CN116332882B

CN116332882B - A synthetic process for a key intermediate of empagliflozin

Info

Publication number: CN116332882B
Application number: CN202310278547.7A
Authority: CN
Inventors: 罗小冬; 罗威; 杨赛; 宋继国; 钱若灿; 庞小召
Original assignee: Jiangsu Alpha Group Furui Pharmaceutical Suqian Co ltd
Current assignee: Jiangsu Alpha Group Furui Pharmaceutical Suqian Co ltd
Priority date: 2023-03-21
Filing date: 2023-03-21
Publication date: 2025-03-18
Anticipated expiration: 2043-03-21
Also published as: CN116332882A

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

Synthesis process of key intermediate of englitz

Technical Field

The invention relates to the technical field related to preparation of pharmaceutical intermediates, in particular to a synthesis process of a key intermediate of englitazone.

Background

Engliflozin (empagliflozin), known as Egliflozin, epgliflozin, is a selective oral SGLT-2 inhibitor developed by Bolin and Gift pharmaceutical company in combination, and is a drug capable of communicating with selective inhibition of reabsorption of filtered glucose by glomerular proximal tubules, so that excessive glucose is discharged from urine and directly reducing blood glucose, and is used for treating type II diabetes hyperglycemia, recent clinical research results show that the efficacy is remarkable, the safety and tolerance are good, 5 months in 2014 first come into the market in Europe, 8 months and 12 months later come into the market in the United states and Japan respectively, and 9 months in 2017 come into the market in China. Engliflozin chemical name (1S) -1, 5-dehydrated-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol, molecular formula C23H27ClO7, molecular weight 450.91, its chemical structural formula is as follows:

。

The synthesis method of (3S) -3- [4- [ (2-chloro-5-iodo (or bromo) phenyl) methyl ] phenoxy ] tetrahydrofuran is a key intermediate for synthesizing the enggliflozin medicine, documents such as US7579449B2, US7713938B2, US7745414B2, WO2006120208A, US7776830B2, CN102574829A, CN102549005A and the like describe a synthesis method which takes 2-chloro-5-iodobenzoic acid as a starting material, reacts with oxalyl chloride under the catalysis of fluorobenzene and DMF to generate 2-chloro-5-iodobenzoyl chloride, then carries out Friedel-crafts reaction with fluorobenzene to generate (2-chloro-5-iodophenyl) (4-fluorophenyl) methanone compound 1, then carries out substitution reaction with (S) -3-hydroxytetrahydrofuran to generate compound 2, and finally reduces carbonyl to obtain the (S) -3- [4- (5-iodo-2-chlorobenzyl) phenoxy ] tetrahydrofuran compound.

The method is widely applied to the process for synthesizing the englitine in industry at present, but the reaction steps are more, the Friedel-crafts acylation reaction easily generates fluorine ortho-position impurities, the mixture of fluorine ortho-position substituted intermediate impurities and products is finally obtained, the reaction selectivity is poor, the properties of the impurities and the products are similar, the separation is difficult, and the key intermediate compounds are synthesized by the following steps:

Route one

Chinese patent CN107311962A discloses a synthetic method of (S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy) tetrahydrofuran, which is shown in the following formula, wherein 1) 4-fluorotoluene and (S) -3-hydroxytetrahydrofuran are used as starting materials, inorganic base is used as a catalyst to react to obtain (S) -3-p-toluol tetrahydrofuran, 2) the obtained product reacts with NCS (N-chlorosuccinimide) under the catalysis of BPO (dibenzoyl peroxide) to obtain (S) -3-p-chlorotoluol tetrahydrofuran, 3) the (S) -3-p-chlorotoluol tetrahydrofuran reacts with 4-bromoaniline under the action of catalyst Lewis acid to obtain (S) -3- (4- (5-bromo-2-aminobenzyl) phenoxy) tetrahydrofuran, and 4) the obtained product reacts with cuprous chloride after diazotization reaction to obtain (S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran.

