A method for preparing a loufeamide intermediate

Abstract

This invention belongs to the field of pharmaceutical chemistry technology and provides a method for preparing a rufiamide intermediate. The specific steps of the preparation method include: (1) using 2,6-difluorobenzyl alcohol as a raw material, reacting it with a chlorinating reagent to obtain 2,6-difluorobenzyl chloride; (2) reacting 2,6-difluorobenzyl chloride with 1H-1,2,3-triazol-4-carboxylic acid and its ester analogs in an organic solvent under the action of an acid-binding agent to obtain the target product. The reaction conditions of this invention are mild, the operation is simple, and the post-processing is simple; all solvents used are Class III solvents specified by ICH Q3C, which are low in toxicity and environmentally friendly; and the target product has high purity and yield, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology and relates to a method for preparing a loufeliamide intermediate. Background Technology

[0002] Rufinamide (trade name Banzel) is primarily used as adjunctive therapy for Lennox-Gastaut syndrome (LGS) epilepsy; its chemical name is 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxamide, and its structure is shown in formula (I):

[0003]

[0004] There are several methods for preparing loufeamide, the most important of which is to prepare it by amination of an intermediate as shown in formula (II);

[0005]

[0006] The intermediate shown in formula (II) is usually prepared by the following synthetic route:

[0007]

[0008] US Patent US08198459B2 discloses a method for preparing this series of loufeamide intermediates. The method involves preparing 2,6-difluorobenzyl azidation from 2,6-difluorobenzyl alcohol, followed by reaction with propynic acid or propynic acid esters under a catalyst to prepare compound (II), and then preparing loufeamide from compound (II) by amination.

[0009] Chinese invention patent application CN103539750A discloses a process for synthesizing loufeamide, in which 2,6-difluorobenzyl azide and methyl propargylate are reacted under the catalysis of nano-cuprous oxide (Cu2O) to obtain methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate.

[0010] Chinese invention patent CN105712943B discloses a preparation process for a loufeamide intermediate. The process uses 2,6-difluorobenzyl azide as a raw material and reacts it with propargyl acid in isopropanol or ethanol solvent in the presence of copper powder and vitamin C at a temperature of 40-45°C to prepare 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid.

[0011] All of the above technologies use azide compounds as raw materials, require harsh conditions and specific catalysts, have complex reaction operations and post-processing, and involve high costs due to the presence of propynic acid and its derivatives as reactants.

[0012] Chinese invention patent CN109438374B discloses a continuous synthesis method for loufeamide. This continuous synthesis method includes: continuously feeding methyl 1,2,3-triazole-4-carboxylate and 2,6-difluorobenzyl chloride into a first continuous reaction apparatus in the presence of an acid-binding agent to carry out a continuous condensation reaction, obtaining a continuous condensation product, and continuously discharging the continuous condensation product; continuously feeding the continuous condensation product into a second continuous reaction apparatus with ammonia gas or an ammonia-containing solution to carry out an ammonolysis reaction, obtaining loufeamide, and continuously discharging the loufeamide; this method simplifies... The purification steps for the final product yield a relatively high amount of product; however, this continuous condensation reaction is vigorous, requires pressurization equipment, and is complex to operate. It is usually used for small-scale trials in processes requiring pressure, high temperature, and unstable reactions, and is not suitable for industrial production. In addition, continuous synthesis reactions are expensive and costly; the system is small, the heat exchange rate is high, and the reaction is vigorous, requiring control of the reaction system pressure, which still poses certain safety concerns. Furthermore, the reaction mainly uses chloroform as a solvent, which is a Class II solvent and is highly toxic, unfriendly to the environment and human health. ICH Q3C stipulates that the residual limit of this solvent cannot exceed 60 ppm.

[0013] In view of the above-mentioned problems in the existing technology, there is an urgent need to develop a preparation process for loufeamide intermediates that has a mild reaction, yield and purity that meet industry requirements, and is suitable for industrial production. Summary of the Invention

[0014] This invention addresses the problems of harsh and complex reaction conditions, high equipment and raw material costs in existing technologies by providing a synthetic route for rufamide intermediates. The route uses 2,6-difluorobenzyl alcohol as a raw material, first chlorinating it to obtain 2,6-difluorobenzyl chloride, which then reacts with 1H-1,2,3-triazole-4-carboxylic acid and its ester analogs to yield 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid or its ester analogs. This method utilizes low-cost raw materials, a simple synthetic route, and straightforward reaction operations, employing three types of solvents: n-heptane, acetone, etc. Furthermore, it requires minimal equipment and is environmentally friendly, reducing costs and improving safety in the preparation of rufamide intermediates.

