Mechanical ball-milling synthesis method of Cenobamate drug intermediate
The synthesis of Cenobamate drug intermediates by mechanical ball milling has solved the problems of large dosage, cumbersome operation, long reaction time and environmental pollution in the prior art, and achieved an efficient and environmentally friendly synthesis process.
Patent Information
- Application Number
- CN202411527577.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-30
- Publication Date
- 2025-02-11
AI Technical Summary
The existing methods of synthesis of Cenobamate drug intermediates have problems such as large dosage, cumbersome operation, long reaction time and environmental pollution.
The Cenobamate drug intermediate was synthesized by mechanical ball milling. After mixing 2-bromo-2-chloroacetophenone, tetraazole, alkali catalyst and cosolvent, add grinding agent to form a ball mill raw material mixture, and in a stainless steel ball milling tank Mechanical ball milling was performed and the target product was finally purified by column chromatography.
It realizes high yield synthesis with simple operation, mild reaction conditions, short reaction time and environmentally friendly, which significantly improves the yield of intermediates.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical engineering, and in particular relates to a mechanical ball milling synthesis method for a Cenobamate drug intermediate. Background Art
[0002] Epilepsy is one of the most common chronic and serious neurological diseases in the world. Focal epilepsy is a clinical syndrome caused by sudden abnormal discharges of local neurons due to known or unknown causes, leading to transient dysfunction of the brain. Antiepileptic drug treatment is currently the main treatment option for epilepsy and is also the first choice. Although there are many antiepileptic drugs available for clinicians to choose from, about 70% of patients' epileptic seizures can be controlled, but 20% of patients still cannot effectively control epileptic seizures after reasonable and sufficient antiepileptic drug treatment, and progress to drug-resistant epilepsy.
[0003] Cenobamate (trade name: Xcopri) is a sodium channel blocker. The U.S. FDA approved its tablets for sale on November 21, 2019 for the treatment of focal epileptic seizures in adult patients. Clinical studies have shown that compared with placebo, Xcopri significantly reduced the frequency of focal epileptic seizures, and up to 20% of patients achieved zero epileptic seizures during the maintenance period. Cenobamate is a new tetrazolidinyl carbamate derivative. Its Chinese name is (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethane-1-ol. Its active ingredient formula is C 10 H 10 ClN5O2, relative molecular mass is 267.67:
[0004]
[0005] In the synthesis process of Cenobamate, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one is a key intermediate substance. The existing technology uses chemical synthesis. For example, in 2010, Lim, SC et al. synthesized 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. Although the yield reached 44%, a large amount of acetonitrile was used as a solvent (Lim, SC, et, al. US20100323410 A1, 2010.). Later, Camille Assaf et al. mixed 2-bromo-1-(2-chlorophenyl)ethanone and tetrazole in ethyl acetate for 12 hours, and achieved separation after multiple heating and cooling. The final yield was only 37% (Camille Assaf, et, al. Chemistry Select, 2024, 9, e202400274, 1-3). These synthetic methods have the disadvantages of large amount of organic reagents, complicated operation, long reaction time and environmental pollution.
[0006] Summary of the invention
[0007] The object of the present invention is to provide a method for preparing a Cenobamate intermediate by a mechanical ball milling method, which has low production cost, short time, mild reaction conditions, simple operation and is environmentally friendly.
[0008] The technical solution adopted by the present invention is as follows:
[0009] A mechanical ball milling synthesis method for a Cenobamate drug intermediate comprises the following steps: after uniformly mixing 2-bromo-2-chloroacetophenone, tetrazole, an alkali catalyst and a cosolvent, a grinding aid is added to form a ball milling raw material mixture; the ball milling raw material mixture is placed in a stainless steel ball milling jar, and stainless steel balls are added to the ball milling jar as ball milling media for mechanical ball milling; after the ball milling is completed, the reactants are scraped out, an organic solvent is added to stir and dissolve, and the reactants are filtered; the filtrate is washed with water and a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated, and finally purified by column chromatography to obtain a Cenobamate drug intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one, and the reaction formula is as follows:
[0010]
[0011] Furthermore, the base catalyst is one of triethylamine, dipotassium hydrogen phosphate, sodium carbonate and potassium carbonate, preferably potassium carbonate; and the molar ratio of the base catalyst to 2-bromo-2-chloroacetophenone is 1-1.1:1.
[0012] Further, the molar ratio of 2-bromo-2-chloroacetophenone to tetrazole is 1:0.8-1.2, preferably 1:1.
