Process for the preparation of a key intermediate of dapagliflozin
By optimizing the synthetic route of 5-bromo-2-chloro-4'-ethoxydiphenylmethane and replacing highly toxic reagents with low-toxicity catalysts, the product yield and purity were improved, solving the problems of high raw material costs and environmental safety, and realizing an efficient and environmentally friendly production process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- WEIFANG HAIXIN PHARM CO LTD
- Filing Date
- 2026-04-29
- Publication Date
- 2026-05-29
AI Technical Summary
The existing synthesis process for 5-bromo-2-chloro-4'-ethoxydiphenylmethane has high raw material costs, low yield, and uses highly toxic reagents, which affects environmental safety.
Using p-cresol as the starting material, the synthesis route was optimized to improve product yield and purity through etherification, thioetherification, hydrodesulfurization, chlorination, and bromination reactions, using low-toxicity catalysts such as aluminum chloride, ferric chloride, and palladium on carbon, while avoiding the use of highly toxic reagents such as AIBN.
The overall yield of 5-bromo-2-chloro-4'-ethoxydiphenylmethane was increased to 90.4-91.7%, and the HPLC purity reached 99.911-99.953%, which reduced production costs and environmental risks and simplified the post-processing procedure.
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Figure CN122102858A_ABST
Abstract
Description
Technical Field
[0001] This invention discloses a method for preparing a key intermediate of dapagliflozin, belonging to the field of pharmaceutical intermediate preparation technology. Background Technology
[0002] Dapagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), is an important drug for the treatment of type 2 diabetes. 5-Bromo-2-chloro-4'-ethoxydiphenylmethane is a crucial intermediate in the synthesis of dapagliflozin, resulting in significant market demand. The quality of the 5-bromo-2-chloro-4'-ethoxydiphenylmethane synthesis process directly impacts the production cost, product quality, and environmental safety of dapagliflozin.
[0003] The prior art disclosed in CN104478670A is a method for synthesizing 5-bromo-2-chloro-4'-ethoxydiphenylmethane. It uses o-toluidine as the starting material and synthesizes it through bromination, diazotization, halogenation and Friedel-Crafts alkylation. The halogenation uses azobisisobutyronitrile (AIBN), which is highly toxic and has a great impact on human health and the environment.
[0004] In addition, there is a technique that uses 5-bromo-2-chlorobenzoic acid as a starting material, first acylates it with oxaloyl chloride, then Friedel-Crafts acylates it with ethoxybenzene, and finally reduces the carbonyl group to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The synthetic route is shown below: However, the disadvantages of this method are high raw material prices and low yield.
[0005] Therefore, developing a method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane that is easy to industrialize, has low raw material costs, does not use highly toxic reagents, and has higher yield and purity has become an urgent technical problem to be solved in this field. Summary of the Invention
[0006] To address the aforementioned problems in the existing technology, this invention provides a method for preparing a key intermediate of dapagliflozin. By optimizing the synthetic route and process parameters, the method achieves simultaneous improvement in product yield and purity, while reducing production costs and environmental risks.
[0007] To achieve the above objectives, the following technical solution is adopted: A method for preparing a key intermediate of dapagliflozin includes the following steps: Step 1: Preparation of 1-ethoxy-4-methylbenzene Dissolve p-cresol in ethanol, add sodium hydroxide, and stir to react.
[0008] Add the ethylating agent dropwise to the reaction system and maintain the temperature for reaction.
[0009] The reaction system was cooled, washed, and allowed to stand to separate into layers, retaining the upper organic phase.
[0010] The organic phase was dried and distilled at atmospheric pressure at a distillation temperature of 196-198℃. The fraction was collected to obtain 1-ethoxy-4-methylbenzene.
[0011] The ethylating agent is diethyl carbonate or bromoethane.
[0012] The molar ratio of p-cresol, sodium hydroxide, and ethylating agent is 1:(1.05~1.3):(1.15~2), and the amount of ethanol used is 5~8 times the mass of p-cresol.
[0013] The stirring reaction is carried out at a stirring rate of 100-400 r / min, a reaction temperature of 50-75℃, and a reaction time of 1-1.5 h.
[0014] The heat preservation reaction: the heat preservation temperature is 60~140℃, and the reaction time is 3~7h.
[0015] Cooling: The reaction system is cooled to below 25°C.
[0016] The washing process involves adding saturated saline solution to the reaction solution for washing; the amount of saturated saline solution used is the same as the volume of the reaction solution.
[0017] The drying process involves adding a desiccant to the organic phase, sealing and stirring for 30-60 minutes, and then filtering to remove the desiccant. The desiccant is anhydrous magnesium sulfate, and the amount of desiccant used is 10-20% of the weight of the organic phase.
[0018] Step 2: Preparation of (4-ethoxybenzyl)phenyl sulfide Under nitrogen protection, 1-ethoxy-4-methylbenzene, thiophenol, base, catalyst ligand, solvent A, deionized water, and PEG-400 were added to the reactor, mixed evenly, and then palladium catalyst and oxidant were added. The mixture was refluxed for 12-24 hours.
[0019] After the reaction solution was cooled to room temperature, it was allowed to stand and separate into layers. The lower aqueous phase containing palladium-TPPTS and the upper organic phase were separated. The organic phase was extracted, dried, and concentrated under reduced pressure to obtain (4-ethoxybenzyl)phenyl sulfide.
[0020] The lower aqueous phase containing palladium-TPPTS can be directly reused in the next step of preparing (4-ethoxybenzyl)phenyl sulfide.
[0021] The molar ratio of 1-ethoxy-4-methylbenzene, thiophenol, palladium catalyst, base, and oxidant is 1:(1.1~1.2):(0.05~0.08):(1.3~1.5):(1.1~1.2).
[0022] The alkali is one of potassium carbonate, cesium carbonate, and potassium phosphate.
[0023] Solvent A is one of toluene and 1,4-dioxane, and the amount of solvent A used is 8 to 10 times the mass of 1-ethoxy-4-methylbenzene.
[0024] The catalyst ligand is TPPTS (sodium triphenylphosphine tris(m-sulfonate)).
[0025] The amount of PEG-400 used is 3 to 5% of the mass of 1-ethoxy-4-methylbenzene.
