A method for the synthesis of empagliflozin

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of empagliflozin. The application uses cobalt dibromide complex and zinc powder as a catalyst, and realizes carbon-carbon bond construction of aryl bromide by using ethyl chloroformate as a bridge, so as to realize synthesis of an important intermediate II of empagliflozin. The intermediate is further reduced and deprotected to obtain empagliflozin. The process can solve the use of n-butyl lithium, the whole synthesis route is short, operation is simple, and the process is more suitable for industrial mass production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of empagliflozin. BACKGROUND

[0002] Empagliflozin is a sodium glucose co-transporter 2 (SGLT-2) inhibitor developed by Boehringer Ingelheim and Eli Lilly, and has the chemical name of (2S, 3R, 4R, 5S, 6R)-2-[3-[4-[(S)-tetrahydrofuran-3-yloxy]benzyl]-4-chlorophenyl]-6-hydroxymethylcyclohexane-3, 4, 5-triol, a molecular weight of 450.91, a CAS registration number of 864070-44-0, and a structural formula as follows:

[0003]

[0004] Most of the reported processes for synthesizing empagliflozin are to first prepare an aryl nucleophile, and then to react the nucleophile with a glycosyl side chain to obtain empagliflozin.

[0005] For example, Chinese Patent Application CN105399735 uses iodo-2-chlorobenzoic acid as a raw material to obtain a side chain compound through a multi-step reaction, and the side chain and the glycosyl group are coupled under the catalysis of n-butyllithium, zinc bromide-lithium bromide to obtain a product, which is deprotected to obtain empagliflozin.

[0006]

[0007] The process is not suitable for industrial mass production because it uses the dangerous n-butyllithium when connecting the glycosyl group and the side chain.

[0008] In US Patent US12892310, a side chain compound is subjected to Grignard reagent exchange reaction with isopropylmagnesium chloride / lithium chloride, and then subjected to nucleophilic addition reaction with a glycosyl ketone to obtain a chiral hydroxyl compound, which is reacted in hydrochloric acid-methanol solution and then subjected to methoxy removal under the action of triethylsilane-aluminum chloride to obtain empagliflozin:

[0009]

[0010] Although the process avoids the use of n-butyllithium, the addition reaction generates an excess of chiral hydroxyl group, which is troublesome to remove, and is not suitable for industrial mass production.

[0011] In view of the above problems in the reaction of the side chain and the glycosyl group in the preparation of empagliflozin, it is currently necessary to solve the problem of finding a route suitable for industrial production of the reaction of the glycosyl group and the side chain, which has mild reaction conditions, simple operation process, high product yield and purity, and low production cost. SUMMARY

[0012] In order to overcome the defects of the prior art, in order to solve the problems of long reaction steps and low yield of dangerous chemicals n-butyllithium required in the reaction of side chain and sugar group in the preparation of empagliflozin, in order to obtain a process more suitable for industrial production, the present application provides a new method for preparing empagliflozin. The target product prepared by the method has high purity and yield, and the reaction conditions are mild, the operation process is simple, and the production cost is lower.

[0013] The specific technical content of the present application is as follows:

[0014] A preparation method of empagliflozin, the specific process of which is as follows:

[0015]

[0016] A preparation method of empagliflozin specifically comprises the following steps:

[0017] Step 1: The catalyst, zinc powder and trifluoroacetic acid are added to an organic solvent, and refluxed until the reaction solution becomes purple. The reaction solution is cooled to room temperature, and chloropropene, ethyl chloroformate, compound SM-1 and compound SM-2 are added for reaction at room temperature until the reaction is completed. After treatment, compound II is obtained.

[0018] Step 2: Compound II and a mixture of dry dichloromethane / acetonitrile are added to a single-neck flask, and ethylsilane and boron fluoride ether complex are added at-10℃. The temperature is raised to 0℃ and stirred until the reaction is completed to obtain empagliflozin.

[0019] Preferably, the organic solvent in step 1 is selected from one or a combination of acetonitrile, tetrahydrofuran and toluene.

[0020] Preferably, the catalyst in step 1 is selected from one of 2,2-bipyridyl cobalt dibromide, bis(triphenylphosphine) cobalt dibromide and 1,10-phenanthroline cobalt dibromide.

[0021] Preferably, the molar ratio of ethyl chloroformate, compound SM-2, compound SM-1, catalyst, zinc powder and chloropropene in step 1 is 1.0:1.0~2.0:1.0~2.0:0.08~0.15:7.0~10.0:0.2~0.5, and particularly preferably 1.0:1.25:1.25:0.1:8.0:0.3.

[0022] Preferably, the molar ratio of compound II, ethylsilane and boron fluoride ether complex in step 2 is 1.0:4.0:3.0.

