A synthetic process for a key intermediate of empagliflozin

Abstract

The invention discloses a synthesis process of a key intermediate of empagliflozin, wherein 4-bromo-2-(bromomethyl)-1-chlorobenzene (compound IV) is used as a raw material to prepare a Grignard reagent, an ether compound (compound IV) prepared by reacting (S)-3-hydroxytetrahydrofuran with 1,4-difluorobenzene is mixed, and a coupling reaction is promoted by activating a C-F bond to obtain a product compound III, and the Grignard reagent and compound III are coupled to finally obtain a key intermediate compound VI of empagliflozin. The invention has the beneficial effects that: the synthetic route of the invention effectively reduces the steps required for the reaction, improves the selectivity of the reaction, reduces the generation of reaction by-products, and the product yield obtained by the route is high, the obtained product is easy to separate, the reaction operation is convenient, the reaction pollution is small, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field related to the preparation of pharmaceutical intermediates, and specifically to a synthesis process of a key intermediate of empagliflozin. Background Art

[0002] Empagliflozin, also known as empagliflozin, is a selective oral SGLT-2 inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly and Company. It is a drug that can directly lower blood sugar by selectively inhibiting the reabsorption of filtered glucose by the proximal glomerular tubules, allowing excess glucose to be excreted from the urine. It is used to treat type 2 diabetes hyperglycemia. Recent clinical research results have shown that it has significant efficacy and good safety and tolerability. It was first launched in Europe in May 2014, and later in the United States and Japan in August and December 2014 respectively, and in China in September 2017. The chemical name of empagliflozin is (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol, molecular formula: C23H27ClO7, molecular weight: 450.91, and its chemical structure is as follows:

[0003] .

[0004] (3S)-3-[4-[(2-chloro-5-iodo(or bromo)phenyl)methyl]phenoxy]tetrahydrofuran is a key intermediate for the synthesis of empagliflozin. The method comprises the following steps: taking iodobenzoic acid as a starting material, reacting with oxalyl chloride under the catalysis of fluorobenzene and DMF to generate 2-chloro-5-iodobenzoyl chloride, and then reacting with fluorobenzene to generate (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone compound 1, and then reacting with (S)-3-hydroxytetrahydrofuran to generate compound 2, and finally reducing the carbonyl group to obtain (S)-3-[4-(5-iodo-2-chlorobenzyl)phenoxy]tetrahydrofuran compound.

[0005] This method is still widely used in the process of synthesizing empagliflozin in industry, but the reaction steps are relatively large. The Friedel-Crafts acylation reaction easily produces fluorine ortho-position impurities. The resulting mixture of fluorine ortho-position substituted intermediate impurities and products has poor reaction selectivity. In addition, the impurities and products have similar properties and are difficult to separate. The synthesis route of the key intermediate compound is as follows:

[0006] Route 1

[0007]

[0008] Chinese patent CN107311962A discloses a method for synthesizing (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran, and the synthesis route is as follows: 1) 4-fluorotoluene and (S)-3-hydroxytetrahydrofuran are used as starting materials and an inorganic base is used as a catalyst to react to obtain (S)-3-p-cresolyltetrahydrofuran; 2) the obtained product is reacted with NCS (N-chlorobutyryl) under the catalysis of BPO (dibenzoyl peroxide) The invention relates to a method for preparing a novel nanostructured carbonyl tetrahydrofuran comprising: reacting (S)-3-(4-(5-bromo-2-aminobenzyl)phenoxy)tetrahydrofuran with imide to obtain (S)-3-(4-chlorocresol-based tetrahydrofuran); 3) under the action of a Lewis acid catalyst, (S)-3-(4-chlorocresol-based tetrahydrofuran is reacted with 4-bromoaniline to obtain (S)-3-(4-(5-bromo-2-aminobenzyl)phenoxy)tetrahydrofuran; 4) the obtained product is subjected to a diazotization reaction and then reacted with cuprous chloride to obtain (S)-3-(4-(5-iodo-2-chlorobenzyl)phenoxy)tetrahydrofuran.