[0015] The technical solution of the present invention is as follows:

[0016] A method for preparing a loufeliamide intermediate, characterized by the following synthetic route:

[0017]

[0018] The specific steps include:

[0019] (1) Using 2,6-difluorobenzyl alcohol as a raw material, 2,6-difluorobenzyl chloride was obtained by chlorination reaction;

[0020] (2) 2,6-Difluorobenzyl chloride reacts with 1H-1,2,3-triazol-4-carboxylic acid or its ester analogue in an organic solvent under the action of an acid-binding agent to obtain the target product.

[0021] Furthermore, in the ester analogues of 1H-1,2,3-triazol-4-carboxylic acid, R is selected from any one of -H, -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

[0022] Furthermore, in step (1), the chlorination reagent used in the chlorination reaction is thionyl chloride or phosphorus oxychloride, and the chlorination reagent can also be used as a reaction solvent, without the need for additional solvent.

[0023] Furthermore, in step (1), the reaction temperature is 100-110℃ and the reaction time is 1h.

[0024] This invention prepares 2,6-difluorobenzyl chloride from 2,6-difluorobenzyl alcohol. The reaction is more conventional and has a higher yield and purity, thereby improving the overall reaction yield. Furthermore, it is less expensive than directly preparing rufamide intermediates from 2,6-difluorobenzyl chloride.

[0025] Furthermore, in step (2), the acid-binding agent is selected from at least one of potassium carbonate, sodium carbonate, triethylamine and N,N-diisopropylethylamine.

[0026] Preferably, in step (2), the acid-binding agent used is potassium carbonate or triethylamine.

[0027] More preferably, in step (2), the acid-binding agent used is potassium carbonate.

[0028] Further, in step (2), the molar ratio of the acid-binding agent to 2,6-difluorobenzyl chloride is 1.2-2:1.

[0029] Preferably, in step (2), the molar ratio of the acid-binding agent to 2,6-difluorobenzyl chloride is 1.2-1.5:1.

[0030] Further, in step (2), the molar ratio of 1H-1,2,3-triazole-4-carboxylic acid or its ester analogue to 2,6-difluorobenzyl chloride is 0.5-1:0.5-1.

[0031] Preferably, in step (2), the molar ratio of 1H-1,2,3-triazole-4-carboxylic acid or its ester analogue to 2,6-difluorobenzyl chloride is 0.8-1:1.

[0032] Further, in step (2), the organic solvent is n-heptane or acetone.

[0033] Preferably, in step (2), the organic solvent is n-heptane.

[0034] Furthermore, in step (2), the reaction temperature is 50-98℃.

[0035] Preferably, in step (2), the reaction temperature is 55-75℃.

[0036] Furthermore, the completion of the reaction in step (1) or step (2) also includes post-processing, and the post-processing in step (1) specifically includes the following steps:

[0037] (1-1) After the reaction is complete, remove the chlorinating reagent;

[0038] (1-2) Dissolve in water and extract with an extraction solvent to obtain organic layer 1;

[0039] (1-3) Wash the organic layer 1 and dry it to obtain 2,6-difluorobenzyl chloride;

[0040] Step (2) post-processing specifically includes the following steps:

[0041] (2-1) After the reaction is complete, remove the organic solvent;

[0042] (2-2) Dissolve in water and extract with an extraction solvent to obtain organic layer 2;

[0043] (2-3) Wash the organic layer 2 and dry it to obtain the target product.

[0044] Furthermore, the extraction solvent is methyl tert-butyl ether or ethyl acetate.

[0045] Furthermore, in steps (1-3), the washing process involves sequentially using water, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution.

[0046] Furthermore, in steps (2-3), the washing process involves sequentially washing with water, 5% dilute hydrochloric acid solution, and saturated sodium chloride solution.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] 1. This invention uses 2,6-difluorobenzyl alcohol to prepare 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxylic acid and its lipid analogs as intermediates of rufamide through a two-step reaction. The synthetic route is simple, and the yield of the target product can reach more than 96% and the purity can reach more than 99.5%.

[0049] 2. Compared with continuous reactions, the reaction conditions of this invention are mild and do not require special pressurization equipment. While ensuring the yield and purity of the target product, the operation process is greatly simplified.

[0050] 3. The process of preparing rufamide intermediates from benzyl chloride in this invention uses three types of solvents as reaction solvents, which have low toxicity and the trace residues do not affect the subsequent use of the product.

