Synthesis method of etifusin

Abstract

The invention provides a synthesis method of etifoxacin, and relates to the technical field of organic synthesis, and the synthesis method comprises the following steps: adding triphenylmethyl phosphorus bromide into a solvent, adding potassium tert-butoxide at 0-5 DEG C to obtain a suspension, preparing a 2-aminobenzophenone solution, reacting the suspension at room temperature for 30-40 minutes, adding the 2-aminobenzophenone solution into the suspension, and reacting for 30-40 minutes at room temperature to obtain the etifoxacin. Completely reacting to obtain a compound 2; dissolving the compound 2 in dichloromethane, dropwise adding ethyl isocyanate, heating to room temperature, and reacting to obtain a compound 3; mixing the compound 3, Selectfluor and a compound A, adding acetonitrile, and reacting at room temperature for 60-70 minutes to obtain a compound 4; and reacting the compound 4 and sodium borohydride in ultra-dry dimethyl sulfoxide at room temperature under the protection of nitrogen to obtain etifusin. The compound A is selected from any one of potassium iodide, Selectfluor, tetrabutylammonium chloride and tetrabutylammonium bromide. According to the invention, synthesis of etifusin is realized by a metal-free catalysis and green chemical method, and the yield is high.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically to a method for synthesizing etefoxine. Background Technology

[0002] The chemical name of etefoxine is [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine]. Etefocin hydrochloride (Stresam) is used in France to treat anxiety disorders. Etefocin was originally disclosed in U.S. Patent No. 3,725,404. Although etefoxine is chiral, to the inventors' knowledge, there are no disclosures regarding its resolution or asymmetric synthesis. Etefocin has a depressant effect on the central nervous system and is an anticonvulsant. It also has sedative, prolonged anesthesia, and analgesic properties, see, for example, Corisco et al., Psychopharmacologia (Berl) 45, 301-303, 1976.

[0003] Etefoxin hydrochloride has been extensively studied and reported for the treatment of a variety of diseases. For example, European Patent No. EP1273301, German Patent No. DE3439055, and US Patents Nos. 3,725,404 and 6,638,528 disclose its use as an anticonvulsant, sedative, and anxiolytic. It has also been reported as a modulator of GABA receptor complex activity; see Hamon et al., 2003, *Neuropharmacology*, 45, 293-303.

[0004] In recent years, etefoxine has been prepared by selective cyclization with diaryl alkenes under palladium catalysis, as shown in Scheme 1 below. For example, useful chiral ligands for obtaining enantiomeric etefoxine are provided in the Journal of Organic Chemistry, Vol. 63, p. 5071, 1998 and Vol. 4, p. 1620, 1999.

[0005] Option 1:

[0006]

[0007] Etefocin can be prepared from p-chloroacetanilide under conditions involving strong oxidizing agents such as titanium tetrachloride, various metal reagents, and potassium iodide, which are considered hazardous chemicals. This method involves too many hazardous chemicals, has complex synthesis steps, and a high risk factor. See Scheme 2 below.

[0008] Option 2:

[0009]

[0010] Etefocin enantiomers can also be prepared by adding a methyl group to commercially available 1-amino-4-chlorobenzophenone. The product is obtained by adding methyllithium, methyl Grignard reagent, Me₂Cu, or MeZn to benzophenone. This method uses flammable and explosive Grignard reagents and iodomethane reagents, requiring strict safety measures during the experiment. The synthesis steps are complex and the risk factor is high. (See Scheme 3).

[0011] Option 3:

[0012] Summary of the Invention

[0013] To address the shortcomings of existing technologies, this invention provides a method for synthesizing etefoxine, which solves the technical problems of high risk and environmental unfriendliness in existing etefoxine synthesis methods.

