A method for preparing a tetrazole-substituted acetophenone compound

Abstract

The present invention belongs to the field of medicinal chemistry and specifically relates to a method for preparing a novel tetrazole-substituted acetophenone compound as a carbamate compound intermediate. The method comprises reacting a hydroxyacetophenone compound with a tetrazole compound. The method solves the technical problem of the prior art that more optional processes suitable for industrial production are urgently needed. The reaction reagents used in the method are inexpensive and readily available, and the post-reaction treatment is simple, making the method suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medicine and specifically provides a method for preparing a tetrazole-substituted acetophenone compound. Background Art

[0002] (R)-1-aryl-2-tetrazol-2-ylethyl carbamate compounds (hereinafter referred to as "carbamate compounds") can be used to treat central nervous system diseases, especially (R)-1-(2-chlorophenyl)-2-tetrazol-2-ylethyl carbamate, which was developed by SK Biopharmaceuticals of South Korea and approved for marketing by the FDA in 2019. It can be used to treat partial epileptic seizures in adult patients.

[0003] The synthesis route was first reported in SK company's patent CN101228138B:

[0004]

[0005] The 1-position and 2-position of 1H-tetrazole can react to generate 1N alcohol and 2N alcohol, respectively, which need to be separated by column chromatography. The reaction formula is as follows:

[0006]

[0007] Subsequently, SK company disclosed a new preparation method in its patents CN102803233B and CN102574821B. The synthesis route is as follows:

[0008]

[0009] In 2020, SK further applied for patent CN114901647A, which claims that the yield of 2N-ketone can be increased by preferentially reacting 1H-tetrazole with an inorganic base to prepare a 1H-tetrazole metal salt, and then adding 2-bromo-2'-chloroacetophenone. It was further discovered that 1N-ketone is unstable at high temperatures and can be decomposed into oxazole under high temperature and high pressure, which can be removed by acid washing to obtain 2N-ketone with higher purity. The decomposition reaction formula of 1N-ketone is as follows:

[0010]

[0011] At present, apart from the above-mentioned SK company patent, there are no other reports on the synthesis routes of (R)-1-aryl-2-tetrazolylethyl carbamate compounds. It is urgently necessary to develop more optional processes suitable for industrial production. Summary of the Invention

[0012] The present invention aims to provide a method for preparing a novel tetrazole-substituted acetophenone compound as a carbamate intermediate, wherein the reaction reagents are cheap and readily available, the post-reaction treatment is simple, and the method is suitable for large-scale industrial production.

[0013] The technical solutions adopted in the present invention are as follows:

[0014] The method for preparing the compound represented by formula (I) comprises:

[0015] The compound of formula (II) reacts with tetrazole to obtain the compound of formula (I)

[0016]

[0017] wherein R1-R5 are independently selected from hydrogen, halogen, cyano, nitro, and C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl and C 2-10 Alkynyl.

[0018] More preferably, R1-R5 are independently selected from hydrogen, halogen, and trifluoromethyl.

[0019] More preferably, R1-R4 are hydrogen, and R5 is halogen, preferably fluorine, chlorine, bromine, or iodine, more preferably chlorine.

[0020] In one embodiment, the reaction is carried out under acid catalysis.

[0021] The reaction temperature is 10-200° C., preferably room temperature or reflux temperature.

[0022] The acid is an organic acid and / or an inorganic acid, preferably sulfuric acid, phosphoric acid, hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid and / or trifluoromethanesulfonic acid, more preferably sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and / or trifluoromethanesulfonic acid.

[0023] The reaction is carried out in the absence of a solvent or in the presence of a solvent, wherein the solvent is one or more of halogenated alkanes, unsubstituted aromatic hydrocarbons, monoalkyl or polyalkyl substituted aromatic hydrocarbons, monohalogenated or polyhalogenated aromatic hydrocarbons, nitriles, ethers, and amides, preferably benzene, toluene, o-xylene, p-xylene, m-xylene, mixed xylenes, chlorobenzene and / or dichlorobenzene.

[0024] In another embodiment, the reaction is carried out in the presence of a solvent, a tricoordinate phosphorus compound, and an azodicarboxylate.

[0025] The reaction temperature is 10-50°C, preferably room temperature.

[0026] The tricoordinate phosphorus compound is a trialkylphosphine, a tricycloalkylphosphine, a triarylphosphine and / or a trialkyl-substituted arylphosphine, preferably tripropylphosphine, tributylphosphine, tricyclohexylphosphine, triphenylphosphine and / or tri-o-tolylphosphine, more preferably tricyclohexylphosphine or triphenylphosphine.

[0027] The azodicarboxylate is dibenzyl azodicarboxylate and / or dialkyl azodicarboxylate, preferably dibenzyl azodicarboxylate, dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate, diisopropyl azodicarboxylate, dibutyl azodicarboxylate and / or di-tert-butyl azodicarboxylate, more preferably dimethyl azodicarboxylate or diisopropyl azodicarboxylate.