[0051] 4. This invention further improves the reaction yield and purity by optimizing the reaction conditions, especially the reaction temperature, solvent selection, and the amount of acid-binding agent and raw material 2,6-difluorobenzyl alcohol.

[0052] 5. This invention provides a low-cost, low-equipment-requirement, green and safe method for synthesizing rufamide intermediates, which reduces the cost and improves the safety of rufamide preparation. Attached Figure Description

[0053] Figure 1 The NMR spectrum of the target product 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl ester in Example 1 is shown below.

[0054] Figure 2 The NMR spectrum of the target product 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-ethyl ester in Example 5 is shown below.

[0055] Figure 3 The NMR spectrum of the target product 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxylic acid in Example 7 is shown. Detailed Implementation

[0056] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection of the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection of the present invention.

[0057] Example 1: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0058] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of thionyl chloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove thionyl chloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 55.32 g of white solid. The yield is 98.1% and the purity is 99.3%.

[0059] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate (35.18 g (276.8 mmol) and potassium carbonate (57.38 g (415.2 mmol), and add 200 mL of n-heptane to a 500 mL reaction flask. Turn on the stirring and heat to 75 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 67.36 g of white solid, with a yield of 96.1% and a purity of 99.2%.

[0060] NMR (400MHz, DMSO-d6), δ = 8.87 (s, 1H), 7.68-7.37 (m, 1H), 7.29-7.10 (m, 2H), 5.76 (s, 2H),

[0061] 3.84 (s, 3H).

[0062] Example 2: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0063] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of phosphorus oxychloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove phosphorus oxychloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 51.81 g of white solid. The yield is 97.2% and the purity is 99.6%.

[0064] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate (35.18 g (276.8 mmol) and triethylamine (42.01 g (415.2 mmol) and add 200 mL of n-heptane to a 500 mL reaction flask. Start stirring and heat to 75 °C. Keep stirring and maintain the temperature for 1 h. Monitor the reaction for completeness by TLC. Concentrate under reduced pressure to remove the solvent. Extract with 200 mL of water and 200 mL of ethyl acetate. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 66.09 g of white solid, with a yield of 94.3% and a purity of 99.1%.

[0065] Example 3: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0066] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of phosphorus oxychloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove phosphorus oxychloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 51.81 g of white solid. The yield is 97.2% and the purity is 99.6%.

[0067] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate (35.18 g (276.8 mmol) and potassium carbonate (57.38 g (415.2 mmol) and add 200 mL of acetone to a 500 mL reaction flask. Turn on the stirring and heat to 55 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Add 200 mL of water and 200 mL of ethyl acetate for extraction. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid and 200 mL of saturated sodium chloride solution, respectively. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 67.15 g of white product, with a yield of 95.8% and a purity of 99.5%.

[0068] Example 4: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0069] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of phosphorus oxychloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove phosphorus oxychloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 51.81 g of white solid. The yield is 97.2% and the purity is 99.6%.

[0070] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate (35.18 g (276.8 mmol) and potassium carbonate (45.90 g (322.16 mmol) and add 200 mL of n-heptane to a 500 mL reaction flask. Turn on the stirring and heat to 75 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Extract with 200 mL of water and 200 mL of ethyl acetate. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid and 200 mL of saturated sodium chloride solution, respectively. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to give 64.69 g of white solid, with a yield of 92.3% and a purity of 99.1%.

[0071] Example 5: Ethyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0072] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of phosphorus oxychloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove phosphorus oxychloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 54.81 g of white solid. The yield is 97.2% and the purity is 99.6%.

[0073] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, 39.06 g (276.8 mmol) of 1H-1,2,3-triazol-4-carboxylic acid ethyl ester, and 57.38 g (415.2 mmol) of potassium carbonate. Add 200 mL of n-heptane to a 500 mL reaction flask, turn on the stir and heat to 75 °C, keep the temperature and stir. Monitor the reaction by TLC until complete, concentrate under reduced pressure and remove the solvent. Extract with 200 mL of water and 200 mL of ethyl acetate. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid and 200 mL of saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to give 71.16 g of white solid, yield 96.2% and purity 99.4%.

[0074] NMR (400MHz, DMSO-d6), δ = 8.83 (s, 1H), 7.54 (tt, J = 8.5, 6.8Hz, 1H), 7.20 (t, J = 8.2Hz, 2H),

[0075] 5.76 (s, 2H), 4.31 (q, J = 7.2Hz, 2H), 1.30 (t, J = 7.2Hz, 3H).