[0023] In a preferred embodiment, the reaction needs to be post-treated after the reaction is completed, and step 1 is specifically as follows: after the reaction is completed, the diatomite is suction filtered, the filter cake is washed with dichloromethane, the filtrate is diluted with 1M hydrochloric acid aqueous solution, the organic phase is separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure to obtain the compound II.

[0024] The post-treatment of step 2 is as follows: after the reaction is completed, saturated sodium bicarbonate aqueous solution is slowly added for quenching, the organic phase is separated, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, the organic phase is washed with water and saturated brine once, the organic phase is dried over anhydrous sodium sulfate. The drying agent is removed by filtration, and the solvent is evaporated under reduced pressure. The crude product is recrystallized with a mixture of ethanol and ethyl acetate (1:1 by volume) to obtain the empagliflozin.

[0025] Compared with the prior art, the present application has the following technical effects:

[0026] 1. The present application provides a novel method for efficiently synthesizing the intermediate compound II of empagliflozin, which uses a cobalt complex and zinc as catalysts, has high selectivity, mild conditions and high yield.

[0027] 2. The process can solve the use of n-butyllithium, has a short synthesis route, simple operation, and is more suitable for industrial mass production.

[0028] 3. The compound II of empagliflozin prepared by the method can be directly used to prepare empagliflozin after reduction and deprotection, and the synthesis method is simple and does not generate addition impurities. DETAILED DESCRIPTION

[0029] The present application will be further described by examples, and it should be understood that the examples of the present application are only used to illustrate the present application, but not to limit the present application, so that simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0030] The structure of the compound obtained by the present application is confirmed as follows:

[0031]

[0032] HPLC peak area normalization method:

[0033] Chromatographic column: YMC-Triart C 18 column (4.6 mm x 250 mm, 5 μm);

[0034] Mobile phase: acetonitrile: water (80:20);

[0035] Column temperature: 30°C;

[0036] Detection wavelength: 220 nm;

[0037] Flow rate: 1.0 ml / min;

[0038] Injection volume: 10 μl;

[0039] Retention time: 13.6 min.

[0040] ESI-HRMS: m / z = 826.3672 [M+Na] + , mp 234-236 °C, 1 H-NMR (400 MHz, DMSO-d6) δ: 7.73 (d, 2H), 7.62 (s, 1H), 7.55 (d, 1H), 7.41 (d, 1H), 7.03 (d, 2H), 5.95 (dd, 1H), 5.74 (dd, 1H), 5.47 (d, 1H), 5.26 (dd, 1H), 4.78 (dt, 1H), 4.32 (d, 1H), 4.25 (d, 1H), 4.07 (d, 1H), 4.05 (m, 1H), 4.00 (d, 1H), 3.80 (t, 1H), 3.70 (t, 1H), 2.36 (dt, 1H), 2.11 (dt, 1H), 1.278 (s, 36H); 13 C-NMR (100 MHz, DMSO-d6) δ: 196.3, 177.7, 177.1, 161.1, 136.9, 136.5, 136.2, 131.6, 131.0, 130.9, 130.8, 130.0, 127.2, 114.1, 114.0, 80.8, 80.6, 79.6, 74.9, 74.7, 70.2, 69.4, 67.5, 63.6, 39.0, 38.7, 32.2, 27.4.

[0041]

[0042] HPLC peak area normalization method:

[0043] Column: YMC-Triart C18 column (4.6 mm x 250 mm, 5 μm);

[0044] Mobile phase: A: acetonitrile, B: water, gradient elution (0→10 min: A 40%, 10→30 min: A 40%~90%);

[0045] Column temperature: 35 °C;

[0046] Detection wavelength: 224 nm;

[0047] Flow rate: 1.0 ml / min;

[0048] Injection volume: 10 ul;

[0049] Retention time: 16.80 min.

[0050] ESI-HRMS: m / z = 451.9212 [M+H] + , mp 149-152 °C, 1 H NMR (400 MHz, MeOD) δ: 7.36 (d, 2H), 7.28 (dd, 1H), 7.13 (d, 2H), 6.81-6.89 (m, 2H), 4.87-4.94 (m, 1H), 4.11 (d, 1H), 4.00 (d, 1H), 3.95 (ddd, 5H), 3.68 (dd, 1H), 3.36-3.53 (m, 3H), 3.24-3.35 (m, 2H), 2.18 (dtd, 1H), 1.98-2.13 (m, 1H). 13 C NMR (400 MHz, MeOD) δ: 154.9, 143.2, 137.7, 133.1, 130.7, 130.6, 129.1, 128.9, 128.8, 125.4, 115.0, 114.9, 84.8, 80.8, 79.6, 78.7, 75.0, 71.5, 70.2, 67.5, 62.2, 36.5, 32.2.