[0026] The amount of deionized water used is 1 / 3 to 1 / 2 of the mass of solvent A.
[0027] The palladium catalyst is Pd(OAc)2 (palladium acetate) or Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium).
[0028] The molar ratio of the catalyst ligand to the palladium catalyst is (1.3~2):1.
[0029] The oxidant is di-tert-butyl peroxide (DTBP) or benzoyl peroxide (BPO).
[0030] The amount of ethyl acetate used is the same as the volume of the reaction solution.
[0031] The reflux reaction is carried out at a temperature of 110~130℃.
[0032] The extraction process uses ethyl acetate as the extractant.
[0033] The drying process involves using anhydrous magnesium sulfate as the desiccant, with the amount of desiccant being 10-20% of the weight of the organic phase.
[0034] The vacuum concentration process involves controlling the temperature at 40~50℃ and the vacuum degree at <-0.09MPa.
[0035] Step 3: Preparation of 1-benzyl-4-ethoxybenzene (4-ethoxybenzyl)phenyl sulfide, catalyst A, and solvent B were added to a high-pressure reactor and reacted under pressure in a hydrogen atmosphere. The reaction solution was filtered to obtain a solid catalyst and a filtrate; the solid catalyst could be reused. A sodium hydroxide solution with a mass fraction of 8% (1 / 2 volume of the filtrate) was added to the filtrate, and the mixture was stirred for 15–30 min. After standing and separating the layers, the upper organic phase was retained and concentrated under reduced pressure to obtain crude 1-benzyl-4-ethoxybenzene. The crude 1-benzyl-4-ethoxybenzene was then distilled under reduced pressure, and the fraction was collected and purified to obtain 1-benzyl-4-ethoxybenzene.
[0036] Wastewater treatment: Add sodium hypochlorite solution with 10% available chlorine to the lower layer of sulfur-containing wastewater phase, stir for 30 minutes to completely oxidize the sulfur-containing compounds into sulfates, and then discharge it into the wastewater treatment system.
[0037] The pressurized reaction is controlled at a pressure of 1-3 MPa for a reaction time of 6-10 hours.
[0038] The vacuum concentration process involves controlling the temperature at 40~50℃ and the vacuum degree at <-0.09MPa.
[0039] The vacuum distillation is carried out with a vacuum level controlled at <-0.095MPa and a distillation temperature of 160~162℃.
[0040] The refined fraction is prepared by dissolving it in hot ethanol at 60-70°C, adding activated carbon, stirring and decolorizing for 10-30 minutes, and filtering while hot. The filtrate is then cooled to 0--5°C, precipitating a white solid, which is filtered and the solid is retained. The amount of hot ethanol used is 5-10 times the mass of the fraction. The amount of activated carbon used is 0.05-0.1 times the mass of the fraction.
[0041] The mass ratio of (4-ethoxybenzyl)phenyl sulfide to catalyst is 1:(0.05~0.1).
[0042] The catalyst A is palladium on carbon (Pd / C, 10% loading) or Raney nickel.
[0043] Solvent B is ethanol, methanol, or ethyl acetate.
[0044] The amount of solvent B used is 10 to 15 times the mass of (4-ethoxybenzyl)phenyl sulfide.
[0045] Step 4: Preparation of 4-ethoxy-2'-chlorodiphenylmethane 1-Benzyl-4-ethoxybenzene, catalyst B, and solvent C were added to the reactor. Under nitrogen protection and light-free conditions, a chlorination reagent was added to the reaction system to carry out the chlorination reaction.
[0046] After the reaction was completed, the reaction solution was filtered under normal pressure, and the filtrate was retained. The filtrate was washed to remove chlorine to obtain the organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 4-ethoxy-2'-chlorodiphenylmethane. The crude 4-ethoxy-2'-chlorodiphenylmethane was then purified to obtain 4-ethoxy-2'-chlorodiphenylmethane.
[0047] The chlorination reagent is one of N-chlorosuccinimide (NCS), tert-butyl hypochlorite (t-BuOCl), or dichlorohydantoin (DCDMH).
[0048] The chlorination reaction is carried out at a temperature controlled between 0 and 5°C.
[0049] The washing and dechlorination process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted chlorinated reagents, followed by washing with saturated saline solution until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0050] The drying process involves using anhydrous magnesium sulfate as the desiccant, with the amount of desiccant being 10-20% of the weight of the organic phase.
[0051] The vacuum concentration process involves controlling the temperature at 30~40℃ and the vacuum level at <-0.09MPa.
[0052] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid; The amount of saturated saline solution used is the same as the volume of the organic phase.
[0053] The purification process involves dissolving the crude 4-ethoxy-2'-chlorodiphenylmethane product in hot ethanol at 60-70°C, adding activated carbon, stirring and decolorizing for 10-30 minutes, and filtering while hot. The filtrate is then cooled to 0--5°C, and a white solid precipitates, which is 4-ethoxy-2'-chlorodiphenylmethane.
[0054] The molar ratio of 1-benzyl-4-ethoxybenzene, chlorinated reagent, and catalyst is 1:(0.54~1.1):(0.03~0.06).
[0055] The catalyst B is one of aluminum chloride (AlCl3) and ferric chloride (FeCl3).
[0056] The solvent C is one of dichloromethane and chloroform.
[0057] The amount of solvent C used is 10 to 15 times the mass of 1-benzyl-4-ethoxybenzene.
[0058] The amount of hot ethanol used is 5 to 10 times the mass of the crude product.
[0059] The amount of activated carbon used is 0.05 to 0.1 times the mass of the crude product.
[0060] Step 5: Preparation of 5-bromo-2-chloro-4'-ethoxydiphenylmethane 4-ethoxy-2'-chlorodiphenylmethane, solvent D, and catalyst C were added to the reactor. Under nitrogen protection and light-free conditions, a brominating reagent was added to the reaction system to carry out the bromination reaction.
[0061] After the reaction was completed, the filtrate was filtered under normal pressure and the filtrate was washed to remove bromine, thus obtaining an organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The crude product was purified to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane.
[0062] The brominating agent is one of N-bromosuccinimide (NBS), dibromohydantoin (DBDMH), or tetrabutylammonium tribromide (TBABr3).