[0013] Furthermore, the co-solvent is one of acetone and ethanol, preferably ethanol; the η value of the ball-milled raw material mixture = 0.2-0.6, preferably 0.3-0.5, and the η value refers to the ratio between the total volume of the liquid material and the total mass of the solid reagent in each component of the mixture feed, the unit of volume is μL, and the unit of mass is mg.
[0014] Furthermore, the grinding aid is one of silica gel, neutral alumina, and basic alumina, preferably silica gel; the ratio of the mass of the grinding aid to the total amount of 2-bromo-2-chloroacetophenone-tetrazolyl is 200-300 mg: 1 mmol.
[0015] Furthermore, the diameter of the stainless steel ball is 6-12 mm, preferably 8 mm.
[0016] Further, based on the total amount of 2-bromo-2-chloroacetophenone-tetrazolyl as 1 mmol, the number of the stainless steel balls is 1-5, preferably 2.
[0017] Furthermore, the ball milling frequency is 10-40 Hz, preferably 30 Hz; the ball milling time is 10-90 min, preferably 10-30 min.
[0018] Furthermore, the organic solvent is ethyl acetate.
[0019] Furthermore, the column chromatography eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1.5-4:1.
[0020] Compared with the prior art, the present invention has the following beneficial effects:
[0021] The method of the invention synthesizes the Cenobamate drug intermediate by means of mechanical ball milling technology. Compared with the existing chemical method, the method of the invention is simple to operate, mild in reaction conditions, short in reaction time, environmentally friendly, and has a high yield of the target product. DETAILED DESCRIPTION
[0022] The present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited thereto.
[0023] Example 1 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Triethylamine as Base Catalyst
[0024] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.5 mmol triethylamine and 300 mg silica gel in sequence, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6 × 15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3 × 15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask, and condense it by rotary evaporation. Finally, purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate = 2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one.
[0025] The standard curve was prepared by high performance liquid chromatography, and the yield was 24% after high performance liquid chromatography detection. The high performance liquid chromatography detection conditions were: Agilent 1200 liquid chromatography, Ultimate LP-C18 column, mobile phase volume ratio of acetonitrile: 0.1% trifluoroacetic acid aqueous solution = 60:40, flow rate 1mL / min, column temperature 30°C, UV detection wavelength 254nm, injection volume 5uL. Peak time 4.8min.
[0026] The specific characterization data are as follows: 1 HNMR(400MHz,Chloroform-d)δ8.59(s,1H),7.73(s,1H),7.51(dd,J=6.4,1.6Hz,2H),7.40(ddd,J=8.5,6.4,2.2Hz,1H),6.15(s,2H).
[0027] Example 2 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Potassium Hydroxide as a Base Catalyst
[0028] The experimental steps of Example 2 were repeated in Example 1, except that triethylamine was replaced by an equal molar amount of potassium hydroxide, and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 9.5%.
[0029] Example 3 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Sodium Hydroxide as Base Catalyst
[0030] The experimental steps of Example 3 were repeated in Example 1, except that triethylamine was replaced by an equal molar amount of sodium hydroxide, and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 4.2%.
[0031] Example 4 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Dipotassium Hydrogen Phosphate as Base Catalyst
[0032] The experimental steps of Example 4 were repeated in Example 1, except that triethylamine was replaced by an equal molar amount of dipotassium hydrogen phosphate, and the other conditions remained unchanged, ultimately obtaining 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one with a yield of 18.3%.
[0033] Example 5 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Disodium Hydrogen Phosphate as Base Catalyst
[0034] The experimental steps of Example 5 were repeated in Example 1, except that triethylamine was replaced by an equal molar amount of disodium hydrogen phosphate, and other conditions remained unchanged, ultimately obtaining 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one with a yield of 5.8%.
[0035] Example 6 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Sodium Carbonate as a Base Catalyst
[0036] The experimental steps of Example 6 were repeated in Example 1, except that triethylamine was replaced by an equal molar amount of sodium carbonate, and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 17.9%.
[0037] Example 7: Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Potassium Carbonate as a Base Catalyst
[0038] The experimental steps of Experiment 1 of Example 7 were repeated in Example 1, with the only difference being that "triethylamine was replaced with an equal molar amount of potassium carbonate" and the other conditions remained unchanged, ultimately obtaining 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one with a yield of 27.5%.