The synthesis method adopts the simple and easily obtained 4-fluorotoluene as the initial raw material, the synthesis route is shorter, but the 1 st-2 nd steps of the synthesis route and the post-treatment steps are more complicated, and the method needs to be further improved. The synthetic process flow of the (3S) -3- [4- [ (2-chloro-5-iodophenyl) methyl ] phenoxy ] tetrahydrofuran is shown as follows:

Disclosure of Invention

Aiming at the defects of more reaction steps, complex operation, poor reaction selectivity, more byproducts, difficult separation and the like in the process of synthesizing an enggliflozin key intermediate in the prior art, the invention provides a method for synthesizing the enggliflozin, which takes 4-bromo-2- (bromomethyl) -1-chlorobenzene (compound IV) as a raw material to prepare a format reagent, mixes (S) 3-hydroxytetrahydrofuran with an ether compound (compound IV) prepared by reacting 1, 4-difluorobenzene, promotes the coupling reaction by activating a C-F bond to obtain a product compound III, and finally prepares the enggliflozin key intermediate compound VI through the coupling reaction of the format reagent and the compound III.

The method has the advantages of few steps, high selectivity, few byproducts, high yield of the product, easy separation of the product, convenient operation, suitability for large-scale industrial production and the like, and the reaction route of the invention is as follows:

The technical scheme provided by the invention is as follows:

a process for synthesizing the key intermediate of Engliflozin includes such steps as,

Firstly, dissolving a reactant I in an organic solvent, dropwise adding a compound II into the solution, stirring and mixing, continuously adding a catalyst, stirring and mixing, reacting for 2-3 hours at room temperature, and separating a product after the reaction is finished to obtain a compound III;

Secondly, adding magnesium scraps into a four-neck flask under the protection of nitrogen, adding a solvent, adding bromoethane to initiate a reaction, continuously heating to 65 ℃, simultaneously slowly dropwise adding a compound IV solution, keeping the reaction temperature at 65 ℃, continuously heating for 1.5-2 h after dropwise adding, cooling to room temperature after the reaction is finished, and filtering to obtain a Grignard reagent compound V;

And thirdly, dissolving the compound III in an organic solvent, adding a catalyst into the solution, adding an organic alkali reagent, gradually dropwise adding the Grignard reagent compound V obtained in the second step into the obtained solution, stirring and mixing, carrying out reflux reaction at 65 ℃ for 2-3 h, and separating a product after the reaction is finished to obtain the Engliflozin key intermediate compound VI.

Further, the solvents used in the first step of reaction, the second step of reaction and the third step of reaction are tetrahydrofuran.

Further, the catalyst used in the first step is potassium tert-butoxide, which is a solution of 20% by weight in tetrahydrofuran.

Further, the molar ratio of the reactant I to the compound II to the catalyst in the first step is 1:1.0-1.1:1.0-1.5, preferably 1:1.05:1.2.

Further, the organic alkali reagent used in the third step is one of organic weak base triethylamine and diisopropylethylamine, and the dosage of the organic alkali reagent is 10-20mol% of the compound V, preferably 15mol%.

Further, the compound IV solution used in the second reaction step is tetrahydrofuran solution with the concentration of 1 mol/L.

Further, the catalyst used in the third reaction step is one of boron trifluoride, niCl2 (dppe) (1, 2-bis (diphenylphosphorus) ethane) and NiCl2 (dppp) (1, 3-bis (diphenylphosphorus) propane).

Further, the catalyst used in the third reaction step is 3-8 mol%, preferably 5mol%, of the compound IV.

Further, the molar ratio of the compound V to the compound III in the third step is 1:1-1.1, preferably 1:1.05.

The invention has the advantages that 1, the steps required by the reaction are reduced, the selectivity of the reaction is improved and the production of reaction byproducts is reduced by activating the C-F bond and the format reagent to catalyze and finish the coupling reaction, and 2, the reaction route has the advantages of high product yield, easy separation of the products, convenient operation, small reaction pollution, suitability for large-scale industrial production and the like.

Drawings

FIG. 1 is a schematic illustration of a scheme of the present invention;

FIG. 2 is a schematic diagram of a second reaction scheme of the present invention;

FIG. 3 is a schematic illustration of a reaction scheme of the present invention;

FIG. 4 is a schematic diagram of the chemical structure of Engliptin.