[0063] The bromination reaction is carried out at a temperature of 0-5℃.
[0064] The bromine removal process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted bromine reagents, followed by washing with saturated saline solution until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0065] The drying process involves using anhydrous magnesium sulfate as the desiccant, with the amount of desiccant being 10-20% of the weight of the organic phase.
[0066] The vacuum concentration process involves controlling the temperature at 30~40℃ and the vacuum level at <-0.09MPa.
[0067] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid.
[0068] The amount of saturated saline solution used is the same as the volume of the organic phase.
[0069] The purification process involves dissolving the crude 5-bromo-2-chloro-4'-ethoxydiphenylmethane product in hot ethanol at 60-70°C, adding activated carbon, stirring and decolorizing for 10-30 minutes, filtering while hot, cooling the resulting filtrate to 0--5°C to precipitate a white solid, filtering and retaining the solid.
[0070] The molar ratio of 4-ethoxy-2'-chlorodiphenylmethane, the brominating reagent, and the catalyst is 1:(0.54~1.1):(0.03~0.08).
[0071] The catalyst C is one of aluminum chloride (AlCl3) and ferric chloride (FeCl3).
[0072] The solvent D is one of dichloromethane and chloroform.
[0073] The amount of solvent D used is 10 to 15 times the mass of 4-ethoxy-2'-chlorodiphenylmethane.
[0074] The amount of hot ethanol used is 5 to 10 times the mass of the crude product.
[0075] The amount of activated carbon used is 0.05 to 0.1 times the mass of the crude product.
[0076] The beneficial effects of this invention are as follows: The 5-bromo-2-chloro-4'-ethoxydiphenylmethane prepared by this invention has a total yield of 90.4-91.7% and an HPLC purity of 99.911-99.953%, exhibiting high yield and high purity.
[0077] This invention uses p-cresol as the initial raw material and proceeds through etherification, thioetherification, hydrodesulfurization, chlorination, and bromination to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The entire process does not use highly toxic or harmful substances such as AIBN and EDC. The catalysts used are conventional low-toxicity reagents such as aluminum chloride, ferric chloride, and palladium on carbon, significantly improving operational and environmental safety.
[0078] The post-processing of this invention is simple. The organic phases of each reaction step can be concentrated by simple washing and drying. The solvent can be recycled after recovery, which reduces solvent consumption and production costs, and reduces wastewater discharge. Attached Figure Description
[0079] Figure 1 This is a graph showing the liquid chromatography detection results of Example 1 of the present invention.
[0080] Figure 2 This is a graph showing the liquid chromatography detection results of Example 2 of the present invention.
[0081] Figure 3 This is a graph showing the liquid chromatography detection results of Example 3 of the present invention. Detailed Implementation
[0082] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be described in further detail below. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.
[0083] Example 1: A method for preparing a key intermediate of dapagliflozin Step 1: Preparation of 1-ethoxy-4-methylbenzene Dissolve p-cresol in ethanol, add sodium hydroxide, and stir to react.
[0084] Add bromoethane dropwise to the reaction system and maintain the temperature for the reaction.
[0085] The reaction system was cooled, washed with saturated brine, allowed to stand and separate into layers, and the upper organic phase was retained.
[0086] The organic phase was dried, and then distilled at atmospheric pressure. The fraction was collected to obtain 1-ethoxy-4-methylbenzene.
[0087] The molar ratio of p-cresol, sodium hydroxide, and bromoethane is 1:1.05:1.2, and the amount of ethanol used is 5 times the mass of p-cresol.
[0088] The stirring reaction was carried out at a stirring rate of 100 r / min, a reaction temperature of 55℃, and a reaction time of 1.5 h.
[0089] The heat preservation reaction: the heat preservation temperature is 60℃, and the reaction time is 5h.
[0090] Cooling: The reaction system is cooled to below 25°C.
[0091] The amount of saturated saline solution used is the same as the volume of the reaction solution.
[0092] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 30 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 20% of the weight of the organic phase.
[0093] The atmospheric distillation process involves fractions distilled at temperatures ranging from 196 to 198°C.
[0094] Step 2: Preparation of (4-ethoxybenzyl)phenyl sulfide Under nitrogen protection, 1-ethoxy-4-methylbenzene, thiophenol, base, catalyst ligand, solvent A, deionized water, and PEG-400 were added to the reactor, mixed evenly, and then palladium catalyst and oxidant were added. The mixture was then refluxed for 20 hours.
[0095] After the reaction solution cooled to room temperature, it was allowed to stand and separate into layers, yielding a lower aqueous phase containing palladium-TPPTS and an upper organic phase. The organic phase was extracted, dried, and concentrated under reduced pressure to obtain (4-ethoxybenzyl)phenyl sulfide. The lower aqueous phase containing palladium-TPPTS can be directly reused in the next step of preparing (4-ethoxybenzyl)phenyl sulfide.
[0096] The molar ratio of 1-ethoxy-4-methylbenzene, thiophenol, palladium catalyst, base, and oxidant is 1:1.2:0.05:1.5:1.2.
[0097] The alkali is potassium carbonate.
[0098] Solvent A is toluene.
[0099] The amount of solvent A used is 8 times the mass of 1-ethoxy-4-methylbenzene.
[0100] The amount of PEG-400 used is 3% of the mass of 1-ethoxy-4-methylbenzene.
[0101] The amount of deionized water used is 1 / 2 of the mass of solvent A.
[0102] The catalyst ligand is TPPTS.
[0103] The palladium catalyst is Pd(OAc)2.
[0104] The molar ratio of the catalyst ligand to the palladium catalyst is 2:1.
[0105] The oxidant is di-tert-butyl peroxide.
[0106] The reflux reaction is carried out at a temperature of 120°C.
[0107] The amount of ethyl acetate used is the same as the volume of the reaction solution.
[0108] Extraction: Add ethyl acetate, stir well, filter and collect the filtrate. Add an equal volume of saturated brine to the filtrate for washing, allow to stand and separate into layers, retaining the upper organic phase.
[0109] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 60 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 10% of the weight of the organic phase.