[0009] The synthesis method uses 4-fluorotoluene, which is easy to obtain, as the starting material. The synthesis route is short, but the reaction and post-treatment steps of the synthesis route are relatively complicated and need to be further improved. The synthesis process of (3S)-3-[4-[(2-chloro-5-iodophenyl)methyl]phenoxy]tetrahydrofuran is as follows:

[0010] Summary of the invention

[0011] In view of the shortcomings of the prior art in the synthesis of the key intermediate of empagliflozin, such as more reaction steps, complicated operation, poor reaction selectivity during alkylation reaction, more by-products and difficulty in separation, the present invention provides a method for synthesizing empagliflozin, wherein 4-bromo-2-(bromomethyl)-1-chlorobenzene (compound IV) is used as a raw material to prepare a Grignard reagent, an ether compound (compound IV) prepared by the reaction of (S) 3 hydroxytetrahydrofuran and 1,4-difluorobenzene is mixed, and the coupling reaction is promoted by activating the CF bond to obtain the product compound III, the Grignard reagent and compound III are subjected to a coupling reaction, and finally the key intermediate compound VI of empagliflozin is obtained.

[0012] The method should have the advantages of fewer steps, high selectivity, fewer by-products, high product yield, easy product separation, convenient operation, and suitability for large-scale industrial production. The reaction route of the present invention is as follows:

[0013]

[0014] The technical solution provided by the present invention is as follows:

[0015] A synthesis process of a key intermediate of empagliflozin comprises the following steps:

[0016] In the first step, reactant I is dissolved in an organic solvent, compound II is added dropwise to the solution, the mixture is stirred and mixed, a catalyst is added continuously, the mixture is stirred and mixed, and the mixture is reacted at room temperature for 2 to 3 hours. After the reaction is completed, the product is separated to obtain compound III;

[0017] Step 2: Under nitrogen protection, magnesium chips and solvent were added to a four-necked flask, and ethyl bromide was added to initiate the reaction. The mixture was heated to 65°C, and the compound IV solution was slowly added dropwise while maintaining the reaction temperature at 65°C. After the addition was completed, the mixture was heated for 1.5 to 2 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain the Grignard reagent compound V.

[0018] In the third step, compound III is dissolved in an organic solvent, a catalyst is added to the solution, an organic base reagent is added, and the Grignard reagent compound V obtained in the second step is gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction is completed, the product is separated to obtain the key intermediate compound VI of empagliflozin.

[0019] Furthermore, the solvents used in the first step reaction, the second step reaction and the third step reaction are all tetrahydrofuran.

[0020] Furthermore, the catalyst used in the first step reaction is potassium tert-butoxide, and the potassium tert-butoxide is a 20% wt solution in tetrahydrofuran.

[0021] Furthermore, in the first step reaction, the molar ratio of reactant I, compound II, and catalyst is 1:1.0-1.1:1.0-1.5, preferably 1:1.05:1.2.

[0022] Furthermore, the organic base reagent used in the third step reaction is one of the organic weak bases triethylamine and diisopropylethylamine, and the amount of the organic base reagent used is 10-20 mol%, preferably 15 mol%, of compound V.

[0023] Furthermore, the solution of compound IV used in the second step reaction is a tetrahydrofuran solution with a concentration of 1 mol / L.

[0024] Furthermore, the catalyst used in the third step reaction is one of boron trifluoride, NiCl2(dppe)(1,2-bis(diphenylphosphine)ethane), and NiCl2(dppp)(1,3-bis(diphenylphosphine)propane).

[0025] Furthermore, the amount of catalyst used in the third step reaction is 3-8 mol%, preferably 5 mol%, of compound IV.

[0026] Furthermore, in the third step reaction, the molar ratio of compound V to compound III is 1:1-1.1, preferably 1:1.05.

