Preparation method of bexagliflozin intermediate

Abstract

The invention provides a preparation method of a bexagliflozin intermediate, and relates to the technical field of organic synthesis. The preparation method provided by the invention comprises the following steps: S1, substitution reaction: under the action of alkali, carrying out substitution reaction on 2-(cyclopropoxy) ethanol and a compound III ((5-halogen-2-chlorphenyl) (4-halophenyl) ketone) to generate a compound II; s2, reduction reaction: under the action of lewis acid, carrying out reduction reaction on a reducing agent and a compound II ((5-halogen-2-chlorphenyl) (4-(2-(cyclopropoxy) ethyoxyl) phenyl) ketone) to generate a compound I; the method has the advantages of mild reaction conditions, high atom utilization rate, high yield, high product quality and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of a bexagliflozin intermediate. BACKGROUND

[0002] Bexagliflozin is an SGLT2 inhibitor for treating type 2 diabetes developed by TheracosBio Biopharmaceutical Company in the United States. The drug was approved by the US FDA in December 2022 for the treatment of feline diabetes, and is also the first SGLT2 inhibitor approved by the FDA for any animal species. Then, on January 23, 2023, it was approved by the US FDA for marketing to assist in improving the glycemic control of patients with type 2 diabetes on the basis of diet and exercise. The structural formula is as shown below.

[0003]

[0004] Compound I ((5-halo-2-chlorophenyl)(4-(2-cyclopropoxy)ethoxyphenyl)methane) is a key intermediate of bexagliflozin drug. Therefore, the research on the synthesis of the intermediate has very important significance.

[0005] At present, the synthesis methods of the bexagliflozin intermediate reported in the literatures and patents at home and abroad mainly include the following methods:

[0006] Method 1:

[0007]

[0008] Method 1 (such as Chinese patent CN101790311B and Chinese patent CN102933592B) is the first generation of the synthetic route of bexagliflozin developed by the original research American TheracosBio pharmaceutical company. The method specifically uses the dapagliflozin intermediate compound 1B ((5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methane) as the raw material, first generates compound 5C ((5-bromo-2-chlorophenyl)(4-hydroxyphenyl)methane) through a de-ethyl reaction, and then generates an ether reaction with compound 5B (p-toluenesulfonic acid 2-(cyclopropoxy) ethyl ester) to generate the key intermediate compound 5D ((5-bromo-2-chlorophenyl)[4-(2-cyclopropoxyethoxy)phenyl]methane) of bexagliflozin. The product prepared by the route needs to be purified for many times, and the dapagliflozin intermediate compound 1B ((5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methane) is used as the raw material, and the macromolecular compound 5B (p-toluenesulfonic acid 2-(cyclopropoxy) ethyl ester) is used as the reagent. There are problems of high cost, low atom utilization rate and difficult product purification in production.

[0009] Method 2:

[0010]

[0011] Method 2 (as Chinese patent CN101628905B) is the original synthesis route of Dapagliflozin by AstraZeneca. This method specifically uses compound C1 (5-bromo-2-chlorobenzoic acid) as the raw material, and through chlorination with oxalyl chloride, Friedel-Crafts acylation with phenetole, reduction with triethylsilane and boron trifluoride ether, and other reaction steps to obtain the key intermediate compound C5 ((5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methane) of Dapagliflozin. At the same time, this product is also the starting material compound 1B of Method 1. This route has the advantages of fewer steps, and cheap and easily available materials, but due to the high reactivity of phenetole at the ortho and para positions, the ortho and para selectivity of the Friedel-Crafts acylation reaction of phenetole is not high (literature reports the ortho / para isomer ratio as 1:7), resulting in low reaction yield of this step, only 64%. Therefore, this route has the production problems of low reaction selectivity and low yield.

[0012] Method 3:

[0013]

[0014] Method 3 (as Chinese patent CN104334568A) is the second generation synthesis route of Bexagliflozin originally researched by Theracos BioPharma, USA. This method has two routes, route one uses compound A (5-iodo-2-chlorobenzoic acid) as the raw material, and through reduction with sodium borohydride, bromination, Friedel-Crafts alkylation with phenol, and other reaction steps to obtain compound H ((5-bromo-2-chlorophenyl)(4-hydroxyphenyl)methane); or route two uses compound E (5-iodo-2-chlorobenzoic acid chloride) as the raw material, and through Friedel-Crafts acylation with anisole, demethylation, and other reaction steps to obtain compound H. Finally, compound H reacts with compound I (2-(cyclopropoxy)ethyl p-toluenesulfonate) to form an ether to generate the key intermediate compound J ((5-bromo-2-chlorophenyl)[4-(2-cyclopropoxyethoxy)phenyl]methane) of Bexagliflozin. The product prepared by this route needs to be purified multiple times, and expensive reagents such as iodine, tetrabutylammonium iodide, and cesium carbonate are used. Similarly, due to the high reactivity of phenol or anisole at the ortho and para positions, the ortho and para selectivity of the Friedel-Crafts alkylation reaction of phenol (route one) and the Friedel-Crafts acylation reaction of anisole (route two) are both low, resulting in low reaction yields of the above two reactions, only 52% or 67% respectively. Therefore, this route still has the production problems of high cost, low reaction selectivity, low yield, low atom utilization rate, and difficult purification of the product.