[0110] The vacuum concentration process involves controlling the temperature at 40°C and the vacuum degree at <-0.09MPa, distilling off the solvent and retaining the bottom liquid.
[0111] Step 3: Preparation of 1-benzyl-4-ethoxybenzene (4-ethoxybenzyl)phenyl sulfide, catalyst A, and solvent B were added to a high-pressure reactor and reacted under pressure in a hydrogen atmosphere.
[0112] The reaction solution was filtered to obtain a solid catalyst and a filtrate. The solid catalyst could be reused. Half the volume of the filtrate was added to an 8% sodium hydroxide solution, and the mixture was stirred for 15 minutes. After standing and separating into layers, the upper organic phase was retained. This upper organic phase was concentrated under reduced pressure to obtain a crude 1-benzyl-4-ethoxybenzene product. The lower sulfur-containing wastewater phase was added to a 10% available chlorine sodium hypochlorite solution and stirred for 30 minutes to completely oxidize the sulfur compounds to sulfates before being discharged into the wastewater treatment system.
[0113] The crude product was distilled under reduced pressure, and the fractions were retained and purified to obtain 1-benzyl-4-ethoxybenzene.
[0114] The pressurized reaction was carried out at a pressure of 3 MPa for 6 hours.
[0115] The vacuum concentration process involves controlling the temperature at 40°C and the vacuum degree at <-0.09MPa, distilling off the solvent and retaining the bottom liquid.
[0116] The vacuum distillation process involves controlling the vacuum level to be < -0.095 MPa and collecting the fraction at 160~162℃.
[0117] The refined fraction: Dissolve the fraction in hot ethanol at 70°C, add activated carbon, stir and decolorize for 10 min, and filter while hot; cool the filtrate to 0°C to precipitate a white solid, filter and retain the solid.
[0118] The mass ratio of (4-ethoxybenzyl)phenyl sulfide to catalyst is 1:0.05.
[0119] Catalyst A is palladium on carbon (Pd / C, 10% loading).
[0120] Solvent B is ethanol, and the amount of solvent B used is 10 times the mass of (4-ethoxybenzyl)phenyl sulfide.
[0121] The amount of hot ethanol used is 10 times the mass of the distillate.
[0122] The amount of activated carbon used is 0.1 times the mass of the distillate.
[0123] Step 4: Preparation of 4-ethoxy-2'-chlorodiphenylmethane 1-Benzyl-4-ethoxybenzene, catalyst B, and solvent C were added to the reactor, and the mixture was purged three times with nitrogen gas, with nitrogen protection throughout the process. The chlorination reaction was carried out under dark conditions.
[0124] After the reaction was completed, the mixture was filtered under normal pressure, and the filtrate was retained. The filtrate was washed to remove chlorine, yielding an organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 4-ethoxy-2'-chlorodiphenylmethane. The crude product was then purified by dissolving it in hot ethanol at 60°C, adding activated carbon, stirring and decolorizing for 30 min, and filtering while hot. The filtrate was cooled to 0°C, precipitating a white solid. The solid was filtered, retained, and dried to obtain 4-ethoxy-2'-chlorodiphenylmethane.
[0125] The chlorination reaction was carried out by adding NCS to the system in 5 batches and stirring continuously at a stirring rate of 50 r / min for a total feeding time of 2.5 h. After the feeding was completed, the reaction continued for 1.5 h while the reaction temperature was controlled at 0 °C.
[0126] The washing and dechlorination process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted NCS, followed by washing with saturated saline solution until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0127] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 60 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 20% of the weight of the organic phase.
[0128] The vacuum concentration process involves controlling the temperature at 40°C and the vacuum degree at <-0.09MPa, distilling off the solvent and retaining the bottom liquid.
[0129] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid.
[0130] The amount of saturated saline solution used is the same as the volume of the organic phase.
[0131] The molar ratio of 1-benzyl-4-ethoxybenzene, NCS, and catalyst B is 1:1.1:0.06.
[0132] The catalyst B is aluminum chloride.
[0133] The solvent C is dichloromethane.
[0134] The amount of solvent C used is 15 times the mass of 1-benzyl-4-ethoxybenzene.
[0135] The amount of hot ethanol used is 10 times the mass of the crude product.
[0136] The amount of activated carbon used is 0.1 times the mass of the crude product.
[0137] Step 5: Preparation of 5-bromo-2-chloro-4'-ethoxydiphenylmethane 4-Ethoxy-2'-chlorodiphenylmethane, solvent D, and catalyst C were added to the reactor, and the mixture was purged three times with nitrogen gas under nitrogen protection throughout the process. The bromination reaction was carried out under dark conditions.
[0138] After the reaction was completed, the mixture was filtered under normal pressure, and the filtrate was retained. The filtrate was washed to remove bromine, yielding an organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The crude product was then purified by dissolving it in hot ethanol at 60°C, adding activated carbon, stirring and decolorizing for 30 min, and filtering while hot. The filtrate was cooled to 0°C, precipitating a white solid. The solid was filtered, retained, and dried to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane.
[0139] The overall yield of 5-bromo-2-chloro-4'-ethoxydiphenylmethane was 90.4%, and the HPLC purity was 99.911%. The bromination reaction was carried out by adding NBS in 5 batches with equal amounts, while continuously stirring at a stirring rate of 50 r / min for a total feeding time of 2.5 h. After the feeding was completed, the reaction continued for 1.5 h while maintaining the reaction temperature at 0 °C.
[0140] The bromine removal process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted NBS, followed by washing with saturated brine until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0141] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 60 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 20% of the weight of the organic phase.
[0142] The vacuum concentration process involves controlling the temperature at 40°C and the vacuum degree at <-0.09MPa, distilling off the solvent and retaining the bottom liquid.
[0143] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid.
[0144] The amount of saturated saline solution used is the same as the volume of the organic phase.
[0145] The molar ratio of 4-ethoxy-2'-chlorodiphenylmethane, NBS, and catalyst C is 1:1.05:0.05.
[0146] The catalyst C is aluminum chloride.
[0147] The solvent D is dichloromethane.
[0148] The amount of solvent D used is 10 times the mass of 4-ethoxy-2'-chlorodiphenylmethane.