[0027] The beneficial effects of the present invention are: 1. The coupling reaction is completed by activating the CF bond and catalyzing the Grignard reagent, thereby reducing the steps required for the reaction, improving the selectivity of the reaction, and reducing the generation of reaction by-products; 2. The product yield obtained by the reaction route of the present invention is high, the product is easy to separate, the operation is convenient, the reaction pollution is small, and it is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is a schematic diagram of the reaction flow of route 1 of the present invention;

[0029] Figure 2 This is a schematic diagram of the reaction flow of route 2 of the present invention;

[0030] Figure 3 It is a schematic diagram of the reaction route of the present invention;

[0031] Figure 4 Schematic diagram of the chemical structure of Engelhardt. DETAILED DESCRIPTION

[0032] The following will be combined with the embodiments of the present invention and the accompanying drawings to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] In the first step, 11.4 g (0.1 mol) of compound I was dissolved in 300 ml of tetrahydrofuran (THF), an organic solvent, and 9.25 g (0.105 mol) of compound II (S)-3-hydroxytetrahydrofuran was slowly added to the resulting solution, stirred and mixed, and 0.12 mol of potassium tert-butoxide (20% wt solution in tetrahydrofuran) as a catalyst was continuously added to the solution, the solution was mixed evenly, and the reaction was stirred at room temperature for 2 to 3 hours. After the reaction was completed, dilute hydrochloric acid was added to quench, and the pH of the neutralized solution was neutral. The organic solvent was removed by vacuum distillation, 100 ml of toluene was added, stirred, allowed to stand, and the organic phase was separated. The aqueous phase was extracted 2 to 3 times with 50 ml of toluene, and the organic phases were combined. The organic phases were washed 2 to 3 times with saturated brine, and the solvent was evaporated. The product was recrystallized with 40 ml of toluene to finally obtain compound III, weighing 17.1 g, with a yield of 93.8% and a purity of 98.5%.

[0034] In the second step, under nitrogen protection, add 2.43g (0.10mol) of magnesium chips into a 1000ml four-necked flask, add 150ml of THF reagent, drop 10ml of 1mol / L tetrahydrofuran solution of compound III into the flask, add 0.3g of initiator bromoethane, continue heating to 65°C, slowly drop 90ml of 1mol / L tetrahydrofuran solution of compound IV, maintain the reaction temperature at 65°C, after the addition is complete, continue heating to reflux for 1.5 to 2h, cool to room temperature after the reaction is completed, filter, and obtain a tetrahydrofuran solution of Grignard reagent compound IV.

[0035] In the third step, 19.1 g (0.105 mol) of compound III was dissolved in 250 ml of THF, 0.005 mol of boron trifluoride as a catalyst was added to the solution, 0.015 mol of triethylamine as an organic base reagent was added, and the Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, the organic solvent was evaporated, 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers. The organic phase was extracted with 50 ml of toluene for 2 to 3 times, the organic phases were combined, washed with saturated brine for 2 to 3 times, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.9 g, with a yield of 89.5% and a purity of 98.9%.

[0036] In the first step, 11.4 g (0.1 mol) of compound I was dissolved in 300 ml of tetrahydrofuran (THF), an organic solvent, and 8.81 g (0.10 mol) of compound II (S)-3-hydroxytetrahydrofuran was slowly added to the resulting solution, stirred and mixed, and 0.12 mol of potassium tert-butoxide (20% wt solution in tetrahydrofuran) as a catalyst was continuously added to the solution, the solution was mixed evenly, and the reaction was stirred at room temperature for 2 to 3 hours. After the reaction was completed, dilute hydrochloric acid was added to quench, and the pH of the neutralized solution was neutral. The organic solvent was removed by vacuum distillation, 100 ml of toluene was added, stirred, allowed to stand, and the organic phase was separated. The aqueous phase was extracted 2 to 3 times with 50 ml of toluene, and the organic phases were combined. The organic phases were washed 2 to 3 times with saturated brine, and the solvent was evaporated. The product was recrystallized with 40 ml of toluene to finally obtain compound III, weighing 16.8 g, with a yield of 92.2% and a purity of 98.3%.