[0015] In summary, the current synthesis process of the intermediate of Besagliflozin has problems of low yield, low atomic utilization rate and difficult purification of the product, therefore, it is of great significance to develop a green, environmentally friendly and high-selectivity synthesis route for the preparation of the intermediate of Besagliflozin. Based on this, the present application provides a preparation method of the intermediate of Besagliflozin. SUMMARY

[0016] The present application provides a preparation method of the intermediate of Besagliflozin, which has the advantages of mild reaction conditions, high atomic utilization rate, high yield and high product quality, and successfully solves the problems of low yield, low atomic utilization rate and difficult purification of the product in the traditional process.

[0017] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0018] In one aspect, the present application provides a preparation method of the intermediate of Besagliflozin, comprising the following steps:

[0019] S1: Substitution reaction: under the action of a base, 2-(cyclopropoxy)ethanol and compound III ((5-halo-2-chlorophenyl)(4-halophenyl) ketone) undergo substitution reaction to generate compound II;

[0020]

[0021] S2: Reduction reaction: under the action of a Lewis acid, a reducing agent and compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) undergo reduction reaction to generate compound I;

[0022]

[0023] X1, X2 are each independently selected from at least one of fluorine, chlorine, bromine and iodine.

[0024] Preferably, X1 is bromine or iodine.

[0025] Preferably, X2 is fluorine or chlorine.

[0026] Preferably, the base in S1 is selected from at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium alcoholate, potassium alcoholate, magnesium alcoholate, alkyl lithium, sodium amide and sodium hydride; further preferably, the base in S1 is selected from at least one of potassium hydroxide and potassium alcoholate; more preferably, the base in S1 is selected from at least one of potassium hydroxide and potassium tert-butoxide.

[0027] Preferably, the substitution reaction in S1 further comprises a solvent.

[0028] Preferably, the solvent is selected from at least one of diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 2-methyltetrahydrofuran, toluene, xylene, hexane, heptane, dichloromethane, or tetrahydrofuran;

[0029] More preferably, the solvent is selected from at least one of diethyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran;

[0030] More preferably, the solvent is tetrahydrofuran.

[0031] Preferably, the molar ratio of 2-(cyclopropoxy)ethanol to compound III ((5-halo-2-chlorophenyl)(4-halophenyl)methyl ketone) in S1 is 1-2.5:1;

[0032] More preferably, the molar ratio of 2-(cyclopropoxy)ethanol to compound III ((5-halo-2-chlorophenyl)(4-halophenyl)methyl ketone) in S1 is 1-2:1;

[0033] More preferably, the molar ratio of 2-(cyclopropoxy)ethanol to compound III ((5-halo-2-chlorophenyl)(4-halophenyl)methyl ketone) in S1 is 1.4-1.6:1.

[0034] Preferably, the substitution reaction described in S1 comprises the following steps: mixing compound III ((5-halo-2-chlorophenyl)(4-halophenyl) methyl ketone), 2-(cyclopropoxy)ethanol with a solvent, cooling to -5 to 5°C, adding a base, heating to 8 to 20°C, and reacting for 0.5 to 2.5 hours.

[0035] More preferably, the substitution reaction described in S1 comprises the following steps: mixing compound III ((5-halo-2-chlorophenyl)(4-halophenyl) methyl ketone), 2-(cyclopropoxy)ethanol with a solvent, cooling to 0-5°C, adding a base, heating to 10-15°C, and reacting for 1-2 hours.

[0036] Preferably, the substitution reaction described in S1 comprises the following steps: mixing compound III ((5-halo-2-chlorophenyl)(4-halophenyl) methyl ketone), 2-(cyclopropoxy)ethanol with a solvent, adding a base and TBAB, heating to 35-55°C, and reacting for 1.5-4.5 hours.

[0037] More preferably, the substitution reaction described in S1 comprises the following steps: mixing compound III ((5-halo-2-chlorophenyl)(4-halophenyl) methyl ketone), 2-(cyclopropoxy)ethanol with a solvent, adding a base and TBAB, heating to 40-50°C, and reacting for 2-4 hours.