[0014] To achieve the above objectives, the present invention provides the following technical solution:

[0015] In a first aspect, the present invention provides a method for synthesizing etofosine, comprising the following steps:

[0016] S1. Add triphenylmethylphosphine bromide to tetrahydrofuran (THF) or diethyl ether, add potassium tert-butoxide at 0-5°C to obtain a suspension, add 2-aminobenzophenone to tetrahydrofuran or diethyl ether to obtain a 2-aminobenzophenone solution, react the suspension at room temperature for 30-40 minutes, add the 2-aminobenzophenone solution to the suspension, stir until the reaction is complete, and obtain compound 2;

[0017] S2. Compound 2 is dissolved in dichloromethane at 0–5 °C under a nitrogen or argon atmosphere, and then ethyl isocyanate is added dropwise. The mixture is heated to room temperature and stirred continuously until the reaction is complete to obtain compound 3.

[0018] S3. Compound 3, Selectfluor, and Compound A are mixed, acetonitrile or THF is added, the reaction is completed, saturated brine or saturated ammonium chloride is added, extraction is performed again, the organic phase is collected, evaporated to dryness, and compound 4 is obtained by separation.

[0019] S4. Compound 4 and sodium borohydride were reacted in ultra-dry dimethyl sulfoxide or ultra-dry N,N-dimethylformamide at room temperature for 12 hours under nitrogen or argon protection, and then atefocin was obtained by vacuum evaporation and separation.

[0020] The compound A is selected from any one of potassium iodide, Selectfluor, tetrabutylammonium chloride, and tetrabutylammonium bromide.

[0021] The reaction formula of this invention is:

[0022] ,

[0023] Where X = F, Cl, Br or I.

[0024] Preferably, in S1, the molar ratio of 2-aminobenzophenone, triphenylmethylphosphine bromide, and potassium tert-butoxide is 1:1.5:1-2.

[0025] Preferably, in S1, the molar ratio of 2-aminobenzophenone, triphenylmethylphosphine bromide, and potassium tert-butoxide is 1:1.5:1.5.

[0026] Preferably, in S2, the molar ratio of 2-aminobenzophenone to ethyl isocyanate is 1:1.

[0027] Preferably, in S3, the molar ratio of 2-aminobenzophenone to Selectfluor is 5:2.

[0028] Preferably, in S3, the molar ratio of 2-aminobenzophenone, Selectfluor, and potassium iodide is 4.2:1:1.

[0029] Preferably, in S3, the molar ratio of 2-aminobenzophenone, Selectfluor, and tetrabutylammonium chloride is 4.2:1:1.

[0030] Preferably, in S3, the molar ratio of 2-aminobenzophenone, Selectfluor, and tetrabutylammonium bromide is 5:1:1.

[0031] Preferably, in step S4, at least one of the following conditions is satisfied:

[0032] The molar ratio of 2-aminobenzophenone to sodium borohydride is 2–3:1;

[0033] The separation process includes column chromatography and solvent elution.

[0034] Preferably, the solvent used for solvent elution is a mixture of petroleum ether and ethyl acetate.

[0035] Etenofocin may be used, for example, to treat, prevent, improve, or control symptoms of diseases or conditions. These diseases or conditions include, but are not limited to, conditions related to anxiety, seizures, central nervous system disorders, and mental illnesses. Central nervous system disorders include, but are not limited to, multiple sclerosis, muscle relaxation in spinal spasticity, cerebral palsy, trigeminal neuralgia, migraine, Alzheimer's disease, pain, drug withdrawal symptoms, and seizure disorders (such as epilepsy). Mental illnesses include, but are not limited to, anxiety disorders; mood disorders; sleep disorders; delirium, dementia, and amnesia and other cognitive impairments; attention deficit and disruptive behavior disorders; and substance-related disorders. In some embodiments, these compounds and compositions may be used to treat, prevent, improve, or control symptoms of diseases or conditions related to cardiovascular diseases (such as hypertension) and intestinal motility disorders (such as irritable bowel syndrome).

[0036] In certain embodiments, ethofosine can be used to treat or prevent anxiety disorders with little or no sedative side effects. In further specific embodiments, ethofosine can be used to treat or prevent pain, such as neuropathic pain, with little or no sedative side effects.