[0037] In the first step, 11.4 g (0.1 mol) of compound I was dissolved in 300 ml of tetrahydrofuran (THF), an organic solvent, and 9.69 g (0.11 mol) of compound II (S)-3-hydroxytetrahydrofuran was slowly added to the resulting solution, stirred and mixed, and 0.12 mol of potassium tert-butoxide (20% wt solution in tetrahydrofuran) as a catalyst was continuously added to the solution, the solution was mixed evenly, and the reaction was stirred at room temperature for 2 to 3 hours. After the reaction was completed, dilute hydrochloric acid was added to quench, and the pH of the neutralized solution was neutral. The organic solvent was removed by vacuum distillation, 100 ml of toluene was added, stirred, allowed to stand, and the organic phase was separated. The aqueous phase was extracted 2 to 3 times with 50 ml of toluene, the organic phases were combined, the organic phases were washed 2 to 3 times with saturated brine, the solvent was evaporated, and the product was recrystallized with 40 ml of toluene to finally obtain compound III, weighing 17.2 g, with a yield of 94.4% and a purity of 98.4%.

[0038] In the first step, 11.4 g (0.1 mol) of compound I was dissolved in 300 ml of tetrahydrofuran (THF), an organic solvent, and 9.25 g (0.105 mol) of compound II (S)-3-hydroxytetrahydrofuran was slowly added to the resulting solution, stirred and mixed, and 0.10 mol of potassium tert-butoxide (20% wt solution in tetrahydrofuran) as a catalyst was continuously added to the solution, the solution was mixed evenly, and the reaction was stirred at room temperature for 2 to 3 hours. After the reaction was completed, dilute hydrochloric acid was added to quench, and the pH of the neutralized solution was neutral. The organic solvent was removed by vacuum distillation, 100 ml of toluene was added, stirred, allowed to stand, and the organic phase was separated. The aqueous phase was extracted 2 to 3 times with 50 ml of toluene, and the organic phases were combined. The organic phases were washed 2 to 3 times with saturated brine, and the solvent was evaporated. The product was recrystallized with 40 ml of toluene to finally obtain compound III, weighing 16.9 g, with a yield of 92.7% and a purity of 98.8%.

[0039] In the first step, 11.4 g (0.1 mol) of compound I was dissolved in 300 ml of tetrahydrofuran (THF), an organic solvent, and 9.25 g (0.105 mol) of compound II (S)-3-hydroxytetrahydrofuran was slowly added to the resulting solution, stirred and mixed, and 0.15 mol of potassium tert-butoxide (20% wt solution in tetrahydrofuran) as a catalyst was continuously added to the solution, the solution was mixed evenly, and stirred and reacted at room temperature for 2 to 3 hours. After the reaction was completed, dilute hydrochloric acid was added to quench, and the pH of the neutralized solution was neutral. The organic solvent was removed by vacuum distillation, 100 ml of toluene was added, stirred, allowed to stand, and the organic phase was separated. The aqueous phase was extracted 2 to 3 times with 50 ml of toluene, and the organic phases were combined. The organic phases were washed 2 to 3 times with saturated brine, and the solvent was evaporated. The product was recrystallized with 40 ml of toluene to finally obtain compound III, weighing 17.2 g, with a yield of 94.4% and a purity of 98.5%.

[0040] In the third step, 19.1 g (0.105 mol) of compound III was dissolved in 250 ml of THF, 0.003 mol of boron trifluoride as a catalyst was added to the solution, 0.015 mol of triethylamine as an organic base reagent was added, and the Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, the organic solvent was evaporated, 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers, the organic phase was separated, the aqueous phase was extracted with 50 ml of toluene for 2 to 3 times, the organic phases were combined, washed with saturated brine for 2 to 3 times, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.5 g, with a yield of 88.4% and a purity of 98.0%.

