A method for preparing a loufeliamide impurity reference standard

Abstract

This invention belongs to the field of medicinal chemistry and pharmaceutical technology, specifically relating to a method for preparing a rufiamide impurity reference standard. The method includes the following steps: (1) mixing o-fluorobenzyl alcohol, 1H-1,2,3-triazol-4-nitrile, photocatalytic reaction reagent, triphenylphosphine, and solvent 1, and reacting to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile; (2) mixing 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile, carbonate, hydrogen peroxide, and solvent 2, and reacting to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-formamide. This invention is simple to operate, has milder reaction conditions, and does not involve the use or generation of azides; the synthesis method is green and novel, and can rapidly and efficiently prepare 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-formamide.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmaceutical technology, and specifically relates to a method for preparing a rufamide impurity reference standard. Background Technology

[0002] Rulfeamide (trade name Banzel) is a drug developed by Novartis in Switzerland for adjunctive treatment of epilepsy, and it was launched in the United States in November 2008. It is an antiepileptic triazole derivative with a chemical structure different from currently marketed antiepileptic drugs, and it works by regulating the activity of sodium ion channels in the brain.

[0003] When rufinamide concentration is greater than 10 μmol / L, it has no significant effect on monoamines, adrenaline, histamine, acetylcholine, AMPA-kainate, glycine, NMDA, or GABA neurotransmitter-receptor systems. Clinical studies have shown that rufinamide adjunctive therapy is well tolerated by epilepsy patients, resulting in a reduction in the frequency of seizures. Furthermore, rufinamide remains effective in patients with tolerant focal or generalized epilepsy and has an adjunctive effect on the treatment of focal seizures and generalized tonic-clonic seizures; it can be administered in combination with other drugs or alone.

[0004] The chemical name of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxamide is CAS number 106308-44-5; its chemical structural formula is as follows:

[0005]

[0006] Chinese invention patent application CN103539750A discloses a process for synthesizing loufeamide, which involves reacting 2,6-difluorobenzyl halide with an azide and tetrabutylammonium chloride to obtain 2-(azidomethyl)-1,3-difluorobenzene; reacting 2-(azidomethyl)-1,3-difluorobenzene with methyl propargylate under the catalysis of nano-cuprous oxide (Cu2O) to obtain methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate; and reacting methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate with ammonia to obtain loufeamide.

[0007] Several impurities are generated during the preparation of rufamide. Currently disclosed impurities include 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-methanol (CAS No.: 1364193-40-7); diphenyl chlorophosphate (CAS No.: 2524-64-3); and methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxylate (CAS No.: 217448-86-7), totaling more than ten impurities. Among them, the structure of impurity 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-carboxamide is shown below:

[0008]

[0009] Although the existing technology has disclosed this impurity, the preparation method of this impurity has not been disclosed. At present, there is a lack of a method for preparing the rufiamide impurity 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide.

[0010] Typically, pharmaceutical impurities / reference standards are standard substances used for identification, testing, content determination, and the examination of impurities and related substances. They are specialized measuring tools used to check reagent quality, serving as a benchmark for measuring reagent quality; they also act as standard substances for calibrating testing instruments and methods.

[0011] Therefore, it is necessary to develop a method for preparing high-purity 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide to be used as a reference standard for loufeamide impurities. Summary of the Invention

[0012] To address the shortcomings of existing technologies, the present invention provides a method for preparing a loufeliamide impurity reference standard. Using o-fluorobenzyl alcohol as the starting material, it undergoes a photoelectrophoresis reaction (Mistunobu reaction) with 1H-1,2,3-triazol-4-onitrile in the presence of diethyl azodicarbonate (DEAD) and triphenylphosphine (PPh3) to prepare 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-onitrile. This 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-onitrile is then reacted with potassium carbonate and hydrogen peroxide to prepare 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-carboxamide.

[0013] To achieve the above-mentioned objectives of this invention, the specific technical solution adopted by this invention is as follows:

[0014] A method for preparing a loufeliamide impurity reference standard includes the following steps:

[0015] (1) o-Fluorobenzyl alcohol, 1H-1,2,3-triazol-4-nitrile, photoresist, triphenylphosphine and solvent 1 were mixed and reacted to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile;

[0016] (2) 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile, carbonate, hydrogen peroxide, and solvent 2 were mixed and reacted to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-carboxamide. The synthetic route is as follows:

[0017]

[0018] Preferably, the molar ratio of o-fluorobenzyl alcohol, 1H-1,2,3-triazol-4-nitrile, photoresist and triphenylphosphine in step (1) is 1:1:2.5-3.0:2.5-3.0.

[0019] Preferably, the photoelectrophoresis reagent in step (1) is selected from either diethyl azodicarbonate or diisopropyl azodicarbonate.