[0037] Compared with existing technologies, it has the following beneficial effects:

[0038] This invention relates to a novel route for synthesizing etefoxine compounds, specifically using 2-aminobenzophenone as a starting material, and obtaining etefoxine compounds through four steps and post-treatment. This invention innovatively achieves the synthesis of etefoxine using a metal-free, green chemistry method with a yield of approximately 85%. The reaction conditions of this invention are mild, and the product only requires column chromatography separation and elution with a mixed solvent of petroleum ether and ethyl acetate to obtain the pure target product. The preparation method is highly practical and easy to industrialize. Detailed Implementation

[0039] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0040] To better understand the above technical solution, the following will provide a detailed explanation of the above technical solution in conjunction with specific implementation methods.

[0041] Example 1

[0042]

[0043] This embodiment provides a method for preparing [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine], comprising the following steps:

[0044] S1. Triphenylmethylphosphine bromide (75 mmol) was added to THF (100 mL), and potassium tert-butoxide (75 mmol) was slowly added at 0 °C. The suspension subsequently turned yellow. The suspension was heated to room temperature and stirred for 30 minutes. 2-Aminobenzophenone (50 mmol) was dissolved in THF (50 mL) and added to the suspension. The reaction was stirred, and the consumption of the starting material was monitored by thin-layer chromatography. The reaction was continued at room temperature until the starting material disappeared, yielding compound 2 in 85% yield.

[0045] S2 and compound 2 were dissolved in DCM at 0°C under a nitrogen atmosphere. Then, ethyl isocyanate (1.0 equivalent) was added dropwise to the reaction mixture, and the system was heated to room temperature. The reaction was continuously stirred and monitored by thin-layer chromatography until the starting material was observed to be completely consumed, yielding compound 3 in 86% yield.

[0046] S3. Take a 250 mL dried round-bottom flask, add compound 3 (20.0 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) Selectfluor (20.0 mmol), and add 20 mL of acetonitrile as solvent. React at room temperature for 60 minutes. After the reaction is complete, add saturated brine to the reaction solution, and then extract three times with ethyl acetate (20 mL × 3). After collecting the organic phase, evaporate to dryness, and elute with a mixed solvent of petroleum ether and ethyl acetate (20:1) by column chromatography to obtain compound 4 in 83% yield.

[0047] S4. In a 100 mL Schlenk tube, compound 4 (10 mmol) and sodium borohydride (20 mmol) were added, and the mixture was reacted overnight at room temperature under nitrogen protection in ultra-dry DMSO solvent. After the reaction was complete, the solvent was evaporated under reduced pressure. The product was subjected to column chromatography, eluted with a mixture of petroleum ether and ethyl acetate (10:1), to obtain [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine] (ethefoxine) in 80% yield.

[0048] Example 2

[0049]

[0050] This embodiment provides a method for preparing [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine], comprising the following steps:

[0051] S1. Triphenylmethylphosphine bromide (75 mmol) was added to THF (100 mL), and potassium tert-butoxide (75 mmol) was slowly added at 0 °C. The suspension subsequently turned yellow. The suspension was heated to room temperature and stirred for 30 minutes. 2-Aminobenzophenone (50 mmol) was dissolved in THF (50 mL) and added to the suspension. The reaction was stirred, and the consumption of the starting material was monitored by thin-layer chromatography. The reaction was continued at room temperature until the starting material disappeared, yielding compound 2 in 85% yield.

[0052] S2 and compound 2 were dissolved in DCM at 0°C under a nitrogen atmosphere. Then, ethyl isocyanate (1.0 equivalent) was added dropwise to the reaction mixture, and the system was heated to room temperature. The reaction was continuously stirred and monitored by thin-layer chromatography until the starting material was observed to be completely consumed, yielding compound 3 in 86% yield.