[0041] In the third step, 19.1 g (0.105 mol) of compound III was dissolved in 250 ml of THF, 0.008 mol of boron trifluoride as a catalyst was added to the solution, 0.015 mol of triethylamine as an organic base reagent was added, and the Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, the organic solvent was evaporated, 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers, the organic phase was separated, the aqueous phase was extracted with 50 ml of toluene for 2 to 3 times, the organic phases were combined, washed with saturated brine for 2 to 3 times, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.6 g, with a yield of 88.6% and a purity of 98.1%.

[0042] In the third step, 19.1 g (0.105 mol) of compound III was dissolved in 250 ml of THF, 0.005 mol of boron trifluoride as a catalyst was added to the solution, 0.010 mol of triethylamine as an organic base reagent was added, and the Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, the organic solvent was evaporated, 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers, the organic phase was separated, the aqueous phase was extracted with 50 ml of toluene for 2 to 3 times, the organic phases were combined, washed with saturated brine for 2 to 3 times, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.2 g, with a yield of 87.5% and a purity of 98.2%.

[0043] In the third step, 19.1 g (0.105 mol) of compound III was dissolved in 250 ml of THF, 0.005 mol of boron trifluoride as a catalyst was added to the solution, 0.020 mol of triethylamine as an organic base reagent was added, and the Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, the organic solvent was evaporated, 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers, the organic phase was separated, the aqueous phase was extracted with 50 ml of toluene for 2 to 3 times, the organic phases were combined, washed with saturated brine for 2 to 3 times, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.6 g, with a yield of 88.6% and a purity of 98.0%.

[0044] In the third step, 18.2 g (0.10 mol) of compound III was dissolved in 250 ml of THF, 0.005 mol of boron trifluoride as a catalyst was added to the solution, 0.015 mol of triethylamine as an organic base reagent was added, and the Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, the organic solvent was evaporated, 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers, the organic phase was separated, the aqueous phase was extracted with 50 ml of toluene for 2 to 3 times, the organic phases were combined, washed with saturated brine for 2 to 3 times, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.5 g, with a yield of 88.4% and a purity of 98.2%.

[0045] In the third step, 2.0 g (0.11 mol) of compound III was dissolved in 250 ml of THF, 0.005 mol of boron trifluoride as a catalyst was added to the solution, 0.015 mol of triethylamine as an organic base reagent was added, and the Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, the organic solvent was evaporated, 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers. The organic phase was extracted with 50 ml of toluene for 2 to 3 times, the organic phases were combined, washed with saturated brine for 2 to 3 times, the solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.7 g, with a yield of 89.0% and a purity of 98.0%.

[0046] In the third step, 19.1 g (0.105 mol) of compound III was dissolved in 250 ml of THF, and 0.005 mol of NiCl2 (dppe) as a catalyst was added to the solution, and 0.015 mol of triethylamine as an organic base reagent was added. The Grignard reagent obtained in the second step was gradually added dropwise to the obtained solution, stirred and mixed, and refluxed at 65°C for 2 to 3 hours. After the reaction was completed, it was neutralized with dilute hydrochloric acid to acidity, and the organic solvent was evaporated. 100 ml of toluene and 100 ml of water were added, stirred, allowed to stand, and separated into layers. The organic phase was separated, and the aqueous phase was extracted with 50 ml of toluene for 2 to 3 times. The organic phases were combined and washed with saturated brine for 2 to 3 times. The solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain the key intermediate compound VI of empagliflozin, weighing 32.3 g, with a yield of 87.8% and a purity of 98.9%.

