Compound AX-Bn capable of improving metabolic activity and preparation method thereof

Abstract

The invention relates to a compound AX-Bn capable of improving metabolic activity. The compound contains trifluoromethyl phenylacetic acid, an organic solvent, a condensing agent, alkali and a reducing agent, the preparation method comprises the following steps: dissolving a compound 3-trifluoromethyl phenylacetic acid in an organic solvent, sequentially adding a condensing agent and alkali, stirring for 24 hours, detecting, after the reaction is completed, adding saturated ammonium chloride, extracting for three times, washing an organic phase with saturated ammonium chloride and a saline solution respectively, drying with anhydrous sodium sulfate, and filtering and concentrating to obtain a crude product ketone; dissolving the crude ketone solution in the organic solvent, adding benzylamine and a reducing agent, reacting at room temperature overnight, adding sodium hydroxide to adjust the pH value to 10, extracting and concentrating to obtain crude amine; dissolving the crude amine in ethyl acetate, introducing hydrogen chloride gas until the pH value of the system is about 1-3, stirring overnight, evaporating to dryness, adding ethyl acetate for washing to obtain a white solid, and drying to obtain AX-Bn; the method is simple to operate, high in yield and suitable for large-scale preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a compound AX-Bn with enhanced metabolic activity and a preparation method thereof. Background Art

[0002] Metabolism, also known as metabolism, generally refers to a series of orderly chemical reactions that occur in organisms to maintain life. These reaction processes enable organisms to grow and reproduce, maintain their structure, and respond to the external environment. Metabolic diseases are diseases caused by metabolic problems, including metabolic disorders and hypermetabolism. Metabolic disorders may lead to the occurrence of many diseases such as diabetes and hypertension. Therefore, it is of great significance to find compounds that can improve metabolic activity.

[0003] Fenfluramine (3-trifluoromethyl-N-ethylamphetamine) is an amphetamine derivative first introduced in France in 1963, initially as an antidepressant and later as an appetite suppressant. It was approved in the United States in 1973, where it is used alone or in combination with phentermine. Figure 5 As shown, fenfluramine is a chiral molecule with one stereocenter and has been marketed as the racemate (Pondimin®) as well as the individual d-enantiomers (also known as dexfenfluramine or (S)-fenfluramine or (+)-fenfluramine) as fenfluramine (Redux®). In 1996, shortly after the approval of dexfenfluramine, reports of cases of valvular heart disease and primary pulmonary hypertension surfaced. A prospective case-control study published by Abenhaim and colleagues involved 95 patients taking fenfluramine, dexfenfluramine, or a fenfluramine-phentermine combination who developed primary pulmonary hypertension. One year later, the understanding of the benefit-risk balance of fenfluramine was dramatically changed by reports of valvular heart disease (primarily mitral and aortic regurgitation) in 24 women taking the fenfluramine-phentermine combination for 1 to 28 months (mean, 11 months). Soon after, the manufacturer announced a voluntary withdrawal of fenfluramine and dexfenfluramine from the market.

[0004] On June 25, 2020, the U.S. Food and Drug Administration (FDA) approved racemic fenfluramine hydrochloride oral solution for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older. On December 21, 2020, the same formulation was approved in the European Union (EU) for the same indication, but European approval is limited to use as add-on therapy for other recently licensed antiepileptic drugs in the EU. In the United States and Europe, the maximum approved daily dose of racemic fenfluramine is 0.7 mg / kg (up to 26 mg), reduced to a maximum of 0.4 mg / kg (not to exceed 17 mg) in patients taking it in combination with stiripentol and clobazam.

[0005] Fenfluramine has also been shown to be a positive modulator of σ1 receptors. σ1 receptor agonists are effective anti-amnestic compounds, especially against learning and memory deficits caused by dizocillin. Studies have shown that fenfluramine racemate and (+)-fenfluramine can significantly alleviate dizocillin-induced learning deficits at doses of 0.3 and 1 mg / kg, and fenfluramine has a synergistic effect when used in combination with σ1 receptor agonists (PRE-084) or σ1 receptor-acting neurosteroids.