[0038] Preferably, the mass-to-volume ratio of compound III ((5-halo-2-chlorophenyl)(4-halophenyl) methyl ketone) to the solvent in S1 is 1:1-3 g / mL;

[0039] More preferably, the mass-to-volume ratio of compound III ((5-halo-2-chlorophenyl)(4-halophenyl)methyl ketone) to the solvent in S1 is 1:1-2 g / mL;

[0040] More preferably, the mass-to-volume ratio of compound III ((5-halo-2-chlorophenyl)(4-halophenyl)methyl ketone) to solvent in S1 is 1:2 g / mL.

[0041] Preferably, the substitution reaction described in S1 further includes recrystallization with isopropanol.

[0042] Preferably, the Lewis acid in the reduction reaction described in S2 is selected from at least one of boron trifluoride diethyl ether, boron trifluoride tetrahydrofuran, trifluoroacetic acid, phosphoric acid, sulfonic acid, sulfuric acid, ferric sulfate, ferrous sulfate, aluminum sulfate, copper sulfate, cuprous sulfate, zinc sulfate, tin sulfate, ferric chloride, ferrous chloride, aluminum chloride, copper chloride, cuprous chloride, zinc chloride, or tin chloride.

[0043] More preferably, the Lewis acid in the reduction reaction described in S2 is selected from at least one of boron trifluoride diethyl ether, boron trifluoride tetrahydrofuran, phosphoric acid, sulfuric acid, ferric sulfate, ferrous sulfate, aluminum sulfate, copper sulfate, cuprous sulfate, tin sulfate, ferrous chloride, aluminum chloride, copper chloride, cuprous chloride, zinc chloride, or tin chloride.

[0044] More preferably, the Lewis acid in the reduction reaction described in S2 is selected from at least one of boron trifluoride ether or aluminum chloride.

[0045] Preferably, the reducing agent described in S2 is selected from at least one of diethylsilane, triethylsilane, trimethylsilane, dimethylphenylsilane, diphenylsilane, triphenylsilane, tris(trimethylsilyl)silane, methyldiethoxysilane, 1,1,3,3-tetramethyldisiloxane, tetramethyldisilazane, polymethylhydrosiloxane, red aluminum, lithium aluminum hydride, lithium borohydride, sodium borohydride, magnesium borohydride, potassium borohydride, or calcium borohydride;

[0046] More preferably, the reducing agent in S2 is selected from at least one of triethylsilane, trimethylsilane, dimethylphenylsilane, diphenylsilane, triphenylsilane, methyldiethoxysilane, 1,1,3,3-tetramethyldisiloxane, tetramethyldisilazane, polymethylhydrosiloxane, lithium aluminum hydride, lithium borohydride, sodium borohydride, magnesium borohydride, potassium borohydride, or calcium borohydride;

[0047] More preferably, the reducing agent in S2 is selected from at least one of triethylsilane or aluminum chloride.

[0048] Preferably, the reduction reaction described in S2 further includes a solvent;

[0049] Preferably, the solvent is selected from at least one of diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, toluene, xylene, hexane, heptane, dichloromethane, or tetrahydrofuran;

[0050] More preferably, the solvent is selected from at least one of dichloromethane or tetrahydrofuran;

[0051] More preferably, the solvent is selected from tetrahydrofuran.

[0052] Preferably, the molar ratio of the reducing agent in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) is 1-2.5:1;

[0053] More preferably, the molar ratio of the reducing agent in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) is 1-2.2:1;

[0054] More preferably, the molar ratio of the reducing agent in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) is 1.4-2.1:1.

[0055] Preferably, the molar ratio of the Lewis acid in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) is 1.5-5:1;

[0056] More preferably, the molar ratio of the Lewis acid in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) is 3-4.5:1;

[0057] More preferably, the molar ratio of the Lewis acid described in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) is 3.0-4.0:1.

[0058] Preferably, the mass-to-volume ratio of compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) to dichloromethane in S2 is 1:5-12 g / mL;

[0059] More preferably, the mass-to-volume ratio of compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) to dichloromethane in S2 is 1:5.4-12 g / mL;

[0060] Preferably, the mass ratio of compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) to tetrahydrofuran in S2 is 1:4-8;

[0061] More preferably, the mass ratio of compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) to tetrahydrofuran in S2 is 1:5-7.

[0062] Preferably, the reduction reaction described in S2 includes the following steps: at -5 to -5°C, a solvent is mixed with a Lewis acid and reacted for 20 to 40 minutes; compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) and a reducing agent are added; the reaction is carried out at -5 to -0°C for 1 to 2 hours; and the temperature is raised to 60 to 75°C and the reaction is carried out for 10 to 20 hours.