[0047] Comparative document example (CN102549005A)

[0048] Example 1: Synthesis of Fluoride VIII.1 Oxalyl chloride (176 kg; 1386 mol; 1.14 equivalents) is added to a mixture of 2-chloro-5-iodobenzoic acid (343 kg; 1214 mol) (compound IX.1), fluorobenzene (858 kg) and N,N-dimethylformamide (2 kg) over 3 hours at a temperature between about 25 and 30° C. (gas formation). After the addition is complete, the reaction mixture is stirred for a further 2 hours at a temperature between about 25 and 30° C. The solvent (291 kg) is removed by distillation (p=200 mbar) at a temperature between 40 and 45° C. The reaction solution (911 kg) is then added to aluminum chloride AlCl3 (181 kg) and fluorobenzene (192 kg) over 2 hours at a temperature between about 25 and 30° C. The reaction mixture is stirred for about a further hour at the same temperature. The reaction mixture is then added to 570 kg of water at a temperature between 20 and 30° C. over a period of about 2 hours and stirred for a further hour. After phase separation, the organic phase (1200 kg) is divided into two portions (600 kg each). The solvent (172 kg) is removed by distillation (p = 200 mbar) from the first organic phase at a temperature of about 40 to 50° C. Then 2-propanol (640 kg) is added. The solution is heated to about 50° C. and then filtered through a carbon cartridge (transparent filtrate). The carbon cartridge can be replaced during the filtration and washed with a fluorobenzene / 2-propanol mixture (1: 4; 40 kg) after the filtration. The solvent (721 kg) is removed by distillation at a temperature of about 40 to 50° C. and p = 200 mbar. Then 2-propanol (240 kg) is added at a temperature between about 40 to 50° C. If the content of fluorobenzene is greater than 1% as determined by GC, 140 kg of solvent are distilled off again and 2-propanol (140 kg) is added. The solution is then cooled from 50°C to 40°C within 1 hour and seed crystals (50 g) are added. The solution is further cooled from about 40°C to 20°C within 2 hours. Water (450 kg) is added at 20°C within 1 hour and after the suspension is stirred at 20°C for another hour, the suspension is filtered. The filter cake is washed with 2-propanol / water (1: 1; 800 kg). The product is dried until a water content of < 0.06% w / w is obtained. The second portion of the organic phase is treated in the same manner. A total of 410 kg (94% yield) of a product having a white to off-white crystalline appearance is obtained. The product is identified by infrared spectroscopy.

[0049] Example 2: Synthesis of ketone VII.1

[0050] A solution of potassium tert-butoxide (20%) in tetrahydrofuran (388 kg) is added to a solution of fluoride VIII.1 (208 kg), tetrahydrofuran (407 kg) and (S)-3-hydroxytetrahydrofuran (56 kg) over 3 hours at a temperature of 16 to 25° C. After the addition is complete, the mixture is stirred at a temperature of 20° C. for 60 minutes. The conversion is then determined by HPLC analysis. Water (355 kg) is added at a temperature of 21° C. over 20 minutes (aqueous termination). The reaction mixture is stirred for 30 minutes (temperature: 20° C.). The stirrer is turned off and the mixture is left to stand for 60 minutes (temperature: 20° C.). The phases are separated and the solvent is distilled off from the organic phase under reduced pressure at a temperature of 19 to 45° C. 2-Propanol (703 kg) is added to the residue at a temperature of 40 to 46° C. and the solvent is distilled off under reduced pressure at a temperature of 41 to 50° C. 2-Propanol (162 kg) was added to the residue at a temperature of 47°C and the solvent was distilled off under reduced pressure at a temperature of 40 to 47°C. The mixture was then cooled to 0°C over 1 hour and 55 minutes. The product was collected by centrifugation, washed with a mixture of 2-propanol (158 kg) and then tert-butyl methyl ether (88 kg), and dried under reduced pressure at 19 to 43°C. 227 kg (91.8%) of the product was obtained as a colorless solid. The product was identified by infrared spectroscopy.