Detailed Description

The following description of the embodiments of the present invention will be made clearly and completely with reference to the embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

In the first step, 11.4g (0.1 mol) of compound I is dissolved in 300ml of organic solvent Tetrahydrofuran (THF), 9.25g (0.105 mol) of compound II (S) -3-hydroxytetrahydrofuran is slowly added into the obtained solution, the mixture is stirred and mixed, 0.12mol of potassium tert-butoxide (20 wt% solution in tetrahydrofuran) is continuously added into the solution, the solution is uniformly mixed, stirring and reacting for 2-3 hours at room temperature, after the reaction is finished, dilute hydrochloric acid is added for quenching, the pH of the neutralized solution is neutral, the organic solvent is removed by reduced pressure distillation, 100ml of toluene is added, stirring, standing and layering are carried out, the organic phase is separated, the aqueous phase is extracted for 2-3 times by 50ml of toluene, the organic phase is combined, the organic phase is washed for 2-3 times by saturated saline, the solvent is evaporated, the product is recrystallized by 40ml of toluene, and finally the compound III is obtained, the calculated weight of 17.1g, the yield is 93.8%, and the purity is 98.5%.

Secondly, adding 2.43g (0.10 mol) of magnesium turnings into a 1000ml four-neck flask under the protection of nitrogen, adding 150ml of THF reagent, dropwise adding 10ml of 1mol/L tetrahydrofuran solution of the compound III into the flask, adding 0.3g of bromoethane as an initiator, continuously heating to 65 ℃, slowly dropwise adding 90ml of 1mol/L tetrahydrofuran solution of the compound IV, keeping the reaction temperature at 65 ℃, continuously heating and refluxing for 1.5-2 h after the dropwise adding is finished, cooling to room temperature after the reaction is finished, and filtering to obtain the tetrahydrofuran solution of the format reagent compound IV.

Thirdly, dissolving 19.1g (0.105 mol) of compound III in 250ml of THF, adding 0.005mol of boron trifluoride serving as a catalyst into the solution, adding 0.015mol of triethylamine serving as an organic alkali reagent, gradually dropwise adding the format reagent obtained in the second step into the obtained solution, stirring and mixing, carrying out reflux reaction for 2-3 h at 65 ℃, neutralizing the reaction by dilute hydrochloric acid until the reaction is finished, evaporating the organic solvent, adding 100ml of toluene and 100ml of water, stirring, standing and layering, separating an organic phase, extracting the aqueous phase for 2-3 times by using 50ml of toluene, merging the organic phase, washing for 2-3 times by using saturated saline, evaporating the solvent, recrystallizing the product by using 50ml of toluene to obtain the key intermediate compound VI of the Engliflozin, weighing 32.9g, and obtaining 89.5% of the product with the purity of 98.9%.

In the first step, 11.4g (0.1 mol) of compound I is dissolved in 300ml of organic solvent Tetrahydrofuran (THF), 8.81g (0.10 mol) of compound II (S) -3-hydroxytetrahydrofuran is slowly added into the obtained solution, stirring and mixing are carried out, 0.12mol of potassium tert-butoxide (20 wt% solution in tetrahydrofuran) is continuously added into the solution, the solution is uniformly mixed, stirring and reacting for 2-3 hours at room temperature, dilute hydrochloric acid is added for quenching after the reaction is finished, the pH value of the neutralized solution is neutral, the organic solvent is removed by reduced pressure distillation, 100ml of toluene is added, stirring, standing and layering are carried out, the organic phase is separated, the aqueous phase is extracted for 2-3 times by 50ml of toluene, the organic phase is combined, the organic phase is washed for 2-3 times by saturated saline, the solvent is evaporated, the product is recrystallized by 40ml of toluene, and finally the compound III is obtained, the calculated weight is 16.8g, the yield is 92.2%, and the purity is 98.3%.