[0039] The experimental steps of Experiment 2 of Example 7 were repeated in Example 1, except that triethylamine was replaced with 0.25 mmol potassium carbonate, and the other conditions remained unchanged, ultimately obtaining 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one with a yield of 20.4%.
[0040] The experimental steps of Experiment 3 of Example 7 were repeated in Example 1, except that triethylamine was replaced with 0.55 mmol potassium carbonate, and the other conditions remained unchanged, ultimately obtaining 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one with a yield of 29.1%.
[0041] From the comparison of the experimental results of Examples 1-7, it can be seen that the technical effect is better when triethylamine, dipotassium hydrogen phosphate, sodium carbonate, potassium carbonate, etc. are selected as the base catalyst, among which potassium carbonate has the best effect, and the molar ratio of potassium carbonate to 2-bromo-2-chloroacetophenone is preferably 1-1.1:1.
[0042] Example 8: Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Water as Cosolvent
[0043] Add two stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, water (η value = 0.5) and 300 mg silica gel in sequence to form a ball milling raw material mixture, and ball mill at 30 Hz for 30 minutes. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6 × 15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3 × 15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask and condense it by rotary evaporation, and finally purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate = 2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yield was 4.8% as determined by high performance liquid chromatography under the same conditions as in Example 1.
[0044] The η value described in the present invention refers to the ratio between the total volume of the liquid material and the total mass of the solid reagent in the ball-milled raw material mixture of 2-bromo-2-chloroacetophenone, tetrazole, alkaline catalyst and co-solvent, the unit of volume is μL, and the unit of mass is mg.
[0045] Specifically in Example 8, 2-bromo-2-chloroacetophenone and co-solvent water are liquid materials, tetrazole and potassium carbonate are solid reagents, and the added volume of co-solvent water is determined according to η value = 0.5.
[0046] Example 9 Synthesis of Cenobamate Drug Intermediate 1-(2-Chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Ethyl Acetate as Cosolvent
[0047] The experimental steps of Example 9 were repeated in Example 8, except that the cosolvent was replaced with ethyl acetate (η value = 0.5) and the other conditions remained unchanged, and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was finally obtained with a yield of 20.3%.
[0048] Example 10 Synthesis of Cenobamate Drug Intermediate 1-(2-Chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Dichloromethane as Cosolvent
[0049] The experimental steps of Example 10 were repeated in Example 8, except that the cosolvent was replaced with dichloromethane (η value = 0.5) and the other conditions remained unchanged, and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was finally obtained with a yield of 25.9%.
[0050] Example 11 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Acetone as Cosolvent
[0051] The experimental steps of Example 11 were repeated in Example 8, except that the cosolvent was replaced with acetone (η value = 0.5) and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 35.9%.
[0052] Example 12 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Ethanol as Cosolvent
[0053] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol with n values of 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, and 300 mg silica gel, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape out the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6 × 15 mL), extract the aqueous phase with ethyl acetate three times (3 × 15 mL), and combine the organic phases. The organic phase was dried by adding anhydrous sodium sulfate and then filtered, and the filtrate was transferred to a round-bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (the eluent used was petroleum ether: ethyl acetate = 2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yields were 38.5%, 36.2%, 25.5%, 28.9%, 26.0%, 25.3%, and 21.7% respectively by high performance liquid chromatography detection under the same detection conditions as in Example 1.
[0054] By comparing the experimental results of Examples 7-12, it can be seen that when water, ethyl acetate, dichloromethane, etc. are selected as the co-solvent, negative technical effects are achieved. When acetone or ethanol is selected as the co-solvent, the effect of the ball milling reaction can be further improved, and the best effect is achieved when the η value is 0.3 or 0.5. Further increasing the η value will achieve negative technical effects.
[0055] Example 13 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Sodium Chloride as Grinding Aid
[0056] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η value = 0.3) and 300 mg sodium chloride in sequence, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6 × 15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3 × 15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask and condense it by rotary evaporation, and finally purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate = 2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yield was 13.9% as determined by high performance liquid chromatography under the same conditions as in Example 1.
[0057] Example 14: Synthesis of Cenobamate Drug Intermediate 1-(2-Chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Potassium Chloride as Grinding Aid
[0058] The experimental steps of Example 14 were repeated in Example 13, except that "the grinding aid was replaced by an equal mass of potassium chloride instead of sodium chloride", and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 8.9%.
[0059] Example 15-1 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Neutral Alumina as Grinding Aid
[0060] The experimental steps of Example 15-1 were repeated as in Example 13, with the only difference being that "the grinding aid was replaced by an equal mass of neutral alumina instead of sodium chloride", and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 30.5%.