[0063] More preferably, the reduction reaction described in S2 includes the following steps: at 0-5°C, a solvent is mixed with a Lewis acid and reacted for 30 min; compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl)methyl ketone) and a reducing agent are added; the reaction is carried out at 0°C for 1-2 hours; and the temperature is raised to 65-70°C and the reaction is carried out for 15-20 hours.

[0064] Preferably, the reduction reaction described in S2 comprises the following steps: mixing compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) methyl ketone), reducing agent and solvent, cooling to -25°C to -10°C, adding Lewis acid, heating to -5°C to 0°C, and reacting for 1-5 hours.

[0065] More preferably, the reduction reaction described in S2 includes the following steps: mixing compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) methyl ketone), reducing agent and solvent, cooling to -20°C to -15°C, adding Lewis acid, heating to 0°C, and reacting for 2-4 hours.

[0066] Preferably, the substitution reaction described in S2 further includes extraction with toluene and recrystallization with ethanol.

[0067] Compared with the prior art, the present invention has the following beneficial effects:

[0068] The present invention provides a method for preparing besagliflozin intermediates, which has the advantages of mild reaction conditions, high atom utilization, high yield and high product quality, and solves the production problems of low yield, low atom utilization and difficult product purification in traditional processes. Detailed Implementation

[0069] To make the technical means, creative features, achieved objectives, and effects of this invention readily understandable, the invention is further illustrated below with specific embodiments. However, these embodiments are merely preferred embodiments and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the scope of protection of this invention. It is worth noting that the raw materials used in this invention are all common commercially available products, and their sources are not specifically limited. The technical and scientific terms used in the embodiments have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0070] Example 1: Preparation of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone

[0071]

[0072] Option 1:

[0073] Add 50 g (159.5 mmol) of (5-bromo-2-chlorophenyl)(4-fluorophenyl) methyl ketone and 100 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, add 24.5 g (239.9 mmol) of 2-(cyclopropoxy)ethanol, cool to 0-5 °C, add 25 g (222.8 mmol) of potassium tert-butoxide in portions, raise the temperature to 10-15 °C after the addition is complete, keep the reaction at this temperature for 1-2 hours, cool to 0 °C, add 100 g of saturated brine to quench the reaction, raise the temperature to 20 °C, separate the liquids, wash the organic phase twice with saturated brine (20 g / time), remove the solvent by vacuum distillation, recrystallize with isopropanol, and dry overnight to obtain 58.3 g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 92.4%, purity: 99.2%.

[0074] Option 2:

[0075] Add 50 g (159.5 mmol) of (5-bromo-2-chlorophenyl)(4-fluorophenyl) methyl ketone and 100 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, then add 24.5 g (239.9 mmol) of 2-(cyclopropoxy)ethanol, 5.0 g (15.5 mmol) of TBAB, and 13.4 g (238.9 mmol) of potassium hydroxide. After addition, heat to 40-50 °C and maintain the reaction temperature for 2-4 hours. Cool to 0 °C and quench the reaction with 100 g of saturated brine. After addition, heat to 20 °C, separate the liquids, and wash the organic phase twice with saturated brine (20 g / time). After washing, distill the organic phase under reduced pressure to remove the solvent. After distillation, recrystallize with isopropanol and dry overnight to obtain 59.5 g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 94.3%, purity: 98.6%.

[0076] Example 2: Preparation of 5-bromo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane

[0077]

[0078] Option 1:

[0079] Under nitrogen protection, 300 g of tetrahydrofuran was added to a four-necked flask, and the temperature was lowered to 0-5°C. 64 g (480 mmol) of aluminum trichloride was added in portions, and the reaction was maintained at this temperature for 0.5 hours. Then, 55 g (139.0 mmol) of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone prepared in Example 1 and 7.9 g (209 mmol) of sodium borohydride were added. After the addition was complete, the reaction was maintained at 0°C for 2 hours, then heated to reflux (65-70°C) and maintained at this temperature for 15-20 hours. The temperature was lowered to 0-5°C and controlled to ≤20°C. 600 g of ice water was added to quench the reaction. After the addition was complete, the temperature was raised to 2... The reaction was kept at 0-30℃ for 1 hour to fully quench the reaction. Tetrahydrofuran was recovered by vacuum distillation. After distillation, the mixture was extracted twice with toluene (500 mL each time). The organic phases were combined and washed once with 100 g of water. Most of the solvent was removed by vacuum distillation of the organic phase, leaving about 100 mL of toluene. 200 mL of ethanol was added and the mixture was heated to 50℃ to dissolve the toluene. The mixture was stirred at this temperature for 1 hour and then cooled to -5℃ to crystallize for 2 hours. The mixture was filtered, and the filter cake was washed with ice-cold ethanol and dried under vacuum at 25-35℃ overnight to obtain 45.3 g of 5-bromo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane, with a yield of 85.4% and a purity of 99.7%.