[0020] Preferably, the solvent 1 in step (1) is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, toluene and dichloromethane.

[0021] Preferably, solvent 1 in step (1) is N,N-dimethylformamide, tetrahydrofuran, or toluene.

[0022] Preferably, the temperature of the reaction in step (1) is 0-30°C and the reaction time is 4-6 hours.

[0023] More preferably, the reaction temperature is 20-30℃ and the reaction time is 4-5h.

[0024] Preferably, after the reaction described in step (1), the process further includes steps of concentration, extraction, washing, and separation and purification.

[0025] More preferably, the solvent used for extraction is a mixture of water and ethyl acetate, wherein the volume ratio of water to ethyl acetate is 1:1-1.5, preferably 1:1.

[0026] More preferably, the washing process includes: washing the extracted organic layer sequentially with an 8-12% hydrochloric acid solution and saturated sodium carbonate solution, and then washing with a saturated sodium chloride solution.

[0027] Preferably, the molar ratio of 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-nitrile, carbonate and hydrogen peroxide in step (2) is 1:0.1-0.2:1.5-2.5.

[0028] The carbonate mentioned in step (2) is sodium carbonate or potassium carbonate.

[0029] Preferably, the solvent 2 in step (2) is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and tetrahydrofuran.

[0030] More preferably, the solvent 2 is dimethyl sulfoxide.

[0031] Preferably, the reaction temperature in step (2) is 10-30℃ and the reaction time is 0.5-1.5h.

[0032] More preferably, the reaction temperature is 20-30℃ and the reaction time is 1-1.5h.

[0033] Preferably, after the reaction described in step (2), the steps of adding water and stirring, filtering, washing and drying are further included.

[0034] More preferably, the temperature for adding water and stirring is 15-25°C, and the stirring time is 1.5-2.5 hours.

[0035] More preferably, the solvent used for washing is water; the drying temperature is 70-80℃, and the drying time is 10-15h.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] (1) The present invention is simple to operate, the reaction conditions are milder, and it does not involve the use and generation of azides;

[0038] (2) The synthesis method of the present invention is environmentally friendly and novel, and can quickly and efficiently prepare the target product;

[0039] (3) The 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide prepared by this invention has a yield of >50% and a purity of about 99%. Attached Figure Description

[0040] Figure 1 This is the 1H NMR spectrum of 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide prepared in Example 1. 1 HNMR (400MHz, DMSO-d6) δ8.58-8.52(m,1H), 7.85(s,1H), 7.51-7.33(m,3H), 7.30-7.17(m,2H), 5.75-5.69(m,2H). Detailed Implementation

[0041] The technical solutions in the embodiments of the present invention will be further described in detail below. The described embodiments are only a part of the present invention and are used to explain the present invention, but are not intended to limit the present invention. Therefore, other embodiments obtained by other people skilled in the art without creative labor are all within the protection scope of the present invention.

[0042] The raw materials used in the embodiments of this invention are all industrial products and are commercially available.

[0043] Example 1

[0044] Step 1:

[0045] Weigh out o-fluorobenzyl alcohol (10.00 g, 79.28 mmol), 1H-1,2,3-triazol-4-onitrile (7.46 g, 79.28 mmol), and triphenylphosphine (62.39 g, 237.84 mmol) and add them to a 500 ml three-necked flask, and measure out 200 ml of the solution. N,N-Dimethylformamide (DMF) was added and stirred until dissolved. The mixture was cooled to 5°C, and 50 mL of a solution of diethyl azodicarbonate (DEAD, 41.42 g, 237.84 mmol) in N,N-dimethylformamide (DMF) was added dropwise. After the addition was complete, the mixture was kept at 25°C for 4 h. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and the mixture was extracted with a mixture of 200 mL of water and 200 mL of ethyl acetate. The organic layer was washed with 10% hydrochloric acid solution and saturated sodium carbonate solution, followed by washing with saturated sodium chloride solution. The mixture was then purified by silica gel column chromatography to obtain 11.42 g of a white solid (1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile), with a yield of 71.2% and a purity of 98.2%.

[0046] Step 2:

[0047] Weigh 10.00 g (49.45 mmol) of 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile and add it to a 500 ml three-necked flask. Measure 100 ml of DMSO and add it to the flask. Start stirring and add potassium carbonate (1.36 g, 9.89 mmol). Control the temperature at 20 °C and add 30% hydrogen peroxide (14.02 g, 123.62 mmol) dropwise. After the addition is complete, cool the flask and keep it at 25 °C with stirring for 1 h. Monitor the reaction by TLC. Once the reaction is complete, add 300 ml of water and keep it at 20 °C with stirring for 2 h. Filter the flask. Wash the filter cake three times with water (300 ml * 3). Collect the filter cake and dry it at 80 °C with forced air for 10 h to constant weight to obtain 8.66 g of white solid (1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-carboxamide), with a yield of 80.6% and a purity of 99.5%.