[0149] The amount of hot ethanol used is 5 times the mass of the crude product.
[0150] The amount of activated carbon used is 0.05 times the mass of the crude product.
[0151] Example 2: A method for preparing a key intermediate of dapagliflozin Step 1: Preparation of 1-ethoxy-4-methylbenzene Dissolve p-cresol in ethanol, add sodium hydroxide, and stir to react.
[0152] Diethyl carbonate was added dropwise to the reaction system, and the reaction was maintained at a constant temperature.
[0153] The reaction system was cooled, washed with saturated brine, allowed to stand and separate into layers, and the upper organic phase was retained.
[0154] The organic phase was dried, and then distilled at atmospheric pressure. The fraction was collected to obtain 1-ethoxy-4-methylbenzene.
[0155] The molar ratio of p-cresol, sodium hydroxide, and diethyl carbonate is 1:1.3:2, and the amount of ethanol used is 8 times the mass of p-cresol.
[0156] The stirring reaction was carried out at a stirring rate of 200 r / min, a reaction temperature of 75℃, and a reaction time of 1 h.
[0157] The heat preservation reaction was carried out at a temperature of 135℃, a pressure of 0.25MPa, and a reaction time of 7h.
[0158] Cooling: The reaction system is cooled to below 25°C.
[0159] The amount of saturated saline solution used is the same as the volume of the reaction solution.
[0160] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 60 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 10% of the weight of the organic phase.
[0161] The atmospheric distillation process involves fractions distilled at temperatures ranging from 196 to 198°C.
[0162] Step 2: Preparation of (4-ethoxybenzyl)phenyl sulfide Under nitrogen protection, 1-ethoxy-4-methylbenzene, thiophenol, base, catalyst ligand, solvent A, deionized water, and PEG-400 were added to the reactor and stirred until homogeneous. Then, palladium catalyst and oxidant were added, and the mixture was refluxed for 12 hours.
[0163] After the reaction solution cooled to the chamber, it was allowed to stand and separate into layers, yielding a lower aqueous phase containing palladium-TPPTS and an upper organic phase. The organic phase was extracted, dried, and concentrated under reduced pressure to obtain (4-ethoxybenzyl)phenyl sulfide. The lower aqueous phase containing palladium-TPPTS can be directly reused in the next step of preparing (4-ethoxybenzyl)phenyl sulfide.
[0164] The molar ratio of 1-ethoxy-4-methylbenzene, thiophenol, palladium catalyst, base, and oxidant is 1:1.1:0.08:1.5:1.1.
[0165] The alkali is cesium carbonate.
[0166] Solvent A is toluene.
[0167] The amount of solvent A used is 10 times the mass of 1-ethoxy-4-methylbenzene.
[0168] The amount of deionized water used is 1 / 3 of the mass of solvent A.
[0169] The amount of PEG-400 used is 5% of the mass of 1-ethoxy-4-methylbenzene.
[0170] The catalyst ligand is TPPTS.
[0171] The palladium catalyst is Pd2(dba)3 (tris(dibenzylacetylacetone)dipalladium).
[0172] The molar ratio of the catalyst ligand to the palladium catalyst is 1.5:1.
[0173] The oxidant is di-tert-butyl peroxide.
[0174] The reflux reaction is carried out at a temperature of 130°C.
[0175] The amount of ethyl acetate used is the same as the volume of the reaction solution.
[0176] Extraction: Add ethyl acetate, stir well, filter and collect the filtrate. Add an equal volume of saturated brine to the filtrate for washing, allow to stand and separate into layers, retaining the upper organic phase.
[0177] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 30 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 20% of the weight of the organic phase.
[0178] The vacuum concentration process involves controlling the temperature at 50°C and the vacuum degree at <-0.09MPa, distilling off the solvent and retaining the bottom liquid.
[0179] Step 3: Preparation of 1-benzyl-4-ethoxybenzene (4-ethoxybenzyl)phenyl sulfide, catalyst A, and solvent B were added to a high-pressure reactor and reacted under pressure in a hydrogen atmosphere.
[0180] The reaction solution was filtered to obtain a solid catalyst and a filtrate. The solid catalyst could be reused. Half the volume of the filtrate was added to an 8% sodium hydroxide solution, and the mixture was stirred for 15 minutes. After standing and separating into layers, the upper organic phase was retained. This upper organic phase was concentrated under reduced pressure to obtain a crude 1-benzyl-4-ethoxybenzene product. The lower sulfur-containing wastewater phase was added to a 10% available chlorine sodium hypochlorite solution and stirred for 30 minutes to completely oxidize the sulfur compounds to sulfates before being discharged into the wastewater treatment system.
[0181] The crude product was distilled under reduced pressure, and the fractions were retained and purified to obtain 1-benzyl-4-ethoxybenzene.
[0182] The pressurized reaction is controlled at a pressure of 2 MPa for a reaction time of 8 hours.
[0183] The vacuum concentration process involves controlling the temperature at 50°C and the vacuum degree at <-0.09MPa, evaporating the solvent, and retaining the remaining liquid.
[0184] The vacuum distillation process involves controlling the vacuum level to be < -0.095 MPa and collecting the fraction at 160~162℃.
[0185] The refined fraction: Dissolve the fraction in hot ethanol at 60°C, add activated carbon, stir and decolorize for 20 minutes, and filter while hot; cool the filtrate to 0°C to precipitate a white solid, filter and retain the solid.
[0186] The mass ratio of (4-ethoxybenzyl)phenyl sulfide to catalyst is 1:0.1.
[0187] Catalyst A is palladium on carbon (Pd / C, 10% loading).
[0188] Solvent B is methanol, and the amount of solvent B used is 15 times the mass of (4-ethoxybenzyl)phenyl sulfide.
[0189] The amount of hot ethanol used is 5 times the mass of the distillate.
[0190] The amount of activated carbon used is 0.05 times the mass of the distillate.
[0191] Step 4: Preparation of 4-ethoxy-2'-chlorodiphenylmethane 1-Benzyl-4-ethoxybenzene, catalyst B, and solvent C were added to the reactor, and the mixture was purged three times with nitrogen gas, with nitrogen protection throughout the process. The chlorination reaction was carried out under completely dark conditions.