[0051] Preparation of compound II

[0052] Example 1

[0053] Into a single-neck flask was added 2,2-dipyridyl cobalt bromide (9.30 g, 0.02 mol), zinc powder (104 g, 1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and stirred vigorously, the reaction system was heated to reflux, the reaction mixture changed from white to purple, when the reaction system was cooled to room temperature, chloroacrylate (4.59 g, 0.06 mol) was added, ethyl chloroformate (200 mL, 0.20 mol) was added, and the reaction was carried out at constant temperature for 1 hour. Compound SM-1 (171.52 g, 0.25 mol) and compound SM-2 (60.78 g, 0.25 mol) were added in turn, and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered with diatomite, the filter cake was washed with dichloromethane (50 mL x 3), the filtrate was diluted with 1 mol / L hydrochloric acid aqueous solution (300 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (300 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain compound II, with a yield of 98.8% and an HPLC purity of 99.90%.

[0054] Example 2

[0055] Into a single-necked flask was added bis(triphenylphosphine) cobalt dibromide (14.83 g, 0.02 mol), zinc powder (104 g, 1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetylene (4.59 g, 0.06 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at room temperature for 1 h. Then, compound SM-1 (137.64 g, 0.20 mol) and compound SM-2 (48.40 g, 0.20 mol) were added successively, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through celite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II in a yield of 94.1% and with a HPLC purity of 99.62%.

[0056] Example 3

[0057] Into a single-necked flask was added bis(triphenylphosphine) cobalt dibromide (14.83 g, 0.02 mol), zinc powder (104 g, 1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetylene (4.59 g, 0.06 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at room temperature for 1 h. Then, compound SM-1 (137.64 g, 0.20 mol) and compound SM-2 (48.40 g, 0.20 mol) were added successively, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through celite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II in a yield of 94.1% and with a HPLC purity of 99.62%.

[0058] Example 4

[0059] Into a single-necked flask was added 2,2-bipyridyl cobalt dibromide (7.44 g, 0.016 mol), zinc powder (104 g, 1.60 mol), trifluoroacetic acid (5 mL) and tetrahydrofuran (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (4.59 g, 0.06 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at room temperature for 1 h. Then, compound SM-1 (171.52 g, 0.25 mol) and compound SM-2 (60.78 g, 0.25 mol) were added successively, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 94.6% and with a HPLC purity of 99.41%.

[0060] Example 5

[0061] Into a single-necked flask was added 2,2-bipyridyl cobalt dibromide (7.44 g, 0.016 mol), zinc powder (104 g, 1.60 mol), trifluoroacetic acid (5 mL) and tetrahydrofuran (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (4.59 g, 0.06 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at room temperature for 1 h. Then, compound SM-1 (171.52 g, 0.25 mol) and compound SM-2 (60.78 g, 0.25 mol) were added successively, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 94.6% and with a HPLC purity of 99.41%.

[0062] Example 6

[0063] Into a single-necked flask was added 2,2-bipyridyl cobalt dibromide (9.30 g, 0.02 mol), zinc powder (91.56 g, 1.40 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (50 mL, 0.06 mol) and ethyl chloroformate (200 mL, 0.20 mol) were added, and the reaction was allowed to proceed at room temperature for 1 h. Then, compound SM-1 (171.52 g, 0.25 mol) and compound SM-2 (60.78 g, 0.25 mol) were added in sequence, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 94.1% and with a HPLC purity of 99.59%.

[0064] Example 7

[0065] Into a single-necked flask was added 2,2-bipyridyl cobalt dibromide (9.30 g, 0.02 mol), zinc powder (91.56 g, 1.40 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (50 mL, 0.06 mol) and ethyl chloroformate (200 mL, 0.20 mol) were added, and the reaction was allowed to proceed at room temperature for 1 h. Then, compound SM-1 (171.52 g, 0.25 mol) and compound SM-2 (60.78 g, 0.25 mol) were added in sequence, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 94.1% and with a HPLC purity of 99.59%.

[0066] Example 8

[0067] Into a single-necked flask was added 2,2-bipyridyl cobalt dibromide (9.30 g, 0.02 mol), zinc powder (104 g, 1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (3.06 g, 0.04 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at constant temperature for 1 h. Then, compound SM-1 (171.52 g, 0.25 mol) and compound SM-2 (60.78 g, 0.25 mol) were added in sequence, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 95.5% and with a HPLC purity of 99.73%.