[0048] Figure 1The 1H NMR spectrum of 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide is shown. 1 H NMR (400MHz, DMSO-d6) δ8.58-8.52(m,1H), 7.85(s,1H), 7.51-7.33(m,3H), 7.30-7.17(m,2H), 5.75-5.69(m,2H).

[0049] Example 2

[0050] Step 1:

[0051] Weigh out o-fluorobenzyl alcohol (10.00 g, 79.28 mmol), 1H-1,2,3-triazol-4-onitrile (7.46 g, 79.28 mmol), and triphenylphosphine (51.99 g, 198.2 mmol) into a 500 ml three-necked flask. Add 200 ml of dimethylformamide (DMF) to the flask and stir until dissolved. Cool to 5°C and add 50 ml of diethyl azodicarbonate (DEAD, 34.52 g, 198.2 mmol) dropwise. DMF solution was added dropwise, and the reaction was maintained at 25°C for 4 hours. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and the mixture was extracted with a mixture of 200 ml of water and 200 ml of ethyl acetate. The organic layer was washed with 10% hydrochloric acid solution and saturated sodium carbonate solution, and then washed with saturated sodium chloride solution. The mixture was purified by silica gel column chromatography to obtain 11.36 g of white solid (1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile), with a yield of 70.9% and a purity of 98.0%.

[0052] Step 2:

[0053] Weigh 10.00 g (49.45 mmol) of 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile and add it to a 500 ml three-necked flask. Measure 100 ml of DMSO and add it to the flask. Start stirring and add potassium carbonate (684 mg, 4.95 mmol). Control the temperature at 20 °C and add 30% hydrogen peroxide (11.22 g, 98.9 mmol) dropwise. After the addition is complete, cool the flask and keep it at 25 °C with stirring for 1 h. Monitor the reaction by TLC. Once the reaction is complete, add 300 ml of water and keep it at 20 °C with stirring for 2 h. Filter the flask. Wash the filter cake three times with water (300 ml * 3). Collect the filter cake and dry it at 80 °C with forced air for 10 h to constant weight to obtain 8.66 g of white solid (1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-carboxamide), with a yield of 79.5% and a purity of 99.3%.

[0054] Example 3

[0055] Step 1:

[0056] Weigh out o-fluorobenzyl alcohol (10.00 g, 79.28 mmol), 1H-1,2,3-triazol-4-onitrile (7.46 g, 79.28 mmol), and triphenylphosphine (51.99 g, 198.2 mmol) and add them to a 500 mL three-necked flask. Measure 200 mL of tetrahydrofuran and add it to the flask, stirring until dissolved. Cool to 10 °C and add 50 mL of a tetrahydrofuran solution of diisopropyl azodicarbonate (DIAD, 40.08 g, 198.2 mmol). After the addition is complete, maintain the temperature at 20 °C for 5 h. Monitor the reaction for completeness by TLC. Concentrate under reduced pressure to remove the solvent. Extract with a mixture of 200 mL of water and 200 mL of ethyl acetate. Wash the organic layer with 10% hydrochloric acid solution and saturated sodium carbonate solution, then wash with saturated sodium chloride solution. Purify by silica gel column chromatography to obtain 12.05 g of white solid, with a yield of 75.2% and a purity of 97.9%.

[0057] Step 2:

[0058] Weigh 10.00 g (49.45 mmol) of 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-onitrile into a 500 ml three-necked flask, add 100 ml of DMSO, start stirring, then add sodium carbonate (787.5 mg, 7.42 mmol) and control the temperature at 15 °C. Add 30% hydrogen peroxide (11.22 g, 98.9 mmol) dropwise. After the addition is complete, cool down and keep at 30 °C with stirring for 0.5 h. Monitor the reaction by TLC. When the reaction is complete, add 300 ml of water, keep at 25 °C with stirring for 1 h, filter, wash the filter cake three times with water (300 ml * 3), collect the filter cake, and dry it at 70 °C with forced air for 15 h to constant weight, giving 8.12 g of white solid, yield 75.3%, purity 99.3%.

[0059] Example 4

[0060] Example 4 is the same as Example 1, except that the solvent in step 1 is tetrahydrofuran, and the product yield in step 1 is 66.5% with a purity of 98.0%.

[0061] Example 5

[0062] Example 5 is the same as Example 1, except that the solvent in step 1 is toluene, and the product yield in step 1 is 53.2% with a purity of 97.8%.

[0063] Example 6

[0064] The preparation method of Example 6 is the same as that of Example 1, except that the reaction temperature in step 1 is 10°C, the reaction time is 6 hours, the product yield in step 1 is 58.6%, and the purity is 97.5%.