[0028] The solvent is one or more of halogenated alkanes, unsubstituted aromatic hydrocarbons, monoalkyl or polyalkyl substituted aromatic hydrocarbons, monohalogenated or polyhalogenated aromatic hydrocarbons, nitriles, ethers, and amides, preferably tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane and / or toluene, more preferably tetrahydrofuran.

[0029]

Definition and explanation

[0030] Unless otherwise indicated, the following terms used herein have the following meanings.

[0031] The term "halogen" includes fluorine, chlorine, bromine or iodine.

[0032] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, and the like.

[0033] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like.

[0034] The term "alkoxy" refers to the group -O-alkyl, the term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, and the term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.

[0035] The term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent that can be monosubstituted, disubstituted, or polysubstituted, can be monovalent, divalent, or polyvalent, and can be monocyclic or polycyclic (e.g., 1 to 3 rings) that are fused together or covalently linked. Non-limiting examples of aryl include phenyl, naphthyl, biphenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl.

[0036] The term "aromatic hydrocarbon" refers to a polyunsaturated aromatic hydrocarbon that may be monosubstituted, disubstituted or polysubstituted, and may be monocyclic or polycyclic (e.g., 1 to 3 rings) that are fused together or covalently linked. Non-limiting examples of aromatic hydrocarbons include benzene, naphthalene, and biphenyl. DETAILED DESCRIPTION

[0037] The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the essence and scope of the present invention are not limited thereto.

[0038] Comparative Example 1

[0039] To a four-necked flask, add acetic acid (120 mL), o-chloroacetophenone (60.0 g), liquid bromine (76.0 g), and p-toluenesulfonic acid (6.0 g). After the addition is complete, the reaction solution is heated to 40-50°C and reacted for 6 hours. The reaction solution is cooled to 20-30°C, 600 mL of dichloromethane is added, and the mixture is washed twice with water (600 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain 90.1 g of 2-bromo-2'-chloroacetophenone.

[0040] To a separate flask, acetonitrile (230 ml), 1H-tetrazole (29.6 g), and potassium carbonate (60.0 g) were added dropwise. A solution of the above-mentioned 2-bromo-2'-chloroacetophenone (90.1 g) in DMF (90 ml) was added, stirred at 45°C for 2 hours, and then distilled under reduced pressure to remove approximately 1500 ml of solvent. The concentrate was diluted with ethyl acetate (2000 ml) and washed with 10% brine (3 x 2000 ml). The separated organic layer was distilled under reduced pressure to yield an oily solid residue. To a solution of the solid residue in ethyl acetate (432 ml), heptane (600 ml) was slowly added. The resulting precipitate was filtered and washed at room temperature to yield 38.6 g of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (hereinafter referred to as "1N ketone"). The filtrate was further concentrated and dissolved in isopropyl alcohol (100 mL), to which heptane (360 mL) was added to complete crystallization. Filtration and washing at 0-5°C afforded 20.8 g of solid 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethan-1-one (hereinafter referred to as "2N ketone").

[0041] Example 1

[0042] 20.0 g of 1-(2-chlorophenyl)-2-hydroxyethane-1-one was placed in a flask, and toluene (250 mL), 1H-tetrazole (9.03 g), and p-toluenesulfonic acid (4.0 g) were added and heated to reflux for 16 hours. The starting material disappeared by TLC monitoring, and 1N ketone was not detected by HPLC. The reaction solution was cooled to below 40°C, washed once with 300 mL of 10% sodium carbonate solution and once with 300 mL of 10% brine. The organic phase was concentrated until no fraction was obtained. 100 mL of isopropanol was added to dissolve the clear solution, and the temperature was gradually decreased to 5°C and crystallized for 2 hours. The product was filtered, and the filter cake was rinsed with ice-cold isopropanol. The wet product was dried at 40°C with air to constant weight to obtain 2N ketone as an off-white solid (5.3 g) with a purity of 98.48%.

[0043] Example 2

[0044] 20.0 g of 1-(2-chlorophenyl)-2-hydroxyethane-1-one was placed in a flask, trifluoromethanesulfonic acid (100 mL) was added, the temperature was lowered to ≤10°C, 1H-tetrazole (9.12 g) was added, and the temperature was raised to room temperature for 4 hours. The reaction of the raw material was monitored by TLC. No 1N ketone was detected by HPLC. The reaction solution was slowly poured into 500 g of ice water for quenching, saturated sodium carbonate solution was added to adjust the pH to 8, and the solution was extracted twice with dichloromethane (400 mL × 2). The combined dichloromethane phases were washed once with 400 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude 2N ketone. 100 mL of isopropanol was added for recrystallization to obtain 7.7 g of pure 2N ketone with a purity of 99.42%.