[0006] Compound AX-Bn is a new compound with the function of enhancing appetite and improving metabolism, which was discovered during the study of fenfluramine. The present invention aims to provide a new compound AX-Bn with the function of improving metabolic activity and a preparation method thereof. Summary of the invention

[0007] The purpose of the present invention is to solve the shortcomings of the prior art mentioned in the background technology, and to propose a compound AX-Bn with enhanced metabolic activity and a preparation method thereof.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions: A compound AX-Bn with enhanced metabolic activity, comprising trifluoromethylphenylacetic acid, an organic solvent, a condensing agent, a base, and a reducing agent; prepared by the following method: S1, dissolving the compound 3-trifluoromethylphenylacetic acid in an organic solvent, and adding a condensing agent and a base in sequence, stirring for 24 hours and then testing, and post-processing after the reaction is complete; S2. After the reaction is complete, add saturated ammonium chloride and extract three times. The organic phase is washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude ketone, and directly proceed to the next step; S3, dissolving the crude ketone in an organic solvent, adding benzylamine and a reducing agent, reacting at room temperature overnight, adding sodium hydroxide to adjust the pH to 10, extracting, and concentrating to obtain a crude amine; S4. The crude amine was dissolved in ethyl acetate, and hydrogen chloride gas was introduced until the pH of the system was about 1-3. After stirring overnight, the mixture was evaporated to dryness, and ethyl acetate was added for washing to obtain a white solid, which was then dried to obtain AX-Bn.

[0009] As a further feature of the method of the present invention, the organic solvent described in S1 and S3 refers to N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, and acetonitrile.

[0010] As a further step in the method of the present invention, the condensing agent described in S1 refers to dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0011] As a further feature of the method of the present invention, the base in S1 refers to 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0012] As a further step in the method of the present invention, the reducing agent described in S3 refers to sodium borohydride, sodium triacetoxyborohydride, zinc borohydride, N,N-dimethylamino lithium borohydride, sodium cyanoborohydride, lithium borohydride, and lithium triisobutylborohydride.

[0013] As a further step in the method of the present invention, a method for preparing a compound AX-Bn having enhanced metabolic activity is more specifically: Step 1: dissolving the compound 3-trifluoromethylphenylacetic acid in N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or acetonitrile, and sequentially adding condensing agents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and bases such as 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), stirring for 24 hours and then testing. After the reaction is complete, post-treatment is performed by adding saturated ammonium chloride and extracting three times. The organic phase is washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude ketone, which is directly carried out to the next step; Step 2: The crude ketone is dissolved in an organic solvent such as N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or acetonitrile, benzylamine and a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, zinc borohydride, N,N-dimethylamino lithium borohydride, sodium cyanoborohydride, lithium borohydride or lithium triisobutylborohydride are added, and the reaction is carried out at room temperature overnight, and then sodium hydroxide is added to adjust the pH to 10, and the mixture is extracted and concentrated to obtain amine. The crude amine is dissolved in ethyl acetate, and hydrogen chloride gas is introduced to a system pH of about 1-3. After stirring overnight, the mixture is evaporated to dryness, and ethyl acetate is added to wash the mixture to obtain a white solid, which is then dried to obtain AX-Bn.

[0014] Compared with the prior art, the present invention has the following beneficial effects: The compound AX-Bn with enhanced metabolic activity of the present invention has the advantages of simple preparation method, high yield, easy separation and purification, and the reagents used are all commonly used reagents. At the same time, this method can easily achieve 100-gram-level preparation in the laboratory, which is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 It is a schematic diagram of the molecular formula of the compound 3-trifluoromethylphenylacetic acid; Figure 2 It is a schematic diagram of the molecular formula of crude ketone; Figure 3 The accompanying figure with the abstract is a schematic diagram of the molecular formula of compound AX-Bn; Figure 4 Schematic diagram of the synthetic route of compound AX-Bn; Figure 5 Dexfenfluramine, levofenfluramine, (S)-desethylfenfluramine, Schematic diagram of the molecular formula of (R)-desethylfenfluramine; DETAILED DESCRIPTION

[0016] The content of the present invention can be more easily understood by selecting the following detailed description of the preferred implementation method of the present invention and the embodiments included. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs. When there is a conflict, the definition in this specification shall prevail.

[0017] As used herein, the term "prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0018] The conjunction "consisting of excludes any unspecified element, step, or component. If used in a claim, this phrase renders the claim closed-ended so that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of" appears in a clause of the body of a claim rather than immediately following the subject matter, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0019] When amount, concentration or other value or parameter is expressed as range, preferred range or a series of upper preferred value and lower preferred value limit range, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value and any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when disclosing range "1 to 5", described range should be interpreted as including range "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5" etc. When numerical range is described in this article, unless otherwise stated, the range is intended to include its end value and all integers and fractions within the range.