[0076] Example 6: Ethyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0077] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of phosphorus oxychloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove phosphorus oxychloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 54.81 g of white solid. The yield is 97.2% and the purity is 99.6%.

[0078] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, 39.06 g (276.8 mmol) of 1H-1,2,3-triazol-4-carboxylic acid ethyl ester, and 42.01 g (415.2 mmol) of triethylamine. Add 200 mL of n-heptane to a 500 mL reaction flask, turn on the stir and heat to 75 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Extract with 200 mL of water and 200 mL of ethyl acetate. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to give 70.64 g of white solid, with a yield of 95.5% and a purity of 99.3%.

[0079] Example 7: 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxylic acid

[0080] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of phosphorus oxychloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove phosphorus oxychloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 54.81 g of white solid. The yield is 97.2% and the purity is 99.6%.

[0081] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, 39.06 g (276.8 mmol) of 1H-1,2,3-triazol-4-carboxylic acid, and 57.38 g (415.2 mmol) of potassium carbonate. Add 200 mL of n-heptane to a 500 mL reaction flask, turn on the stir and heat to 75 °C, keep the temperature and stir. Monitor the reaction by TLC until complete, concentrate under reduced pressure and remove the solvent. Extract with 200 mL of water and 200 mL of ethyl acetate. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid and 200 mL of saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 60.98 g of white solid, yield 92.1% and purity 99.1%.

[0082] NMR (400MHz, DMSO-d6), δ = 13.13 (s, 1H), 8.73 (s, 1H), 7.53 (tt, J = 8.5, 6.7Hz, 1H), 7.33-

[0083] 7.02 (m, 2H), 5.73 (s, 2H).

[0084] Example 8: 1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxylic acid

[0085] (1) Weigh 50.00 g of 2,6-difluorobenzyl alcohol (346.9 mmol) and add it to a 500 mL three-necked flask. Measure 200 mL of phosphorus oxychloride and add it to the reaction flask. Turn on the stirring and heat to 105 °C. Reflux the reaction solution and keep it warm and stirring for 1 h. Monitor the reaction by TLC until it is complete. Concentrate under reduced pressure to remove phosphorus oxychloride. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer successively with 200 mL of water, 100 mL of saturated sodium bicarbonate solution, and 200 mL of saturated sodium chloride solution. Finally, add anhydrous sodium sulfate and stir to dry for 30 min. Filter and concentrate the filtrate to dryness to obtain 54.81 g of white solid. The yield is 97.2% and the purity is 99.6%.

[0086] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, 39.06 g (276.8 mmol) of 1H-1,2,3-triazol-4-carboxylic acid, and 53.66 g (415.2 mmol) of N,N-diisopropylethylamine (DIPEA, 415.2 mmol). Add 200 mL of n-heptane to a 500 mL reaction flask, turn on the stir and heat to 75 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure to remove the solvent. Extract with 200 mL of water and 200 mL of ethyl acetate. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to give 57.21 g of white solid, with a yield of 86.4% and a purity of 99.3%.

[0087] Comparative Example 1: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0088] (1) Same as Example 1;

[0089] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate, 35.18 g (276.8 mmol) and sodium carbonate (44.01 g, 415.2 mmol) prepared in Example 1, and add 200 mL of n-heptane to a 500 mL reaction flask. Turn on the stirring and heat to 75 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution, respectively. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 59.09 g of white solid, with a yield of 84.3% and a purity of 95.4%.

[0090] Comparative Example 2: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0091] (1) Same as Example 1;

[0092] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate, 35.18 g (276.8 mmol) and potassium carbonate (38.20 g (276.8 mmol) prepared in Example 1, and add 200 mL of n-heptane to a 500 mL reaction flask. Turn on the stirring and heat to 75 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution, respectively. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 60.14 g of white solid, with a yield of 85.8% and a purity of 98.6%.

[0093] Comparative Example 3: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0094] (1) Same as Example 1;

[0095] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate, 35.18 g (276.8 mmol) and 42.01 g (415.2 mmol) of potassium carbonate prepared in Example 1, and add 200 mL of cyclohexane to a 500 mL reaction flask. Start stirring and heat to 75 °C, keep warm and stir for 1 h. Monitor the reaction by TLC until complete, concentrate under reduced pressure and remove the solvent; extract with 200 mL of water and 200 mL of ethyl acetate; wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid and 200 mL of saturated sodium chloride solution respectively; dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness to obtain 60.48 g of white solid, yield 86.3% and purity 96.8%.