[0061] Example 15-2 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Basic Alumina as Grinding Aid
[0062] The experimental steps of Example 15-2 were repeated in Example 13, with the only difference being that "the grinding aid was replaced by an equal mass of basic alumina instead of sodium chloride", and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 30.6%.
[0063] Example 16 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Sodium Sulfate as Grinding Aid
[0064] The experimental steps of Example 16 were repeated in Example 13, except that "the grinding aid was replaced by sodium chloride with an equal mass of sodium sulfate", and the other conditions remained unchanged. Finally, 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one was obtained with a yield of 25.1%.
[0065] Example 17 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one Using Silica Gel as Grinding Aid
[0066] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) in sequence, add 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg silica gel respectively, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape out the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. The organic phase was dried by adding anhydrous sodium sulfate and then filtered, and the filtrate was transferred to a round-bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (the eluent used was petroleum ether: ethyl acetate = 2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. After high performance liquid chromatography detection, the detection conditions were the same as in Example 1, and the yields were 32.9%, 41.0%, 39.6%, 38.5%, 28.5%, and 24.5%, respectively.
[0067] The comparison of the experimental results of Examples 12-17 shows that the technical effect is better when the grinding aid is selected from silica gel, neutral alumina, basic alumina, etc., among which silica gel has the best effect. The ratio of the mass of silica gel to the total amount of 2-bromo-2-chloroacetophenone-tetrazolyl is 200-300 mg: 1 mmol.
[0068] Example 18 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one from Small Spheres of Different Diameters and Numbers
[0069] Add 3, 4, and 5 stainless steel balls with a diameter of 6 mm to a 25 mL stainless steel ball mill, respectively, and then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask and condense it by rotary evaporation, and finally purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yields were 30.8%, 30.4% and 27.5% respectively after high performance liquid chromatography detection under the same detection conditions as in Example 1.
[0070] Add 1, 2, 3, and 4 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3), and 200 mg silica gel, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask, and condense it by rotary evaporation. Finally, purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yields were 28.9%, 41.0%, 31.5% and 26.0% respectively after high performance liquid chromatography detection under the same detection conditions as in Example 1.
[0071] Add 1, 2, and 3 stainless steel balls with a diameter of 10 mm to a 25 mL stainless steel ball mill, respectively, and then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask, and condense it by rotary evaporation. Finally, purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yields were 32.2%, 30.9% and 21.0% respectively after high performance liquid chromatography detection under the same detection conditions as in Example 1.
[0072] Add 1, 2, and 3 stainless steel balls with a diameter of 12 mm to a 25 mL stainless steel ball mill, respectively, and then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 30 minutes at 30 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask, and condense it by rotary evaporation. Finally, purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yields were 31.2%, 28.5% and 20.1% respectively after high performance liquid chromatography detection under the same detection conditions as in Example 1.
[0073] From the experimental results of Example 17 and Example 18, it can be seen that when the reaction raw material feeding amount is 0.5 mmol 2-bromo-2-chloroacetophenone and 0.5 mmol tetrazole, the ball milling reaction is best performed using 2 stainless steel balls with a diameter of 8 mm.
[0074] Example 19 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one by Different Ball Milling Frequencies
[0075] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 30 minutes at 10 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask and condense it by rotary evaporation, and finally purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yield was 18.7% as determined by high performance liquid chromatography under the same conditions as in Example 1.
[0076] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 30 minutes at 15 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask and condense it by rotary evaporation, and finally purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yield was 26.3% as determined by high performance liquid chromatography under the same conditions as in Example 1.
[0077] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 30 minutes at 20 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask and condense it by rotary evaporation, and finally purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yield was 25.9% as determined by high performance liquid chromatography under the same conditions as in Example 1.
[0078] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 30 minutes at 25 Hz. After the ball milling, scrape the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), respectively, extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. Add anhydrous sodium sulfate to the organic phase and dry it, then filter it, transfer the filtrate to a round-bottom flask, and condense it by rotary evaporation. Finally, purify it by column chromatography (the eluent used is petroleum ether: ethyl acetate=2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. The yield was 31.2% as determined by high performance liquid chromatography under the same conditions as in Example 1.