[0053] S3. Take a 250 mL dried round-bottom flask, add compound 3 (20.0 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) Selectfluor (24.0 mmol), and potassium iodide KI (24.0 mmol), and add 20 mL of acetonitrile as solvent. React at room temperature for 60 minutes. After the reaction is complete, add saturated brine to the reaction solution, and extract three times with ethyl acetate (20 mL × 3). After collecting the organic phase, evaporate to dryness, and elute with a mixed solvent of petroleum ether and ethyl acetate (20:1) by column chromatography to obtain compound 4 in 90% yield.

[0054] S4. In a 100 mL Schlenk tube, compound 4 (10 mmol) and sodium borohydride (20 mmol) were added, and the mixture was reacted overnight at room temperature under nitrogen protection in ultra-dry DMSO solvent. After the reaction was complete, the solvent was evaporated under reduced pressure. The product was subjected to column chromatography, eluted with a mixture of petroleum ether and ethyl acetate (10:1), to obtain [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine] (ethefoxine) in 85% yield.

[0055] Example 3

[0056]

[0057] This embodiment provides a method for preparing [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine], comprising the following steps:

[0058] S1. Triphenylmethylphosphine bromide (75 mmol) was added to diethyl ether (100 mL), and potassium tert-butoxide (75 mmol) was slowly added at 0 °C. The suspension subsequently turned yellow. The suspension was heated to room temperature and stirred for 30 minutes. 2-Aminobenzophenone (50 mmol) was dissolved in diethyl ether (50 mL) and added to the suspension. The reaction mixture was stirred and the consumption of the starting material was monitored by thin-layer chromatography. The reaction was continued at room temperature until the starting material disappeared. Compound 2 was obtained in 85% yield.

[0059] S2 and compound 2 were dissolved in DCM at 0 °C under an argon atmosphere. Ethyl isocyanate (1.0 equivalent) was then added dropwise to the reaction mixture, and the system was heated to room temperature. The reaction was continuously stirred, and the process was monitored by thin-layer chromatography until complete consumption of the starting material was observed. Compound 3 was given in 86% yield.

[0060] S3. Take a 250 mL dry round-bottom flask, mix compound 3 (20.0 mmol), Selectfluor (24.0 mmol), and tetrabutylammonium chloride (TBAC) (24.0 mmol), add 20 mL of THF as solvent, and heat to 100 °C. o The reaction was carried out at C for 2 hours. After the reaction was completed, saturated ammonium chloride was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). After the organic phase was collected, it was evaporated to dryness and eluted by column chromatography with a mixed solvent of petroleum ether and ethyl acetate (20:1) to give compound 4 in 80% yield.

[0061] S4. In a 100 mL Schlenk tube, compound 4 (10 mmol) and sodium borohydride (20 mmol) were added. The mixture was reacted overnight at room temperature under argon protection in ultradry N,N-dimethylformamide solvent. After the reaction was complete, the solvent was evaporated under reduced pressure. The product was subjected to column chromatography, eluting with a mixture of petroleum ether and ethyl acetate (10:1), to give etefoxine in 82% yield.

[0062] Example 4

[0063]

[0064] This embodiment provides a method for preparing [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine], comprising the following steps:

[0065] S1. Triphenylmethylphosphine bromide (75 mmol) was added to THF (100 mL), and potassium tert-butoxide (75 mmol) was slowly added at 0 °C. The suspension subsequently turned yellow. The suspension was heated to room temperature and stirred for 30 minutes. 2-Aminobenzophenone (50 mmol) was dissolved in THF (50 mL) and added to the suspension. The reaction was stirred, and the consumption of the starting material was monitored by thin-layer chromatography. The reaction was continued at room temperature until the starting material disappeared. Compound 2 was given in 85% yield.

[0066] S2 and compound 2 were dissolved in DCM at 0 °C under a nitrogen atmosphere. Ethyl isocyanate (1.0 equivalent) was then added dropwise to the reaction mixture, and the system was heated to room temperature. The reaction was continuously stirred, and the process was monitored by thin-layer chromatography until complete consumption of the starting material was observed. Compound 3 was given in 86% yield.