[0096] Comparative Example 4: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0097] (1) Same as Example 1;

[0098] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazole-4-carboxylate, 35.18 g (276.8 mmol) and potassium carbonate (42.01 g, 415.2 mmol) prepared in Example 1, and add 200 mL of chloroform to a 500 mL reaction flask. Turn on the stirring and heat to 60 °C. Keep the temperature and stir for 1 h. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure to remove the solvent. Add 200 mL of water and 200 mL of ethyl acetate for extraction. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution, respectively. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 53.40 g of white solid, with a yield of 76.2% and a purity of 98.6%.

[0099] Comparative Example 5: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0100] (1) Same as Example 1;

[0101] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate, 35.18 g (276.8 mmol) and potassium carbonate (57.38 g, 415.2 mmol) prepared in Example 1, and add 200 mL of n-heptane to a 500 mL reaction flask. Turn on the stirring and heat to 65 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution, respectively. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 31.61 g of white solid, with a yield of 45.1% and a purity of 94.2%.

[0102] Comparative Example 6: Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate

[0103] (1) Same as Example 1;

[0104] (2) Weigh 45.00 g (276.8 mmol) of 2,6-difluorobenzyl chloride, methyl 1H-1,2,3-triazol-4-carboxylate, 35.18 g (276.8 mmol) and potassium carbonate (57.38 g, 415.2 mmol) prepared in Example 1, and add 200 mL of n-heptane to a 500 mL reaction flask. Turn on the stirring and heat to 98 °C. Keep the temperature and stir the reaction. Monitor the reaction with TLC until it is complete. Concentrate under reduced pressure and remove the solvent. Add 200 mL of water and 200 mL of methyl tert-butyl ether for extraction. Wash the organic layer with 200 mL of water, 100 mL of 5% dilute hydrochloric acid, and 200 mL of saturated sodium chloride solution, respectively. Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness to obtain 60.06 g of white solid, with a yield of 85.7% and a purity of 97.5%.

[0105] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A process for the preparation of a norfluoxetine intermediate, characterized in that, The synthetic route is as follows: The specific steps include: (1) taking 2,6-difluorobenzyl alcohol as a raw material, chlorination reaction is carried out with a chlorinating agent to obtain 2,6-difluorobenzyl chloride; (2) 2,6-difluorobenzyl chloride reacts with an ester compound of 1H-1,2,3-triazole-4-carboxylic acid in an organic solvent under the action of an acid binding agent to obtain the target product; The acid binding agent is at least one of potassium carbonate, triethylamine and N,N-diisopropyl ethylamine; The molar ratio of the acid binding agent to 2,6-difluorobenzyl chloride is 1.2-2:1; the molar ratio of the ester compound of 1H-1,2,3-triazole-4-carboxylic acid to 2,6-difluorobenzyl chloride is 1:1; When the organic solvent is n-heptane, the reaction temperature is 75°C; when the organic solvent is acetone, the reaction temperature is 55°C; In the ester compound of 1H-1,2,3-triazole-4-carboxylic acid, the R group is any one of -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

2. The production method according to claim 1, characterized by, In step (2), the acid binding agent is potassium carbonate or triethylamine.

3. The method of claim 1, wherein, In step (2), the molar ratio of the acid binding agent to 2,6-difluorobenzyl chloride is 1.2-1.5:

1.

4. The method of claim 1, wherein, The reaction in step (1) or step (2) also includes post-treatment, and the post-treatment in step (1) specifically includes the following steps: (1-1) After the reaction is completed, the chlorinating agent is removed; (1-2) Water is added for dissolution, and an extraction solvent is used for extraction to obtain organic layer 1; (1-3) Organic layer 1 is washed and dried to obtain 2,6-difluorobenzyl chloride; The post-treatment in step (2) specifically includes the following steps: (2-1) After the reaction is completed, the organic solvent is removed; (2-2) Water is added for dissolution, and an extraction solvent is used for extraction to obtain organic layer 2; (2-3) Organic layer 2 is washed and dried to obtain the target product.

5. The preparation method according to claim 4, characterized in that, The extraction solvent is methyl tert-butyl ether or ethyl acetate.

6. The preparation method according to claim 4, characterized in that, In step (1-3), water, saturated sodium bicarbonate solution and saturated sodium chloride solution are used to wash the organic layer in turn; in step (2-3), water, 5% dilute hydrochloric acid solution and saturated sodium chloride solution are used to wash the organic layer in turn.

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