[0192] After the reaction was completed, the mixture was filtered under normal pressure, and the filtrate was retained. The filtrate was washed to remove chlorine, yielding an organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 4-ethoxy-2'-chlorodiphenylmethane. The crude product was then purified by dissolving it in hot ethanol at 70°C, adding activated carbon, stirring and decolorizing for 10 min, and filtering while hot. The filtrate was cooled to -5°C, precipitating a white solid. The solid was filtered, retained, and dried to obtain 4-ethoxy-2'-chlorodiphenylmethane.
[0193] The chlorination reaction was carried out by adding tert-butyl hypochlorite dropwise to the system and stirring continuously at a stirring rate of 100 r / min for a total dropwise addition time of 3 h. After the dropwise addition was completed, the reaction was continued for 1 h at a controlled temperature of 0 °C.
[0194] The washing and dechlorination process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted tert-butyl hypochlorite, followed by washing with saturated saline solution until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0195] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 30 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 10% of the weight of the organic phase.
[0196] The vacuum concentration process involves controlling the temperature at 40°C and the vacuum degree at <-0.09MPa, distilling off the solvent, and retaining the remaining liquid.
[0197] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid.
[0198] The amount of saturated saline solution used is the same as the volume of the organic phase.
[0199] The molar ratio of 1-benzyl-4-ethoxybenzene, tert-butyl hypochlorite, and catalyst B is 1:1.03:0.03.
[0200] The catalyst B is ferric chloride (FeCl3).
[0201] The solvent C is dichloromethane.
[0202] The amount of solvent C used is 15 times the mass of 1-benzyl-4-ethoxybenzene.
[0203] The amount of hot ethanol used is 5 times the mass of the crude product.
[0204] The amount of activated carbon used is 0.05 times the mass of the crude product.
[0205] Step 5: Preparation of 5-bromo-2-chloro-4'-ethoxydiphenylmethane 4-Ethoxy-2'-chlorodiphenylmethane, solvent D, and catalyst C were added to the reactor, and the mixture was purged three times with nitrogen gas under nitrogen protection throughout the process. The bromination reaction was carried out under dark conditions.
[0206] After the reaction was completed, the mixture was filtered under normal pressure, and the filtrate was retained. The filtrate was washed to remove bromine, yielding an organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The crude product was then purified by dissolving it in hot ethanol at 60°C, adding activated carbon, stirring for decolorization for 30 min, and filtering while hot. The filtrate was cooled to 0°C, precipitating a white solid. This solid was filtered, retained, and dried to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The overall yield of 5-bromo-2-chloro-4'-ethoxydiphenylmethane was 90.8%, and the HPLC purity was 99.953%. The bromination reaction was carried out by adding dibromohydantoin to the system in 7 batches while continuously stirring at a stirring rate of 50 r / min for a total feeding time of 3.5 h. After the feeding was completed, the reaction continued for another 2.5 h while maintaining the reaction temperature at 0 °C.
[0207] The bromine removal process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted dibromohydantoin, followed by washing with saturated saline solution until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0208] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 30 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 10% of the weight of the organic phase.
[0209] The vacuum concentration process involves controlling the temperature at 40°C and the vacuum degree at <-0.09MPa, distilling off the solvent, and retaining the remaining liquid.
[0210] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid.
[0211] The amount of saturated saline solution used is the same as the volume of the organic phase.
[0212] The molar ratio of 4-ethoxy-2'-chlorodiphenylmethane, dibromohydantoin, and catalyst C is 1:0.54:0.03.
[0213] The catalyst C is ferric chloride.
[0214] The solvent D is dichloromethane.
[0215] The amount of solvent D used is 15 times the mass of 4-ethoxy-2'-chlorodiphenylmethane.
[0216] The amount of hot ethanol used is 5 times the mass of the crude product.
[0217] The amount of activated carbon used is 0.05 times the mass of the crude product.
[0218] Example 3: A method for preparing a key intermediate of dapagliflozin Step 1: Preparation of 1-ethoxy-4-methylbenzene Dissolve p-cresol in ethanol, add sodium hydroxide, and stir to react.
[0219] Add bromoethane dropwise to the reaction system and maintain the temperature for the reaction.
[0220] The reaction system was cooled, washed with saturated brine, allowed to stand and separate into layers, and the upper organic phase was retained.
[0221] The organic phase was dried, and then distilled at atmospheric pressure. The fraction was collected to obtain 1-ethoxy-4-methylbenzene.
[0222] The molar ratio of p-cresol, sodium hydroxide, and bromoethane is 1:1.1:1.15, and the amount of ethanol used is 5 times the mass of p-cresol.
[0223] The stirring reaction was carried out at a stirring rate of 400 r / min, a reaction temperature of 50℃, and a reaction time of 1.5 h.
[0224] The heat preservation reaction: the heat preservation temperature is 70℃, and the reaction time is 3h.
[0225] Cooling: The reaction system is cooled to below 25°C.
[0226] The amount of saturated saline solution used is the same as the volume of the reaction solution.
[0227] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 60 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 15% of the weight of the organic phase.
[0228] The atmospheric distillation process involves fractions distilled at temperatures ranging from 196 to 198°C.
[0229] Step 2: Preparation of (4-ethoxybenzyl)phenyl sulfide Under nitrogen protection, 1-ethoxy-4-methylbenzene, thiophenol, base, catalyst ligand, solvent A, deionized water, and PEG-400 were added to the reactor and stirred until homogeneous. Then, palladium catalyst and oxidant were added, and the mixture was refluxed for 24 hours.
[0230] After the reaction solution cooled to room temperature, it was allowed to stand and separate into layers, yielding a lower aqueous phase containing palladium-TPPTS and an upper organic phase. The organic phase was extracted, dried, and concentrated under reduced pressure to obtain (4-ethoxybenzyl)phenyl sulfide. The lower aqueous phase containing palladium-TPPTS can be directly reused in the next step of preparing (4-ethoxybenzyl)phenyl sulfide.
[0231] The molar ratio of 1-ethoxy-4-methylbenzene, thiophenol, palladium catalyst, base, and oxidant is 1:1.2:0.05:1.3:1.2.
[0232] The alkali is potassium phosphate.