In the first step, 11.4g (0.1 mol) of compound I is dissolved in 300ml of organic solvent Tetrahydrofuran (THF), 9.69g (0.11 mol) of compound II (S) -3-hydroxytetrahydrofuran is slowly added into the obtained solution, the mixture is stirred and mixed, 0.12mol of potassium tert-butoxide (20 wt% solution in tetrahydrofuran) is continuously added into the solution, the solution is uniformly mixed, stirring and reacting for 2-3 hours at room temperature, after the reaction is finished, dilute hydrochloric acid is added for quenching, the pH of the neutralized solution is neutral, the organic solvent is removed by reduced pressure distillation, 100ml of toluene is added, stirring, standing and layering are carried out, the organic phase is separated, the aqueous phase is extracted for 2-3 times by 50ml of toluene, the organic phase is combined, the organic phase is washed for 2-3 times by saturated saline, the solvent is evaporated, the product is recrystallized by 40ml of toluene, and finally the compound III is obtained, the weight of 17.2g is calculated, the yield is 94.4%, and the purity is 98.4%.

In the first step, 11.4g (0.1 mol) of compound I is dissolved in 300ml of organic solvent Tetrahydrofuran (THF), 9.25g (0.105 mol) of compound II (S) -3-hydroxytetrahydrofuran is slowly added into the obtained solution, the mixture is stirred and mixed, 0.10mol of potassium tert-butoxide (20 wt% solution in tetrahydrofuran) serving as a catalyst is continuously added into the solution, the solution is uniformly mixed, stirring and reacting for 2-3 hours at room temperature, after the reaction is finished, dilute hydrochloric acid is added for quenching, the pH of the neutralized solution is neutral, the organic solvent is removed by reduced pressure distillation, 100ml of toluene is added, stirring, standing and layering are carried out, the organic phase is separated, the aqueous phase is extracted for 2-3 times by 50ml of toluene, the organic phase is combined, the organic phase is washed for 2-3 times by saturated saline, the solvent is evaporated, the product is recrystallized by 40ml of toluene, and finally the compound III is obtained, the calculated weight is 16.9g, the yield is 92.7%, and the purity is 98.8%.

In the first step, 11.4g (0.1 mol) of compound I is dissolved in 300ml of organic solvent Tetrahydrofuran (THF), 9.25g (0.105 mol) of compound II (S) -3-hydroxytetrahydrofuran is slowly added into the obtained solution, the mixture is stirred and mixed, 0.15mol of potassium tert-butoxide (20 wt% solution in tetrahydrofuran) is continuously added into the solution, the solution is uniformly mixed, stirring and reacting for 2-3 hours at room temperature, after the reaction is finished, dilute hydrochloric acid is added for quenching, the pH of the neutralized solution is neutral, the organic solvent is removed by reduced pressure distillation, 100ml of toluene is added, stirring, standing and layering are carried out, the organic phase is separated, the aqueous phase is extracted for 2-3 times by 50ml of toluene, the organic phase is combined, the organic phase is washed for 2-3 times by saturated saline, the solvent is evaporated, the product is recrystallized by 40ml of toluene, and finally the compound III is obtained, the weight of 17.2g is calculated, the yield is 94.4%, and the purity is 98.5%.

Thirdly, dissolving 19.1g (0.105 mol) of compound III in 250ml of THF, adding 0.003mol of boron trifluoride serving as a catalyst into the solution, adding 0.015mol of triethylamine serving as an organic base reagent, gradually dropwise adding the format reagent obtained in the second step into the obtained solution, stirring and mixing, carrying out reflux reaction for 2-3 h at 65 ℃, neutralizing the reaction by dilute hydrochloric acid until the reaction is finished, evaporating an organic solvent, adding 100ml of toluene and 100ml of water, stirring, standing and layering, separating an organic phase, extracting the aqueous phase for 2-3 times by using 50ml of toluene, merging the organic phases, washing for 2-3 times by using saturated saline, evaporating the solvent, recrystallizing the product by using 50ml of toluene to obtain the key intermediate compound VI of the Engliflozin, weighing 32.5g, and obtaining the product with the yield of 88.4% and the purity of 98.0%.