[0080] Option 2:

[0081] Under nitrogen protection, 55 g (139.0 mmol) of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone prepared in Example 1 and 500 mL of dichloromethane were added to a four-necked flask and stirred until dissolved. Then, 32.4 g (278.6 mmol) of triethylsilane was added, and the mixture was cooled to -20°C to -15°C. 78.9 g (555.9 mmol) of boron trifluoride ether was added dropwise. After the addition was complete, the temperature was raised to 0°C and the reaction was maintained for 2-4 hours. The pH was adjusted by adding saturated sodium bicarbonate solution. Add H to 6-7, then heat to 20-30℃, separate the liquid and liquid phases, wash the organic phase once with water, separate the liquid and liquid phases again, and recover dichloromethane by vacuum distillation of the organic phase. After distillation, add toluene with distillation, and after distillation, add 200mL of ethanol and heat to 50℃ to dissolve the solidified liquid. Keep the liquid at this temperature and stir for 1 hour, then cool to -5℃ to crystallize for 2 hours. Filter the liquid, wash the filter cake with ice-cold ethanol, and dry it under vacuum at 25-35℃ overnight to obtain 48.6g of 5-bromo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane, yield: 91.6%, purity: 99.5%.

[0082] Example 3: Preparation of (5-iodo-2-chlorophenyl)(4-fluorophenyl) methyl ketone

[0083]

[0084] Option 1:

[0085] Add 50 g (138.7 mmol) of (5-iodo-2-chlorophenyl)(4-fluorophenyl) methyl ketone and 200 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, add 21.2 g (207.6 mmol) of 2-(cyclopropoxy)ethanol, cool to 0-5 °C, add 21.8 g (194.3 mmol) of potassium tert-butoxide in portions, raise the temperature to 10-15 °C, maintain the reaction temperature for 1-2 hours, cool to 0 °C, add 100 g of saturated brine to quench the reaction, raise the temperature to 20 °C, separate the liquids, wash the organic phase twice with saturated brine (20 g / time), remove the solvent by vacuum distillation, recrystallize with isopropanol, and dry overnight to obtain 56.1 g of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 91.4%, purity: 99.8%.

[0086] Option 2:

[0087] Add 50 g (138.7 mmol) of (5-iodo-2-chlorophenyl)(4-fluorophenyl) methyl ketone and 200 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, then add 21.5 g (207.6 mmol) of 2-(cyclopropoxy)ethanol, 5.0 g (15.5 mmol) of TBAB, and 15.6 g (278 mmol) of potassium hydroxide. After addition, heat to 40-50 °C and maintain the reaction temperature for 2-4 hours. Cool to 0 °C and quench the reaction with 100 g of saturated brine. After addition, heat to 20 °C, separate the liquids, and wash the organic phase twice with saturated brine (20 g / time). After washing, distill the organic phase under reduced pressure to remove the solvent. After distillation, recrystallize with isopropanol and dry overnight to obtain 58.2 g of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 94.8%, purity: 99.6%.

[0088] Example 4: Preparation of 5-iodo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane

[0089]

[0090] Option 1:

[0091] Under nitrogen protection, 300 g of tetrahydrofuran was added to a four-necked flask, and the temperature was lowered to 0-5°C. 22.6 g (169.5 mmol) of aluminum trichloride was added in portions, and the reaction was maintained at this temperature for 0.5 hours. Then, 50 g (112.9 mmol) of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone prepared in Example 3 and 5.2 g (137.6 mmol) of sodium borohydride were added. After the addition was complete, the reaction was maintained at 0°C for 2 hours, then heated to reflux (65-70°C) and maintained at this temperature for 15-20 hours. The temperature was lowered to 0-5°C, and controlled to ≤20°C. 600 g of ice water was added to quench the reaction. After the addition was complete, the temperature was raised... The reaction was heated to 20-30℃ and kept at this temperature for 1 hour to fully quench the reaction. Tetrahydrofuran was recovered by vacuum distillation. After distillation, the mixture was extracted twice with toluene (500 mL each time). The organic phases were combined and washed once with 100 g of water. Most of the solvent was removed by vacuum distillation of the organic phase, leaving about 80 mL of toluene. 220 mL of ethanol was added and the mixture was heated to 50℃ to dissolve the toluene. The mixture was stirred at this temperature for 1 hour and then cooled to -5℃ to crystallize for 2 hours. The mixture was filtered, and the filter cake was washed with ice-cold ethanol and dried under vacuum at 25-35℃ overnight to obtain 40.5 g of 5-iodo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane, with a yield of 83.7% and a purity of 99.6%.