[0020] Singular forms include plural references unless the context clearly indicates otherwise. "Optional" or "either" means that the subsequently described event or incident may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0021] Approximate terms in the specification and claims are used to modify quantities, indicating that the present invention is not limited to the specific quantity, but also includes acceptable and modified parts close to the quantity without causing changes in the relevant basic functions. Accordingly, the use of "about", "approximately", etc. to modify a numerical value means that the present invention is not limited to the exact numerical value. In some examples, the approximate terms may correspond to the accuracy of the instrument for measuring the numerical value. In the specification and claims of this application, range limitations can be combined and / or interchanged, and if not otherwise stated, these ranges include all subranges contained therein.

[0022] In addition, the indefinite articles "a" and "an" before the elements or components of the present invention have no restrictions on the quantity requirements (i.e. the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the elements or components in the singular form also include the plural form, unless the number is obviously intended to be in the singular form.

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0024] Embodiment 1 Reference Figure 1-4 , a compound AX-Bn with enhanced metabolic activity, containing trifluoromethylphenylacetic acid, an organic solvent, a condensing agent, a base, and a reducing agent; prepared by the following method: S1, dissolving the compound 3-trifluoromethylphenylacetic acid in an organic solvent, and adding a condensing agent and a base in sequence, stirring for 24 hours and then testing, and post-processing after the reaction is complete; S2. After the reaction is complete, add saturated ammonium chloride and extract three times. The organic phase is washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude ketone, and directly proceed to the next step; S3, dissolving the crude ketone in an organic solvent, adding benzylamine and a reducing agent, reacting at room temperature overnight, adding sodium hydroxide to adjust the pH to 10, extracting, and concentrating to obtain a crude amine; S4. The crude amine was dissolved in ethyl acetate, and hydrogen chloride gas was introduced until the pH of the system was about 1-3. After stirring overnight, the mixture was evaporated to dryness, and ethyl acetate was added for washing to obtain a white solid, which was then dried to obtain AX-Bn.

[0025] The organic solvents described in S1 and S3 above refer to N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, and acetonitrile; The condensing agent described in S1 refers to dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; The base described in S1 refers to 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0026] As a further step in the method of the present invention, the reducing agent described in S3 refers to sodium borohydride, sodium triacetoxyborohydride, zinc borohydride, N,N-dimethylamino lithium borohydride, sodium cyanoborohydride, lithium borohydride, and lithium triisobutylborohydride.

[0027] Embodiment 2 Reference Figure 1-4 , a method for preparing a compound AX-Bn having enhanced metabolic activity, more specifically: Step 1: dissolving the compound 3-trifluoromethylphenylacetic acid in N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or acetonitrile, and sequentially adding condensing agents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and bases such as 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), stirring for 24 hours and then testing. After the reaction is complete, post-treatment is performed by adding saturated ammonium chloride and extracting three times. The organic phase is washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude ketone, which is directly carried out to the next step; Step 2: The crude ketone is dissolved in an organic solvent such as N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform or acetonitrile, benzylamine and a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, zinc borohydride, N,N-dimethylamino lithium borohydride, sodium cyanoborohydride, lithium borohydride or lithium triisobutylborohydride are added, and the reaction is carried out at room temperature overnight, and then sodium hydroxide is added to adjust the pH to 10, and the mixture is extracted and concentrated to obtain amine. The crude amine is dissolved in ethyl acetate, and hydrogen chloride gas is introduced to a system pH of about 1-3. After stirring overnight, the mixture is evaporated to dryness, and ethyl acetate is added to wash the mixture to obtain a white solid, which is then dried to obtain AX-B.

[0028] Embodiment 3 The compound (3-trifluoromethylphenylacetic acid) (150 g) was dissolved in 2.5 liters of dichloromethane, and dicyclohexylcarbodiimide (1 eq) and 4-dimethylaminopyridine (1 eq) were added in sequence. After stirring for 24 hours, the reaction was detected. After the reaction was complete, saturated ammonium chloride was added, and the dichloromethane was extracted three times. The organic phase was washed with saturated ammonium chloride and brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude ketone compound (63.6 g, 50%). The crude ketone compound (10 g) was dissolved in 60 ml of dichloromethane, and benzylamine (2 eq) and sodium triacetoxyborohydride (1.5 eq) were added at room temperature. The temperature was naturally raised to react overnight. Sodium hydroxide was added to adjust the pH to 10, and the mixture was extracted and concentrated to obtain amine. The crude amine was dissolved in ethyl acetate, and hydrogen chloride gas was introduced until the pH of the system was about 1-3. After stirring overnight, the mixture was evaporated to dryness, and ethyl acetate was added for washing to obtain a white solid, which was dried to obtain AX-Bn (9.6 g, 70%).