[0045] Example 3

[0046] 20.0g 1-(2-chlorophenyl)-2-hydroxyethane-1-one was placed in a flask, mixed xylene (250mL), 1H-tetrazole (12.3g), and methanesulfonic acid (4.0g) were added and heated to 110-120°C for 16 hours. The starting material disappeared after TLC monitoring, and 1N ketone was not detected by HPLC. The reaction solution was cooled to below 40°C, washed once with 300mL of 10% sodium carbonate solution and once with 300mL of 10% brine. The organic phase was concentrated to no fraction, dissolved with 100mL of isopropanol, and then gradually cooled to 5°C for crystallization for 2 hours. The filter cake was rinsed with ice isopropanol and the wet product was dried at 40°C to constant weight to obtain 2N ketone as an off-white solid (12.1g) with a purity of 99.52%.

[0047] Example 4

[0048] 100mL concentrated sulfuric acid was placed in a flask, 1H-tetrazole (4.52g) was slowly added, and after stirring for 10 minutes, 10.0g 1-(2-chlorophenyl)-2-hydroxyethane-1-one was added in batches at room temperature, and the temperature was raised to 40-50°C for 24 hours. The starting material disappeared by TLC monitoring, and 1N ketone was not detected by HPLC. The reaction solution was cooled to room temperature and poured into 300g ice for quenching. 200mL of ethyl acetate was added for extraction and separation. The organic phase was washed once with 200mL of 10% brine, separated and concentrated to no fraction. 40mL of isopropanol was added to dissolve the clear solution, and the temperature was gradually lowered to 5°C for crystallization for 2 hours. The filter cake was rinsed with ice isopropanol, and the wet product was dried at 40°C with air to constant weight to obtain 2N ketone as an off-white solid with a purity of 97.25%.

[0049] Example 5

[0050] 5.0g of 1-(2-chlorophenyl)-2-hydroxyethane-1-one was placed in a flask, and 50mL of tetrahydrofuran, 1H-tetrazole (2.46g), triphenylphosphine (9.23g), and diisopropyl azodicarboxylate (7.11g) were added. After the addition was complete, the mixture was reacted at room temperature for 16 hours. HPLC confirmed that it was a mixture of 2N ketone and 1N ketone. 80mL of 1M hydrochloric acid and 100mL of ethyl acetate were added, washed, and separated. The organic phase was concentrated until no fractions were obtained. 80mL of isopropyl ether was added and the mixture was pulped and extracted twice. The filtrate was concentrated to obtain a crude 2N ketone. The crude product was recrystallized from 20mL of isopropyl alcohol to obtain 1.2g of 2N ketone with a purity of 99.1%.

[0051] Example 6

[0052] 5.0 g of 1-(2-chlorophenyl)-2-hydroxyethane-1-one was placed in a flask, followed by 50 mL of tetrahydrofuran, 1H-tetrazole (2.46 g), tricyclohexylphosphine (9.86 g), and dimethyl azodicarboxylate (5.14 g). After the addition was complete, the mixture was reacted at 40-50°C for 16 hours. HPLC confirmed the mixture to be a mixture of 2N ketone and 1N ketone. 80 mL of 1M hydrochloric acid and 100 mL of ethyl acetate were added, followed by washing and separation. The organic phase was concentrated until no fraction remained. 80 mL of isopropyl ether was added for extraction twice, and the filtrate was concentrated to obtain crude 2N ketone. This crude product was recrystallized from 20 mL of isopropyl alcohol to yield 1.1 g of 2N ketone with a purity of 98.6%.

[0053] Although the present invention has been described in detail above, it will be understood by those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention.

Claims

1. A method for preparing a compound represented by formula (I), comprising: The compound of formula (II) reacts with tetrazole to obtain the compound of formula (I) wherein R1-R5 are independently selected from hydrogen, halogen, cyano, nitro, and C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl and C 2-10 Alkynyl; the reaction is carried out under acid catalysis at a reaction temperature of 10-200°C; the acid is sulfuric acid, phosphoric acid, hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid; or, The reaction is carried out in the presence of a solvent, a tricoordinate phosphorus compound and an azodicarboxylate at a temperature of 10-50° C. The tricoordinate phosphorus compound is tricyclohexylphosphine or triphenylphosphine, and the azodicarboxylate is dimethyl azodicarboxylate or diisopropyl azodicarboxylate.

2. The method according to claim 1, wherein The reaction is carried out in the presence of a solvent, a tricoordinate phosphorus compound and an azodicarboxylate, and the reaction temperature is room temperature.

3. The method according to claim 2, wherein The solvent is tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane or toluene.

4. The method according to claim 1, wherein The reaction is carried out under acid catalysis at a reaction temperature of 10-200° C., in the absence of a solvent or in the presence of a solvent, wherein the solvent is benzene, toluene, o-xylene, p-xylene, m-xylene, mixed xylene, chlorobenzene or dichlorobenzene.

5. The method according to any one of claims 1 to 4, characterized in that R1-R5 are independently selected from hydrogen, halogen, trifluoromethyl.

6. The method according to any one of claims 1 to 4, wherein: R1-R4 are hydrogen, and R5 is halogen.

7. The method according to any one of claims 1 to 4, wherein: R1-R4 are hydrogen, and R5 is chlorine.

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