[0092] Option 2:

[0093] Under nitrogen protection, 50 g (112.9 mmol) of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone prepared in Example 1 and 600 mL of dichloromethane were added to a four-necked flask and stirred until dissolved. Then, 26.2 g (225.6 mmol) of triethylsilane was added, and the mixture was cooled to -20°C to -15°C. 80.2 g (564.8 mmol) of boron trifluoride ether was added dropwise. After the addition was complete, the temperature was raised to 0°C and the reaction was maintained for 2-4 hours. The pH was adjusted with saturated sodium bicarbonate solution. Add H to 6-7, then heat to 20-30℃, separate the liquid and liquid phases, wash the organic phase once with water, separate the liquid and liquid phases again, and recover dichloromethane by vacuum distillation of the organic phase. After distillation, add toluene with distillation, and after distillation, add 150mL of ethanol and heat to 50℃ to dissolve the solidified liquid. Keep the liquid at this temperature and stir for 1 hour, then cool to -5℃ to crystallize for 2 hours. Filter the liquid, wash the filter cake with ice-cold ethanol, and dry it under vacuum at 25-35℃ overnight to obtain 45.3g of 5-iodo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane, yield: 93.6%, purity: 99.2%.

[0094] Example 5: Preparation of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone

[0095]

[0096] Option 1:

[0097] Add 50 g (151.5 mmol) of (5-bromo-2-chlorophenyl)(4-chlorophenyl) methyl ketone and 100 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, add 23.2 g (227.2 mol) of 2-(cyclopropoxy)ethanol, cool to 0-5 °C, add 25.5 g (227.3 mmol) of potassium tert-butoxide in portions, raise the temperature to 10-15 °C, maintain the reaction temperature for 1-2 hours, cool to 0 °C, add 100 g of saturated brine to quench the reaction, raise the temperature to 20 °C, separate the liquids, wash the organic phase twice with saturated brine (20 g / time), remove the solvent by vacuum distillation, recrystallize with isopropanol, and dry overnight to obtain 52.8 g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 88.1%, purity: 99.5%.

[0098] Option 2:

[0099] Add 50 g (151.5 mmol) of (5-bromo-2-chlorophenyl)(4-chlorophenyl) methyl ketone and 100 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, then add 23.2 g (227.2 mol) of 2-(cyclopropoxy)ethanol, 5.0 g (15.5 mmol) of TBAB, and 17.0 g (302.9 mmol) of potassium hydroxide. After addition, heat to 40-50 °C and maintain the reaction temperature for 2-4 hours. Cool to 0 °C and quench the reaction with 100 g of saturated brine. After addition, heat to 20 °C, separate the liquids, and wash the organic phase twice with saturated brine (20 g / time). After washing, remove the solvent by vacuum distillation of the organic phase. After distillation, recrystallize with isopropanol and dry overnight to obtain 55.6 g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 92.8%, purity: 99.4%.

[0100] Example 6: Preparation of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone

[0101]

[0102] Option 1:

[0103] Add 50 g (132.6 mmol) of (5-iodo-2-chlorophenyl)(4-chlorophenyl) methyl ketone and 200 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, add 20.3 g (198.9 mmol) of 2-(cyclopropoxy)ethanol, cool to 0-5 °C, add 22.3 g (198.7 mmol) of potassium tert-butoxide in portions, raise the temperature to 10-15 °C, maintain the reaction temperature for 1-2 hours, cool to 0 °C, add 100 g of saturated brine to quench the reaction, raise the temperature to 20 °C, separate the liquids, wash the organic phase twice with saturated brine (20 g / time), remove the solvent by vacuum distillation, recrystallize with isopropanol, and dry overnight to obtain 49.2 g of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 83.8%, purity: 99.7%.

[0104] Option 2:

[0105] Add 50 g (132.6 mmol) of (5-iodo-2-chlorophenyl)(4-chlorophenyl) methyl ketone and 200 mL of tetrahydrofuran to a 500 mL four-necked flask, stir to dissolve, then add 20.3 g (198.9 mmol) of 2-(cyclopropoxy)ethanol, 5.0 g (15.5 mmol) of TBAB, and 14.9 g (265.5 mmol) of potassium hydroxide. After addition, heat to 40-50 °C and maintain the reaction temperature for 2-4 hours. Cool to 0 °C and quench the reaction with 100 g of saturated brine. After addition, heat to 20 °C, separate the liquids, and wash the organic phase twice with saturated brine (20 g / time). After washing, remove the solvent by vacuum distillation of the organic phase. After distillation, recrystallize with isopropanol and dry overnight to obtain 53.8 g of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone, yield: 91.7%, purity: 99.6%.