Thirdly, dissolving 19.1g (0.105 mol) of compound III in 250ml of THF, adding 0.008mol of boron trifluoride serving as a catalyst into the solution, adding 0.015mol of triethylamine serving as an organic alkali reagent, gradually dropwise adding the format reagent obtained in the second step into the obtained solution, stirring and mixing, refluxing at 65 ℃ for 2-3 h, neutralizing with dilute hydrochloric acid until acidity is achieved after the reaction is finished, evaporating an organic solvent, adding 100ml of toluene and 100ml of water, stirring, standing and layering, separating an organic phase, extracting the aqueous phase with 50ml of toluene for 2-3 times, merging the organic phases, washing with saturated saline for 2-3 times, evaporating the solvent, recrystallizing a product with 50ml of toluene to obtain an Engliflozin key intermediate compound VI, weighing 32.6g, and obtaining 88.6% yield and purity of 98.1%.

Thirdly, dissolving 19.1g (0.105 mol) of compound III in 250ml of THF, adding 0.005mol of boron trifluoride serving as a catalyst into the solution, adding 0.010mol of triethylamine serving as an organic alkali reagent, gradually dropwise adding the format reagent obtained in the second step into the obtained solution, stirring and mixing, refluxing at 65 ℃ for 2-3 h, neutralizing with dilute hydrochloric acid until acidity is achieved after the reaction is finished, evaporating an organic solvent, adding 100ml of toluene and 100ml of water, stirring, standing and layering, separating an organic phase, extracting the aqueous phase with 50ml of toluene for 2-3 times, merging the organic phases, washing with saturated saline for 2-3 times, evaporating the solvent, recrystallizing a product with 50ml of toluene to obtain the key intermediate compound VI of the Engliflozin, weighing 32.2g, and obtaining the product with the yield of 87.5% and the purity of 98.2%.

Thirdly, dissolving 19.1g (0.105 mol) of compound III in 250ml of THF, adding 0.005mol of boron trifluoride serving as a catalyst into the solution, adding 0.020mol of triethylamine serving as an organic alkali reagent, gradually dropwise adding the format reagent obtained in the second step into the obtained solution, stirring and mixing, carrying out reflux reaction for 2-3 h at 65 ℃, neutralizing with dilute hydrochloric acid until acidity is achieved after the reaction is finished, evaporating an organic solvent, adding 100ml of toluene and 100ml of water, stirring, standing and layering, separating an organic phase, extracting the aqueous phase with 50ml of toluene for 2-3 times, merging the organic phases, washing with saturated saline for 2-3 times, evaporating the solvent, recrystallizing a product with 50ml of toluene to obtain the key intermediate compound VI of the Engliflozin, weighing 32.6g, and obtaining the product with 88.6% of purity of 98.0%.

Thirdly, dissolving 18.2g (0.10 mol) of compound III in 250ml of THF, adding 0.005mol of boron trifluoride serving as a catalyst into the solution, adding 0.015mol of triethylamine serving as an organic alkali reagent, gradually dropwise adding the format reagent obtained in the second step into the obtained solution, stirring and mixing, refluxing at 65 ℃ for 2-3 h, neutralizing with dilute hydrochloric acid until acidity is achieved after the reaction is finished, evaporating an organic solvent, adding 100ml of toluene and 100ml of water, stirring, standing and layering, separating an organic phase, extracting the aqueous phase with 50ml of toluene for 2-3 times, merging the organic phases, washing with saturated saline for 2-3 times, evaporating the solvent, recrystallizing a product with 50ml of toluene to obtain the key intermediate compound VI of the Engliflozin, weighing 32.5g, and obtaining the product with 88.4% of purity of 98.2%.

Thirdly, 2.0g (0.11 mol) of compound III is dissolved in 250ml of THF, 0.005mol of boron trifluoride serving as a catalyst is added into the solution, 0.015mol of triethylamine serving as an organic base reagent is added, the format reagent obtained in the second step is gradually dripped into the obtained solution, stirring and mixing are carried out, reflux reaction is carried out for 2-3 h at 65 ℃, dilute hydrochloric acid is neutralized to acidity after the reaction is finished, an organic solvent is evaporated, 100ml of toluene and 100ml of water are added, stirring, standing and layering are carried out, an organic phase is separated, the aqueous phase is extracted for 2-3 times by 50ml of toluene, the organic phase is combined, the organic phase is washed for 2-3 times by saturated saline, the solvent is evaporated, the product is recrystallized by 50ml of toluene, and the key intermediate compound VI of Engliflozin is obtained, the calculated weight is 32.7g, the yield is 89.0%, and the purity is 98.0%.