[0065] Example 7

[0066] The preparation method of Example 7 is the same as that of Example 1, except that the amount of triphenylphosphine added in step 1 is different. The molar ratio of o-fluorobenzyl alcohol, 1H-1,2,3-triazol-4-nitrile, triphenylphosphine and DEAD is 1:1:2:2.5. The yield of the product in step 1 is 55.3% and the purity is 97.6%.

[0067] Example 8

[0068] The preparation method of Example 8 is the same as that of Example 1, except that the solvent in step 2 is N,N-dimethylformamide, the product yield in step 2 is 55.4%, and the purity is 99.2%.

[0069] Example 9

[0070] The preparation method of Example 9 is the same as that of Example 1, except that the amount of hydrogen peroxide added in step 2 is different. The molar ratio of 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile, potassium carbonate and hydrogen peroxide is 1:0.2:1.5. The yield of the product in step 2 is 64.5% and the purity is 99.0%.

[0071] Example 10

[0072] The preparation method of Example 10 is the same as that of Example 1, except that the reaction temperature in step 2 is 10°C, the product yield in step 2 is 56.2%, and the purity is 98.7%.

[0073] Comparative Example 1

[0074] The preparation method of Comparative Example 1 is the same as that of Example 1, except that the solvent in step 1 is dichloromethane, and the product yield in step 1 is 42.4% with a purity of 80.9%.

[0075] Comparative Example 2

[0076] The preparation method of Comparative Example 2 is the same as that of Example 1, except that the reaction temperature in step 1 is 40°C, the product yield in step 1 is 45.8%, and the purity is 81.7%.

[0077] Comparative Examples 3-5

[0078] The preparation methods of Comparative Examples 3-5 are the same as those of Example 1, except that the amount of triphenylphosphine or DEAD added in step 1 is different. The yield and purity of the product in step 1 are shown in Table 1.

[0079] Table 1 shows the effect of reactant addition amount on product in step 1.

[0080]

[0081] Comparative Examples 6-7

[0082] The preparation methods of Comparative Examples 6-7 are the same as those of Example 1, except that the solvents used in step 2 are different, namely N-methylpyrrolidone and tetrahydrofuran. The yield and purity of the product in step 2 are shown in Table 2.

[0083] Table 2 shows the effect of solvent on the product in step 2.

[0084]

[0085]

[0086] Comparative Examples 8-9

[0087] The preparation methods of Comparative Examples 8-9 are the same as those of Example 1, except that the amount of potassium carbonate or hydrogen peroxide added in step 2 is different. The yield and purity of the product in step 2 are shown in Table 3.

[0088] Table 3 shows the effect of reactant addition amount on product in step 2.

[0089]

[0090] Comparative Examples 10-11

[0091] The preparation method of Comparative Examples 10-11 is the same as that of Example 1, except that the reaction temperature in step 2 is different. The yield and purity of the product in step 2 are shown in Table 4.

[0092] Table 4 shows the effect of reaction temperature on the product in step 2.

[0093] reaction temperature reaction time Step 2 Product Yield Step 2 Product Purity Example 1 25℃ 1h 80.6％ 99.5％ Comparative Example 10 40℃ 1h 46.1％ 84.5％ Comparative Example 11 50℃ 1h 27.5％ 86.1％

[0094] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A method of preparing a reference standard of a lufiram impurity, characterized in that, The method comprises the following steps: (1) mixing o-fluorobenzyl alcohol, 1H-1,2,3-triazole-4-carbonitrile, Mitsunobu reagent, triphenylphosphine and solvent 1, and reacting at 20-30°C for 3-5h to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile; The molar ratio of the o-fluorobenzyl alcohol, 1H-1,2,3-triazole-4-carbonitrile, Mitsunobu reagent and triphenylphosphine is 1:1-1.2:2.5-3.0:2.5-3.0; The solvent 1 is one or both of N,N-dimethylformamide and toluene; (2) mixing 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile, carbonate, hydrogen peroxide and solvent 2, and reacting at 20-30°C for 1-1.5h to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide; The molar ratio of the 1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-carbonitrile, carbonate and hydrogen peroxide is 1:0.1-0.2:1.5-2.5; The solvent 2 is one or both of N,N-dimethylformamide and dimethyl sulfoxide.

2. The production method according to claim 1, characterized by, The Mitsunobu reagent in step (1) is selected from any one of diethyl azodicarboxylate and diisopropyl azodicarboxylate.

3. The preparation method according to claim 1, characterized in that, After the reaction in step (1), the method further comprises the steps of concentration, extraction, washing and separation and purification.

4. The production method according to claim 1, characterized by, The carbonate in step (2) is sodium carbonate or potassium carbonate.

5. The method of claim 1, wherein, After the reaction in step (2), the method further comprises the steps of adding water, stirring, filtering, washing and drying.

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