[0051] Example 3: Synthesis of iodide V.1

[0052] 1,1,3,3-Tetramethyldisiloxane (TMDS, 82.5 kg) is added to a solution of ketone VII.1 (217.4 kg) and aluminum chloride (AlCl3, 81.5 kg) in toluene (366.8 kg) over 1 hour and 30 minutes (temperature: 18 to 26°C). After the addition is complete, the mixture is stirred for a further hour at a temperature of 24°C. The conversion is then determined by HPLC analysis. The reaction mixture is subsequently treated with acetone (15.0 kg), stirred at a temperature of 27°C for 1 hour and 5 minutes, and analyzed for the residual TMDS content by GC. A mixture of water (573 kg) and concentrated HCl (34 kg) is then added to the reaction mixture at a temperature of 20 to 51°C (aqueous termination). The reaction mixture is stirred for 30 minutes (temperature: 51°C). The stirrer is turned off and the mixture is left to stand for 20 minutes (temperature: 52°C). The phases are separated and the solvent is distilled off from the organic phase under reduced pressure at a temperature of 53 to 73°C. Toluene (52.8 kg) and ethanol (435.7 kg) were added to the residue at a temperature of 61 to 70°C. The reaction mixture was cooled to 36°C and seed crystals (0.25 kg) were added. Stirring was continued at this temperature for 35 minutes. The mixture was then cooled to 0 to 5°C and stirred for another 30 minutes. The product was collected by centrifugation, washed with ethanol (157 kg) and dried under reduced pressure at 15 to 37°C. 181 kg (82.6%) of the product was obtained as a colorless solid. The product was identified by HPLC retention time.

[0053] In summary, compared with the prior art, the technical solution of the present invention has higher yield and fewer steps. The alkylation reaction is completed by activating the CF bond, which reduces the steps required for the reaction, improves the selectivity of the reaction, reduces the generation of reaction by-products, has high reaction product yield, low reaction raw material cost, easy product separation, convenient operation, low reaction pollution, and is suitable for large-scale industrial production.

[0054] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0055] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A synthesis process of a key intermediate of empagliflozin, characterized in that The following steps are involved: In the first step, reactant I is dissolved in an organic solvent, compound II is added dropwise to the solution, the mixture is stirred and mixed, a catalyst is added continuously, the mixture is stirred and mixed, and the mixture is reacted at room temperature for 2 to 3 hours. After the reaction is completed, the product is separated to obtain compound III; Step 2: Under nitrogen protection, magnesium chips and solvent were added to a four-necked flask, and ethyl bromide was added to initiate the reaction. The mixture was heated to 65°C, and the compound IV solution was slowly added dropwise while maintaining the reaction temperature at 65°C. After the addition was completed, the mixture was heated for 1.5 to 2 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain the Grignard reagent compound V. The third step is to dissolve compound III in an organic solvent, add a catalyst to the solution, add an organic base reagent, gradually dropwise add the Grignard reagent compound V obtained in the second step to the obtained solution, stir and mix, and reflux at 65° C. for 2 to 3 hours. After the reaction is completed, separate the product to obtain the key intermediate compound VI of empagliflozin; The structural formula of the reactant I is: The structural formula of the compound II is: The structural formula of the compound III is: The structural formula of the compound IV is: The structural formula of the compound V is: The structural formula of the compound VI is: The solvents used in the first step reaction, the second step reaction and the third step reaction are all tetrahydrofuran; The catalyst used in the first step reaction is potassium tert-butoxide, which is a 20% wt solution in tetrahydrofuran; The organic base reagent used in the third step reaction is one of the organic weak bases triethylamine and diisopropylethylamine, and the amount of the organic base reagent used is 10-20 mol% of compound V; The solution of the second step reaction compound IV is a 1 mol / L tetrahydrofuran solution; The catalyst used in the third step reaction is one of boron trifluoride, NiCl2 (dppe) and NiCl2 (dppp).

2. The synthesis process of a key intermediate of empagliflozin according to claim 1, characterized in that: In the first step reaction, the molar ratio of reactant I, compound II and catalyst is 1:1.0-1.1:1.0-1.

5.

3. The synthesis process of a key intermediate of empagliflozin according to claim 1, characterized in that: The amount of catalyst used in the third step reaction is 3-8 mol% of compound IV.

4. The synthesis process of a key intermediate of empagliflozin according to claim 1, characterized in that: In the third step reaction, the molar ratio of compound V to compound III is 1:1 to 1.1.

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