[0106] Comparative Example 1

[0107] According to the method of step 4 in Example 17 of Chinese Patent CN 105001213 B.

[0108] Preparation of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone

[0109]

[0110] Under ice bath conditions, potassium tert-butoxide (413 mg, 3.68 mmol) was added to a solution of 2-(cyclopropoxy)ethanol (0.43 g, 4.21 mmol) and (5-bromo-2-chlorophenyl)(4-fluorophenyl) methyl ketone (1.10 g, 3.51 mmol) in N,N-dimethylformamide (10 mL). The reaction system turned dark brown, and the mixture was heated to room temperature and stirred overnight.

[0111] The reaction was quenched with water (50 mL), and the reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 0.71 g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone, yield: 51.1%, purity: 99.1%.

[0112] Comparative Example 2

[0113] According to the method of step 5 in Example 17 of Chinese Patent CN 105001213 B.

[0114] Preparation of 5-bromo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane

[0115]

[0116] Under ice bath and nitrogen protection, boron trifluoride diethyl ether (0.62 mL, 5 mmol) was added dropwise to a mixture of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) ketone (660 mg, 1.67 mmol) and triethylchlorosilane (1.07 mL, 6.67 mmol) prepared in Example 1, along with 1,2-dichloroethane (3 mL) and acetonitrile (3 mL). After the addition was complete, the reaction system was gradually raised to room temperature and stirred overnight. Water (30 mL) and ethyl acetate (50 mL) were added, and the mixture was allowed to separate into layers. The aqueous phase was extracted with ethyl acetate (30 mL), and the organic phases were combined. The organic phases were washed with saturated sodium bicarbonate aqueous solution (20 mL × 2) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1) to give 0.36 g of 5-bromo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane, yield: 56.5%, purity: 99.2%.

[0117] Comparative Example 3

[0118] Preparation of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone

[0119]

[0120] 25 g (79.75 mmol) of (5-bromo-2-chlorophenyl)(4-fluorophenyl) methyl ketone and 100 mL of tetrahydrofuran were added to a 500 mL four-necked flask and stirred to dissolve. 24.4 g (238.9 mmol) of 2-(cyclopropoxy)ethanol was added, and the mixture was cooled to 10 °C. 50 g (445.6 mmol) of potassium tert-butoxide was added in portions. After the addition was complete, the mixture was heated to 25 °C and reacted for 3 hours. The mixture was then cooled to 0 °C, and 100 g of saturated brine was added to quench the reaction. After the addition was complete, the mixture was heated to 20 °C, and the mixture was separated. The organic phase was washed twice with saturated brine (20 g / time). After washing, the organic phase was distilled under reduced pressure to remove the solvent. After distillation, isopropanol was added for recrystallization, and the mixture was dried overnight to obtain 25.3 g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methyl ketone. Yield: 80.2%, purity: 99.6%.

[0121] Comparative Example 4

[0122] Compared with Scheme 2 of Example 1, the solvent for recrystallization was changed to ethanol, yielding 48.8g of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone, with a yield of 77.3% and a purity of 99.5%.

[0123] Comparative Example 5

[0124] Preparation of 5-bromo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane

[0125]

[0126] Under nitrogen protection, 100 mL of tetrahydrofuran was added to a four-necked flask, and the temperature was lowered to 10°C. 18.5 g (139.0 mmol) of aluminum trichloride was added in portions, and the reaction was maintained at this temperature for 0.5 hours. Then, 55 g (139.0 mmol) of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone prepared in Example 1 and 3.95 g (104.5 mmol) of sodium borohydride were added. After the addition was complete, the reaction was maintained at 10°C for 2 hours, then the temperature was raised to 40°C and maintained for 25 hours. The temperature was lowered to 0–5°C, and controlled to ≤20°C. 600 g of ice water was added to quench the reaction. After the addition was complete, the temperature was raised to 20–30°C and the reaction was maintained for 1 hour to fully quench the reaction. The tetrahydrofuran was recovered by vacuum distillation. After distillation, the mixture was extracted twice with toluene (500 mL each time).

[0127] Combine the organic phases, wash once with 100g of water, and remove most of the solvent by vacuum distillation, leaving approximately 100mL of toluene. Add 200mL of ethanol and heat to 50°C to dissolve completely. Maintain the temperature and stir for 1 hour, then cool to -5°C to crystallize for 2 hours. Filter, rinse the filter cake with ice-cold ethanol, and dry under vacuum overnight at 25–35°C to obtain 5-bromo-2-chloro-4'-

[0128] 24.3 g of (2-cyclopropoxyethoxy)diphenylmethane, yield: 45.8%, purity: 98.5%.