[0068] Example 9

[0069] Into a single-necked flask was added 2,2-bipyridyl cobalt dibromide (9.30 g, 0.02 mol), zinc powder (104 g, 1.60 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (3.06 g, 0.04 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at constant temperature for 1 h. Then, compound SM-1 (171.52 g, 0.25 mol) and compound SM-2 (60.78 g, 0.25 mol) were added in sequence, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 95.5% and with a HPLC purity of 99.73%.

[0070] Example 10

[0071] Into a single-neck flask was added 2,2-bipyridyl cobalt dibromide (6.51 g, 0.014 mol), zinc powder (78.48 g, 1.20 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (1.53 g, 0.02 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at constant temperature for 1 h. Then, compound SM-1 (137.64 g, 0.2 mol) and compound SM-2 (48.40 g, 0.2 mol) were added in sequence, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 88.0% and with an HPLC purity of 98.84%.

[0072] Example 11

[0073] Into a single-neck flask was added 2,2-bipyridyl cobalt dibromide (6.51 g, 0.014 mol), zinc powder (78.48 g, 1.20 mol), trifluoroacetic acid (5 mL) and acetonitrile (300 mL), and the reaction system was stirred vigorously and heated to reflux. The reaction mixture changed from white to purple. When the reaction system reached room temperature, chloroacetaldehyde (1.53 g, 0.02 mol) was added, followed by the addition of ethyl chloroformate (200 mL, 0.20 mol). The reaction was allowed to proceed at constant temperature for 1 h. Then, compound SM-1 (137.64 g, 0.2 mol) and compound SM-2 (48.40 g, 0.2 mol) were added in sequence, and the reaction was allowed to proceed at room temperature for 5 h. After the reaction was completed, the reaction system was filtered through diatomite, and the filter cake was washed with dichloromethane (50 mL x 3). The filtrate was diluted with 1 mol / L aqueous hydrochloric acid (300 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound II, in a yield of 88.0% and with an HPLC purity of 98.84%.

[0074] Preparation of empagliflozin

[0075] To a single-neck flask was added compound II (80.14 g, 0.10 mol) and dry dichloromethane / acetonitrile (v:v = 1:1, 400 mL) and stirred to dissolve, cooled to -10 °C, and ethylsilane (23.26 g, 0.20 mol) and boron trifluoride etherate (21.29 g, 0.15 mol) were added sequentially, slowly raised to 0 °C, and reacted for 5 hours at constant temperature. After the reaction was completed, saturated aqueous sodium bicarbonate solution (400 mL) was slowly added to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (400 mL x 3), the combined organic phases were washed once each with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was removed by concentration under reduced pressure to obtain a white solid which was used directly in the next step. To a single-neck flask was added the white solid and methanesulfonic acid (1.44 g, 15 mmol) and anhydrous methanol (75 mL) and stirred to dissolve, and reacted for 2 hours at room temperature. After the reaction was completed, sodium bicarbonate (1.3 g) was added and stirred for 30 minutes, anhydrous sodium sulfate was added to dry, the drying agent was removed by filtration, and the solvent was removed by concentration under reduced pressure to obtain a crude product which was recrystallized from a mixture of ethanol and ethyl acetate (200 mL, volume ratio 1:1) to obtain englitazin with a yield of 98.5% and a purity of 99.98% by HPLC.

Claims

1. A method for synthesizing empagliflozin, characterized in that: The synthesis method comprises the following steps: Step 1: Add the catalyst, zinc powder and trifluoroacetic acid to an organic solvent, reflux until the reaction solution turns purple, cool the reaction solution to room temperature, add allyl chloride, ethyl chloroformate, compound SM-1 and compound SM-2, and react at room temperature until the reaction is complete. The reaction is post-processed to obtain compound II; Step 2: Add compound II and a dry dichloromethane / acetonitrile mixed solvent to a single-necked flask, add ethylsilane and boron fluoride ether complex at -10°C, raise the temperature to 0°C and stir until the reaction is complete to obtain empagliflozin; Wherein, the catalyst described in step 1 is selected from one of 2,2-bipyridyl cobalt dibromide, bis(triphenylphosphine) cobalt dibromide, and 1,10-phenanthroline cobalt dibromide; The synthetic route is as follows: 。 2. The synthesis method according to claim 1, wherein The organic solvent in step 1 is selected from acetonitrile, tetrahydrofuran, toluene or a combination thereof.

3. The synthesis method according to claim 1, wherein The molar ratio of ethyl chloroformate, compound SM-2, compound SM-1, catalyst, zinc powder, and propylene chloride described in step 1 is: 1.0:1.0~2.0:1.0~2.0:0.08~0.15:7.0~10.0:0.2~0.

5.

4. The synthesis method according to claim 1, characterized in that The molar ratio of compound II, ethylsilane, and boron fluoride ether complex in step 2 is 1.0:4.0:3.0.

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