluramine active pharmaceutical ingredient.

17. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 1.0% by weight of the fenfluramine active pharmaceutical ingredient.

18. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 1.5% by weight of the fenfluramine active pharmaceutical ingredient.

19. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 2.0% by weight of the fenfluramine active pharmaceutical ingredient.

20. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 3.0% by weight of the fenfluramine active pharmaceutical ingredient.

21. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 4.0% by weight of the fenfluramine active pharmaceutical ingredient.

22. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 5.0% by weight of the fenfluramine active pharmaceutical ingredient.

23. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 10% by weight of the fenfluramine active pharmaceutical ingredient.

24. The use according to claim 1, wherein: The at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount of at least 0.2% by weight of the fenfluramine active pharmaceutical ingredient.

25. Use of a preparation comprising fenfluramine as an active pharmaceutical ingredient in the preparation of a medicament for treating a neurological disease, wherein the fenfluramine as an active pharmaceutical ingredient is prepared by a method comprising the following steps: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition by crystallization to produce purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% total trifluoromethyl-phenyl regioisomer; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminated the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition using a borohydride reducing agent and ethylamine to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount; The fenfluramine active pharmaceutical ingredient has less than 1.0 weight percent of a reduced alcohol by-product.

26. The use according to claim 25, wherein the fenfluramine active pharmaceutical ingredient is prepared by a method comprising the following steps: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition by crystallization to produce purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% total trifluoromethyl-phenyl regioisomer; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminated the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition using a borohydride reducing agent and ethylamine to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount; The method for preparing the fenfluramine active pharmaceutical ingredient further comprises crystallizing fenfluramine or its salt from the crude fenfluramine composition.

27. Use of a preparation comprising fenfluramine as an active pharmaceutical ingredient in the preparation of a medicament for treating a neurological disease, wherein the fenfluramine as an active pharmaceutical ingredient is prepared by a method comprising the following steps: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition by crystallization to produce purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% total trifluoromethyl-phenyl regioisomer; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminated the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition using a borohydride reducing agent and ethylamine to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount; The preparation method of the fenfluramine active pharmaceutical ingredient further comprises the following steps: converting fenfluramine into a pharmaceutically acceptable salt of fenfluramine; and Crystallizing a pharmaceutically acceptable salt of fenfluramine, wherein the pharmaceutically acceptable salt of fenfluramine has the following purity characteristics: At least 95% of a pharmaceutically acceptable salt of fenfluramine; at least 0.01% by weight of 2-fenfluramine; at least 0.01% by weight of 4-fenfluramine; and Less than 0.1 wt% of fenfluramine reduced alcohol by-product.

28. The use according to any one of claims 1 to 27, wherein the method for preparing the fenfluramine active pharmaceutical ingredient further comprises: The fenfluramine active pharmaceutical ingredient is converted to fenfluramine hydrochloride.

29. Use of a preparation comprising fenfluramine as an active pharmaceutical ingredient in the preparation of a medicament for treating a neurological disease, wherein the fenfluramine as an active pharmaceutical ingredient is prepared by a method comprising the following steps: (a) hydrolyzing a 2-(3-(trifluoromethyl)phenyl)acetonitrile composition to produce a 2-(3-(trifluoromethyl)phenyl)acetic acid composition; (b) purifying the 2-(3-(trifluoromethyl)phenyl)acetic acid composition by crystallization to produce purified 2-(3-(trifluoromethyl)phenyl)acetic acid having less than 0.2% total trifluoromethyl-phenyl regioisomer; (c) reacting the purified 2-(3-(trifluoromethyl)phenyl)acetic acid composition with acetic anhydride and a catalyst to produce a 1-(3-(trifluoromethyl)phenyl)propan-2-one composition; and (d) reductively aminated the 1-(3-(trifluoromethyl)phenyl)propan-2-one composition using a borohydride reducing agent and ethylamine to produce a fenfluramine active pharmaceutical ingredient comprising at least one trifluoromethyl-phenyl regioisomer of fenfluramine, wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in an amount; The preparation method of the fenfluramine active pharmaceutical ingredient further comprises the following steps: converting fenfluramine into a pharmaceutically acceptable salt of fenfluramine; and Crystallizing a pharmaceutically acceptable salt of fenfluramine, wherein the pharmaceutically acceptable salt of fenfluramine has the following purity characteristics: At least 99% of a pharmaceutically acceptable salt of fenfluramine; at least 0.01% by weight of 4-fenfluramine; and Less than 0.1 wt% of fenfluramine reduced alcohol by-product.

30. The use according to claim 1, wherein: The neurological disease is epilepsy.

31. The use according to claim 30, wherein: The epilepsy is Dravet syndrome.

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