[0079] Example 20 Synthesis of Cenobamate Drug Intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one by Different Ball Milling Times
[0080] Add 2 stainless steel balls with a diameter of 8 mm to a 25 mL stainless steel ball mill, then add 0.5 mmol 2-bromo-2-chloroacetophenone, 0.5 mmol tetrazole, 0.55 mmol potassium carbonate, ethanol (η=0.3) and 200 mg silica gel in sequence, and ball mill for 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 minutes at 30 Hz. After the ball milling, scrape out the reaction mixture, add 30 mL ethyl acetate, filter, wash the filtrate with water and saturated sodium bicarbonate aqueous solution three times (6×15 mL), extract the aqueous phase with ethyl acetate three times (3×15 mL), and combine the organic phases. The organic phase was dried by adding anhydrous sodium sulfate and then filtered, and the filtrate was transferred to a round-bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (the eluent used was petroleum ether: ethyl acetate = 2:1, v / v) to obtain 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one. After high performance liquid chromatography detection, the detection conditions were the same as those in Example 1, and the yields were 20.4%, 41.0%, 42.1%, 41.0%, 32.7%, 33.1%, 35.0%, 24.8%, 24.0%, and 24.1%, respectively.
[0081] Compared with the prior art, the method of the present invention synthesizes Cenobamate drug intermediates by means of mechanical ball milling technology. Compared with the existing chemical method, the method of the present invention is simple to operate, has mild reaction conditions, short reaction time, and is environmentally friendly.
Claims
1. A mechanical ball milling synthesis method for a Cenobamate drug intermediate, characterized in that The following steps are involved: After 2-bromo-2-chloroacetophenone, tetrazole, an alkali catalyst and a co-solvent are mixed, a grinding aid is added to form a ball-milled raw material mixture; the ball-milled raw material mixture is placed in a stainless steel ball milling jar, and stainless steel balls are added to the ball milling jar as ball milling media for mechanical ball milling. After the ball milling is completed, the reactants are scraped out, an organic solvent is added, stirred and dissolved, and filtered. The filtrate is washed with water and a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated, and finally purified by column chromatography to obtain Cenobamate drug intermediate 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazolyl-2-yl)ethane-1-one, and the reaction formula is as follows:
2. The mechanical ball milling synthesis method of a Cenobamate drug intermediate according to claim 1, characterized in that The base catalyst is one of triethylamine, dipotassium hydrogen phosphate, sodium carbonate and potassium carbonate, preferably potassium carbonate; the molar ratio of the base catalyst to 2-bromo-2-chloroacetophenone is 1-1.1:
1.
3. The mechanical ball milling synthesis method of a Cenobamate drug intermediate as claimed in claim 1, characterized in that The molar ratio of 2-bromo-2-chloroacetophenone to tetrazole is 1:0.8-1.2, preferably 1:
1.
4. The mechanical ball milling synthesis method of a Cenobamate drug intermediate as claimed in claim 1, characterized in that The co-solvent is one of acetone and ethanol, preferably ethanol; the η value of the ball-milled raw material mixture is 0.2-0.6, preferably 0.3-0.5, and the η value refers to the ratio between the total volume of the liquid material and the total mass of the solid reagent in each component of the mixture feed, the unit of volume is μL, and the unit of mass is mg.
5. The mechanical ball milling synthesis method of a Cenobamate drug intermediate as claimed in claim 1, characterized in that The grinding aid is one of silica gel, neutral alumina, and basic alumina, preferably silica gel; the ratio of the mass of the grinding aid to the total amount of 2-bromo-2-chloroacetophenone-tetrazolyl is 200-300 mg: 1 mmol.
6. The mechanical ball milling synthesis method of a Cenobamate drug intermediate according to claim 1, characterized in that The diameter of the stainless steel ball is 6-12 mm, preferably 8 mm.
7. The mechanical ball milling synthesis method of a Cenobamate drug intermediate as claimed in claim 6, characterized in that Based on the total amount of 2-bromo-2-chloroacetophenone-tetrazolyl as 1 mmol, the number of the stainless steel balls is 1-5, preferably 2.
8. The mechanical ball milling synthesis method of a Cenobamate drug intermediate according to claim 1, characterized in that The ball milling frequency is 10-40 Hz, preferably 30 Hz; the ball milling time is 10-90 min, preferably 10-30 min.
9. The mechanical ball milling synthesis method of a Cenobamate drug intermediate according to claim 1, characterized in that The organic solvent is ethyl acetate.
10. The mechanical ball milling synthesis method of a Cenobamate drug intermediate according to claim 1, characterized in that The column chromatography eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1.5-4:1.