[0029] 1 HNMR (400MHz, DMSO- d6)δ9.90-9.70(m,1H),7.67-7.60(m,2H),7.49-7.28(m,11H),4.38-4.30(m,2H),4.04-3.94(m,1H),3.52-3.45(m,2H),3.04-2.94(m,2H).

[0030] Embodiment 4 The compound 3-trifluoromethylphenylacetic acid (150 g) was dissolved in 2.5 liters of dichloromethane, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 eq) and 4-dimethylaminopyridine (1 eq) were added in sequence. The mixture was stirred for 24 hours and then tested. After the reaction was complete, saturated ammonium chloride was added and the mixture was extracted with dichloromethane three times. The organic phase was washed with saturated ammonium chloride and brine respectively, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude ketone compound (76.3 g, 60%). The crude ketone compound (10 g) was dissolved in 60 ml of dichloromethane, and benzylamine (2 eq) and sodium borohydride (1.5 eq) were added at room temperature. The temperature was naturally raised to react overnight, and sodium hydroxide was added to adjust the pH to 10. The mixture was extracted and concentrated to obtain amine. The crude amine was dissolved in ethyl acetate, and hydrogen chloride gas was introduced until the pH of the system was about 1-3. After stirring overnight, the mixture was evaporated to dryness, and ethyl acetate was added for washing to obtain a white solid, which was dried to obtain AX-Bn (1.37 g, 10%).

[0031] The examples referred to herein are merely illustrative and are used to explain some features of the method of the present invention. The appended claims are intended to claim the widest possible range that can be imagined, and the embodiments presented herein are only illustrations of selected implementations according to the combination of all possible embodiments. Therefore, it is the applicant's intention that the appended claims are not limited by the selection of examples that illustrate the features of the present invention. Some numerical ranges used in the claims also include sub-ranges within them, and changes in these ranges should also be interpreted as being covered by the appended claims where possible.

Claims

1. A compound AX-Bn having enhanced metabolic activity, characterized in that: Contains trifluoromethylphenylacetic acid, organic solvent, condensing agent, alkali, and reducing agent; Prepared by the following method: S1, dissolving the compound 3-trifluoromethylphenylacetic acid in an organic solvent, and adding a condensing agent and a base in sequence, stirring for 24 hours and then testing, and post-processing after the reaction is complete; S2. After the reaction is complete, add saturated ammonium chloride and extract three times. The organic phase is washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude ketone, and directly proceed to the next step; S3, dissolving the crude ketone in an organic solvent, adding benzylamine and a reducing agent, reacting at room temperature overnight, adding sodium hydroxide to adjust the pH to 10, extracting, and concentrating to obtain a crude amine; S4. The crude amine was dissolved in ethyl acetate, and hydrogen chloride gas was introduced until the pH of the system was about 1-3. After stirring overnight, the mixture was evaporated to dryness, and ethyl acetate was added for washing to obtain a white solid, which was then dried to obtain AX-Bn.

2. The method for preparing a compound AX-Bn having enhanced metabolic activity according to claim 1, characterized in that: The organic solvents described in S1 and S3 are N,N-dimethylformamide, dichloromethane, tetrahydrofuran, ethyl acetate, chloroform, and acetonitrile.

3. The method for preparing a compound AX-Bn having enhanced metabolic activity according to claim 1, characterized in that: The condensing agent described in S1 refers to dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

4. The method for preparing a compound AX-Bn having enhanced metabolic activity according to claim 1, characterized in that: The base described in S1 refers to 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

5. The method for preparing a compound AX-Bn having enhanced metabolic activity according to claim 1, characterized in that: The reducing agent described in S3 refers to sodium borohydride, sodium triacetoxyborohydride, zinc borohydride, N,N-dimethylamino lithium borohydride, sodium cyanoborohydride, lithium borohydride, and lithium triisobutylborohydride.

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