[0233] Solvent A is 1,4-dioxane.
[0234] The amount of solvent A used is 10 times the mass of 1-ethoxy-4-methylbenzene.
[0235] The amount of deionized water used is 1 / 3 of the mass of solvent A.
[0236] The amount of PEG-400 used is 3% of the mass of 1-ethoxy-4-methylbenzene.
[0237] The catalyst ligand is TPPTS.
[0238] The palladium catalyst is Pd(OAc)2.
[0239] The molar ratio of the catalyst ligand to the palladium catalyst is 1.3:1.
[0240] The oxidant is benzoyl peroxide.
[0241] The reflux reaction is carried out at a temperature of 110°C.
[0242] The amount of ethyl acetate used is the same as the volume of the reaction solution.
[0243] Extraction: Add ethyl acetate, stir well, filter and collect the filtrate. Add an equal volume of saturated brine to the filtrate for washing, allow to stand and separate into layers, retaining the upper organic phase.
[0244] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 60 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 20% of the weight of the organic phase.
[0245] The vacuum concentration process involves controlling the temperature at 50°C and the vacuum degree at <-0.09MPa, evaporating the solvent, and retaining the remaining liquid.
[0246] Step 3: Preparation of 1-benzyl-4-ethoxybenzene (4-ethoxybenzyl)phenyl sulfide, catalyst A, and solvent B were added to a high-pressure reactor and reacted under pressure in a hydrogen atmosphere.
[0247] The reaction solution was filtered to obtain a solid catalyst and a filtrate. The solid catalyst could be reused. Half the volume of the filtrate was added to an 8% sodium hydroxide solution, and the mixture was stirred for 30 minutes. After standing and separating into layers, the upper organic phase was retained. This upper organic phase was concentrated under reduced pressure to obtain a crude 1-benzyl-4-ethoxybenzene product. The lower sulfur-containing wastewater phase was added to a 10% available chlorine sodium hypochlorite solution and stirred for 30 minutes to completely oxidize the sulfur compounds to sulfates before being discharged into the wastewater treatment system.
[0248] The crude product was distilled under reduced pressure, and the fractions were retained and purified to obtain 1-benzyl-4-ethoxybenzene.
[0249] The pressurized reaction is controlled at a pressure of 1 MPa for a reaction time of 10 hours.
[0250] The vacuum concentration process involves controlling the temperature at 50°C and the vacuum degree at <-0.09MPa, evaporating the solvent, and retaining the remaining liquid.
[0251] The vacuum distillation process involves controlling the vacuum level to be < -0.095 MPa and collecting the fraction at 160~162℃.
[0252] The refined fraction: Dissolve the fraction in hot ethanol at 60°C, add activated carbon, stir and decolorize for 30 minutes, and filter while hot; cool the filtrate to -5°C to precipitate a white solid, filter and retain the solid.
[0253] The mass ratio of (4-ethoxybenzyl)phenyl sulfide to catalyst is 1:0.1.
[0254] Catalyst A is Raney nickel.
[0255] Solvent B is ethyl acetate, and the amount of solvent B used is 15 times the mass of (4-ethoxybenzyl)phenyl sulfide.
[0256] The amount of hot ethanol used is 5 times the mass of the distillate.
[0257] The amount of activated carbon used is 0.05 times the mass of the distillate.
[0258] Step 4: Preparation of 4-ethoxy-2'-chlorodiphenylmethane 1-Benzyl-4-ethoxybenzene, catalyst B, and solvent C were added to the reactor, and the mixture was purged three times with nitrogen gas, with nitrogen protection throughout the process. The chlorination reaction was carried out under dark conditions.
[0259] After the reaction was completed, the reaction solution was filtered under normal pressure, and the filtrate was retained. The filtrate was washed to remove chlorine, yielding an organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 4-ethoxy-2'-chlorodiphenylmethane. The crude product was then purified by dissolving it in hot ethanol at 60°C, adding activated carbon, stirring and decolorizing for 30 min, and filtering while hot. The filtrate was cooled to 0°C, precipitating a white solid. The solid was filtered, retained, and dried to obtain 4-ethoxy-2'-chlorodiphenylmethane.
[0260] The chlorination reaction was carried out by adding dichlorohydantoin to the system in 8 batches and stirring continuously at a stirring rate of 200 r / min for a total feeding time of 4 hours. After the feeding was completed, the reaction continued for 3 hours, and the reaction temperature was controlled at 5°C.
[0261] The washing and dechlorination process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted dichlorohydantoin, followed by washing with saturated saline solution until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0262] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 30 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 20% of the weight of the organic phase.
[0263] The vacuum concentration process involves controlling the temperature at 30°C and the vacuum degree at <-0.09MPa, distilling off the solvent, and retaining the remaining liquid.
[0264] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid.
[0265] The amount of saturated saline solution used is the same as the volume of the organic phase.
[0266] The molar ratio of 1-benzyl-4-ethoxybenzene, dichlorohydantoin, and catalyst B is 1:0.54:0.03.
[0267] Catalyst B is ferric chloride.
[0268] The solvent C is chloroform.
[0269] The amount of solvent C used is 10 times the mass of 1-benzyl-4-ethoxybenzene.
[0270] The amount of hot ethanol used is 5 times the mass of the crude product.
[0271] The amount of activated carbon used is 0.05 times the mass of the crude product.
[0272] Step 5: Preparation of 5-bromo-2-chloro-4'-ethoxydiphenylmethane 4-Ethoxy-2'-chlorodiphenylmethane, solvent D, and catalyst C were added to the reactor, and the mixture was purged three times with nitrogen gas under nitrogen protection throughout the process. The bromination reaction was carried out under dark conditions.
[0273] After the reaction was completed, the mixture was filtered under normal pressure, and the filtrate was retained. The filtrate was washed to remove bromine, yielding an organic phase. The organic phase was dried and concentrated under reduced pressure to obtain crude 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The crude product was purified by dissolving it in hot ethanol at 70°C, adding activated carbon, stirring and decolorizing for 10 min, and filtering while hot. The filtrate was cooled to 0°C, and a white solid precipitated. The solid was filtered, retained, and dried to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane.