Thirdly, dissolving 19.1g (0.105 mol) of compound III in 250ml of THF, adding 0.005mol of NiCl2 (dppe) as a catalyst into the solution, adding 0.015mol of triethylamine as an organic alkali reagent, gradually dropwise adding the format reagent obtained in the second step into the obtained solution, stirring and mixing, carrying out reflux reaction for 2-3 h at 65 ℃, neutralizing with dilute hydrochloric acid until acidity is achieved after the reaction is finished, evaporating an organic solvent, adding 100ml of toluene and 100ml of water, stirring, standing and layering, separating an organic phase, extracting the aqueous phase with 50ml of toluene for 2-3 times, merging the organic phases, washing with saturated saline for 2-3 times, evaporating the solvent, recrystallizing the product with 50ml of toluene to obtain the key intermediate compound VI of Engliflozin, weighing 32.3g, and obtaining the product with 87.8% of yield and 98.9% of purity.

Comparative document example (CN 102549005A)

Example 1 synthesis of fluoride viii.1 oxalyl chloride (176 kg; 1386 mol; 1.14 eq.) was 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 of between about 25 and 30 ℃ (forming gas). After the addition was complete, the reaction mixture was stirred at a temperature of about 25 to 30 ℃ for an additional 2 hours. The solvent (291 kg) was removed by distillation at a temperature between 40 and 45 ℃ (p=200 mbar). The reaction solution (911 kg) was then added to aluminum chloride AlCl3 (181 kg) and fluorobenzene (192 kg) at a temperature between about 25 and 30 ℃ over 2 hours. The reaction mixture was stirred at the same temperature for about another 1 hour. The reaction mixture was then added to 570kg of water at a temperature between 20 and 30 ℃ over about 2 hours and stirred for an additional 1 hour. After phase separation, the organic phase (1200 kg) was separated into two parts (600 kg each). The solvent (172 kg) was distilled off from the first part of the organic phase at a temperature of about 40 to 50 ℃ (p=200 mbar). 2-propanol (640 kg) was then added. The solution was heated to about 50 ℃ and then filtered through a carbon cartridge (clear filtrate). The carbon cartridge was replaced during filtration and washed with a fluorobenzene/2-propanol mixture (1:4; 40 kg) after filtration. The solvent (721 kg) was distilled off at a temperature of about 40 to 50℃and p=200 mbar. 2-propanol (240 kg) was then added at a temperature between about 40 and 50 ℃. If the fluorobenzene content is determined to be greater than 1% by GC, 140kg of solvent is distilled off again and 2-propanol (140 kg) is added. The solution was then cooled from 50 ℃ to 40 ℃ over 1 hour and seeded (50 g). The solution was further cooled from about 40 ℃ to 20 ℃ over 2 hours. After adding water (450 kg) at 20 ℃ over 1 hour and stirring the suspension at 20 ℃ for 1 hour again, the suspension was filtered. The filter cake was washed with 2-propanol/water (1:1; 800 kg). The product was dried until a water content of < 0.06% w/w was obtained. The same treatment is performed on the second part of the organic phase. A total of 410kg (94% yield) of product having a white to off-white crystalline appearance was obtained. The products were identified via infrared spectroscopy.

EXAMPLE 2 Synthesis of Ketone VII.1

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

EXAMPLE 3 Synthesis of iodide V.1

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

In summary, compared with the prior art, the invention has the advantages of higher yield, fewer steps, reduced steps required by the reaction, improved reaction selectivity, reduced reaction byproducts, high reaction product yield, low reaction raw material cost, easy separation of the products, convenient operation, small reaction pollution, suitability for large-scale industrial production and the like

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.

Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims

1. A synthesis process of a key intermediate of empagliflozin, characterized by comprising the following steps:

In the first step, reactant I is dissolved in an organic solvent, compound II is added dropwise to the solution, stirred and mixed, a catalyst is added continuously, 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 is characterized in that the molar ratio of reactant I, compound II, and catalyst in the first step reaction is 1:1.0-1.1:1.0-1.5.

3. A 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 to 8 mol% of compound IV.

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