[0067] S3. Take a 250 mL dried round-bottom flask, mix compound 3 (20.0 mmol), Selectfluor (20.0 mmol), and tetrabutylammonium bromide (TBAB) (20.0 mmol), add 20 mL of acetonitrile as solvent, and react at room temperature for 60 minutes. The yield of the reaction product is 95%. After the reaction is complete, add saturated brine to the reaction solution, and then extract three times with ethyl acetate (20 mL × 3). After collecting the organic phase, evaporate to dryness, and elute by column chromatography with a mixed solvent of petroleum ether and ethyl acetate (20:1) to give compound 4, with a yield of 90%.

[0068] S4. In a 100 mL Schlenk tube, compound 4 (10 mmol) and sodium borohydride (20 mmol) were added, and the mixture was reacted overnight at room temperature under nitrogen protection in ultra-dry dimethyl sulfoxide (DMSO) solvent. After the reaction was complete, the solvent was evaporated under reduced pressure. The product was separated by column chromatography, eluting with a mixture of petroleum ether and ethyl acetate (10:1), to give etefoxine in 85% yield.

[0069] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0070] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0071] The present invention has been illustrated with the above embodiments to describe the detailed process flow of the present invention. However, the present invention is not limited to the above detailed process flow, that is, it does not mean that the present invention must rely on the above detailed process flow to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing etefoxine, characterized in that, Includes the following steps: S1. Add triphenylmethylphosphine bromide to tetrahydrofuran or diethyl ether, add potassium tert-butoxide at 0-5°C to obtain a suspension, add 2-aminobenzophenone to tetrahydrofuran or diethyl ether to obtain a 2-aminobenzophenone solution, react the suspension at room temperature for 30-40 minutes, add the 2-aminobenzophenone solution to the suspension, stir until the reaction is complete, and obtain compound 2; S2. Compound 2 is dissolved in dichloromethane at 0–5 °C under a nitrogen or argon atmosphere, and then ethyl isocyanate is added dropwise. The mixture is heated to room temperature and stirred continuously until the reaction is complete to obtain compound 3. S3. Compound 3, Selectfluor, and Compound A are mixed, acetonitrile or tetrahydrofuran is added, the reaction is completed, saturated brine or saturated ammonium chloride is added, extraction is performed again, the organic phase is collected, evaporated to dryness, and compound 4 is obtained by separation. S4. Compound 4 and sodium borohydride were reacted in ultra-dry dimethyl sulfoxide or ultra-dry N,N-dimethylformamide at room temperature for 12 hours under nitrogen or argon protection, and then atefocin was obtained by vacuum evaporation and separation. The compound A is selected from any one of potassium iodide, Selectfluor, tetrabutylammonium chloride, and tetrabutylammonium bromide.

2. The method for synthesizing etefoxine as described in claim 1, characterized in that, The reaction formula for the method is: ， Where X = F, Cl, Br or I.

3. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S1, the molar ratio of 2-aminobenzophenone, triphenylmethylphosphine bromide, and potassium tert-butoxide is 1:1.5:1-2.

4. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S1, the molar ratio of 2-aminobenzophenone, triphenylmethylphosphine bromide, and potassium tert-butoxide is 1:1.5:1.

5.

5. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S2, the molar ratio of 2-aminobenzophenone to ethyl isocyanate is 1:

1.

6. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S3, the molar ratio of 2-aminobenzophenone to Selectfluor is 5:

2.

7. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S3, the molar ratio of 2-aminobenzophenone, Selectfluor, and potassium iodide is 4.2:1:

1.

8. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S3, the molar ratio of 2-aminobenzophenone, Selectfluor, and tetrabutylammonium chloride is 4.2:1:

1.

9. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S3, the molar ratio of 2-aminobenzophenone, Selectfluor, and tetrabutylammonium bromide is 5:1:

1.

10. The method for synthesizing etefoxine as described in claim 1, characterized in that, In S4, at least one of the following conditions must be met: The molar ratio of 2-aminobenzophenone to sodium borohydride is 2–3:1; The separation includes column chromatography and solvent elution, wherein the solvent used for solvent elution is a mixture of petroleum ether and ethyl acetate.

Images