[0129] Comparative Example 6

[0130] Compared with Scheme 2 of Example 2, only the post-processing operation is changed, specifically:

[0131] Under nitrogen protection, 55 g (139.0 mmol) of (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methyl ketone prepared in Example 1 and 500 mL of dichloromethane were added to a four-necked flask and stirred until dissolved. 32.4 g (278.6 mmol) of triethylsilane was added, and the mixture was cooled to -20°C to -15°C. 78.9 g (555.9 mmol) of boron trifluoride ether was added dropwise. After the addition was complete, the mixture was heated to 0°C and reacted for 2-4 hours. Saturated sodium bicarbonate solution was added to adjust the pH to 6-7. After the addition was complete, the mixture was heated to 20-30°C, and the mixture was separated. The organic phase was washed once with water, separated again, and the dichloromethane was recovered by vacuum distillation of the organic phase. The residue was purified using a thin-layer chromatography plate to obtain 40.2 g of 5-bromo-2-chloro-4'-(2-cyclopropoxyethoxy)diphenylmethane, with a yield of 75.8% and a purity of 99.3%.

[0132] As can be seen from the examples and comparative examples, the preparation method of the present invention, by optimizing the raw materials and their ratios and optimizing the parameters in the reaction process, significantly improves the yield of the product while ensuring high purity.

[0133] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a besagliflozin intermediate, characterized in that, Includes the following steps: S1: Substitution reaction: Under the action of a base, 2-(cyclopropoxy)ethanol reacts with compound III ((5-halo-2-chlorophenyl)(4-halophenyl)methyl ketone) to generate compound II; S2: Reduction reaction: Under the action of Lewis acid, the reducing agent reacts with compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) to generate compound I; X1 and X2 are each independently selected from at least one of fluorine, chlorine, bromine, and iodine.

2. The preparation method according to claim 1, characterized in that, X1 is independently selected from bromine or iodine, and X2 is independently selected from fluorine or chlorine.

3. The preparation method according to claim 1, characterized in that, The alkali described in S1 is selected from at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, magnesium alkoxide, alkyl lithium, sodium amino, and sodium hydride.

4. The preparation method according to claim 1, characterized in that, The substitution reaction described in S1 further includes a solvent; the solvent is selected from at least one of diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 2-methyltetrahydrofuran, toluene, xylene, hexane, heptane, dichloromethane, or tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that, The molar ratio of 2-(cyclopropoxy)ethanol to compound III ((5-halo-2-chlorophenyl)(4-halophenyl)methyl ketone) described in S1 is 1-2.5:

1.

6. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of compound III ((5-halo-2-chlorophenyl)(4-halophenyl) methyl ketone) to solvent in S1 is 1:2 g / mL.

7. The preparation method according to claim 1, characterized in that, The Lewis acid in the reduction reaction described in S2 is selected from at least one of boron trifluoride diethyl ether, boron trifluoride tetrahydrofuran, trifluoroacetic acid, phosphoric acid, sulfonic acid, sulfuric acid, ferric sulfate, ferrous sulfate, aluminum sulfate, copper sulfate, cuprous sulfate, zinc sulfate, tin sulfate, ferric chloride, ferrous chloride, aluminum chloride, copper chloride, cuprous chloride, zinc chloride, or tin chloride.

8. The preparation method according to claim 1, characterized in that, The reducing agent described in S2 is selected from at least one of diethylsilane, triethylsilane, trimethylsilane, dimethylphenylsilane, diphenylsilane, triphenylsilane, tris(trimethylsilyl)silane, methyldiethoxysilane, 1,1,3,3-tetramethyldisiloxane, tetramethyldisilazane, polymethylhydrosiloxane, red aluminum, lithium aluminum hydride, lithium borohydride, sodium borohydride, magnesium borohydride, potassium borohydride, or calcium borohydride.

9. The preparation method according to claim 1, characterized in that, The reduction reaction described in S2 further includes a solvent; the solvent is selected from at least one of diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, toluene, xylene, hexane, heptane, dichloromethane, or tetrahydrofuran.

10. The preparation method according to claim 1, characterized in that, The molar ratio of the reducing agent in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) is 1-2.5:1; the molar ratio of the Lewis acid in S2 to compound II ((5-halo-2-chlorophenyl)(4-(2-(cyclopropoxy)ethoxy)phenyl) ketone) is 1.5-5:1.

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