[0274] The overall yield of 5-bromo-2-chloro-4'-ethoxydiphenylmethane was 91.7%, and the HPLC purity was 99.951%.
[0275] The bromination reaction was carried out by adding a diluted tetrabutylammonium tribromide solution dropwise into the reactor and stirring continuously at a stirring rate of 200 r / min for 2 hours. After the addition was completed, the reaction was kept at a constant temperature for 1 hour, with the reaction temperature controlled at 5°C.
[0276] The diluent for tetrabutylammonium tribromide is prepared by dissolving tetrabutylammonium tribromide in solvent D, wherein the mass ratio of tetrabutylammonium tribromide to solvent D is 1:2.
[0277] The bromine removal process involves adding a saturated sodium sulfite solution to the reaction solution for washing to quench unreacted tetrabutylammonium tribromide, followed by washing with saturated brine until neutral, and allowing the solution to stand and separate into layers to retain the organic phase.
[0278] Add saturated saline solution to the organic phase and wash until the pH of the aqueous phase is neutral. Let it stand again to separate the layers, keeping the organic phase.
[0279] The washing process involves adding saturated saline solution to the organic phase and washing until the pH of the aqueous phase is neutral.
[0280] The drying process involves adding anhydrous magnesium sulfate to the organic phase, sealing and stirring for 30 minutes, and then filtering to remove the anhydrous magnesium sulfate. The amount of anhydrous magnesium sulfate used is 20% of the weight of the organic phase.
[0281] The vacuum concentration process involves controlling the temperature at 30°C and the vacuum degree at <-0.09MPa, distilling off the solvent, and retaining the remaining liquid.
[0282] The amount of saturated sodium sulfite solution used is the same as the volume of the reaction liquid.
[0283] The amount of saturated saline solution used is the same as the volume of the organic phase.
[0284] The molar ratio of 4-ethoxy-2'-chlorodiphenylmethane, tetrabutylammonium tribromide, and catalyst C is 1:1.1:0.08.
[0285] The catalyst C is ferric chloride.
[0286] The solvent D is chloroform.
[0287] The amount of solvent D used is 10 times the mass of 4-ethoxy-2'-chlorodiphenylmethane.
[0288] The amount of hot ethanol used is 10 times the mass of the crude product.
[0289] The amount of activated carbon used is 0.1 times the mass of the crude product.
[0290] Obviously, there are many other possible implementation methods under the concept of this invention. It should be stated here that any changes made under the inventive concept of this invention will fall within the protection scope of this invention.
Claims
1. A method for preparing a key intermediate of dapagliflozin, characterized in that, Includes the following steps: Step 1: Dissolve p-cresol in ethanol, add sodium hydroxide and stir to react, add ethylating reagent dropwise and keep the reaction at a constant temperature, dry the obtained organic phase and distill under normal pressure to obtain 1-ethoxy-4-methylbenzene; the ethylating reagent is diethyl carbonate or bromoethane; Step 2: Under nitrogen protection, 1-ethoxy-4-methylbenzene, thiophenol, base, catalyst ligand, solvent A, water, PEG-400, palladium catalyst, and oxidant are refluxed for 12-24 hours to obtain (4-ethoxybenzyl)phenyl sulfide. Step 3: (4-ethoxybenzyl)phenyl sulfide, catalyst A, and solvent B are reacted under pressure in a hydrogen atmosphere to obtain 1-benzyl-4-ethoxybenzene; the catalyst A is palladium on carbon or Raney nickel; Step 4: Add 1-benzyl-4-ethoxybenzene, catalyst B, and solvent C to the reactor. Under nitrogen protection and light-free conditions, add a chlorination reagent to carry out a chlorination reaction to obtain 4-ethoxy-2'-chlorodiphenylmethane. The chlorination reagent is one of N-chlorosuccinimide, tert-butyl hypochlorite, and dichlorohydantoin. Step 5: Add 4-ethoxy-2'-chlorodiphenylmethane, solvent D, and catalyst C to the reactor. Under nitrogen protection and light-free conditions, add a brominating reagent to carry out a bromination reaction to obtain 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The brominating reagent is one of N-bromosuccinimide, dibromohydantoin, and tetrabutylammonium tribromide.
2. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, The stirring reaction in step 1: the stirring rate is 100~400 r / min, the reaction temperature is 50~75℃, and the reaction time is 1~1.5h; the heat preservation reaction: the heat preservation temperature is 60~140℃, and the reaction time is 3~7h.
3. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, In step 1, the molar ratio of p-cresol, sodium hydroxide, and ethylating agent is 1:(1.05~1.3):(1.15~2), and the amount of ethanol used is 5~8 times the mass of p-cresol.
4. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, In step 2, solvent A is one of toluene and 1,4-dioxane, and the amount of solvent A is 8 to 10 times the mass of 1-ethoxy-4-methylbenzene; the oxidant is di-tert-butyl peroxide or benzoyl peroxide.
5. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, The alkali mentioned in step 2 is one of potassium carbonate, cesium carbonate, and potassium phosphate; the catalyst ligand is sodium triphenylphosphine tris(m-sulfonate); the palladium catalyst is palladium acetate or tris(dibenzylacetone)dipalladium; and the molar ratio of the catalyst ligand to the palladium catalyst is (1.3~2):
1.
6. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, The molar ratio of 1-ethoxy-4-methylbenzene, thiophenol, palladium catalyst, base, and oxidant in step 2 is 1:(1.1~1.2):(0.05~0.08):(1.3~1.5):(1.1~1.2).
7. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, In step 2, the amount of PEG-400 used is 3-5% of the mass of 1-ethoxy-4-methylbenzene; the amount of water used is 1 / 3 to 1 / 2 of the mass of solvent A; the reflux reaction is carried out at a temperature of 110-130℃.
8. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, The pressurized reaction described in step 3 is controlled at a pressure of 1-3 MPa for a reaction time of 6-10 hours.
9. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, The chlorination reaction described in step 4: the reaction temperature is controlled at 0~5℃; the molar ratio of 1-benzyl-4-ethoxybenzene, chlorination reagent, and catalyst is 1:(0.54~1.1):(0.03~0.06); The catalyst B is one of aluminum chloride and ferric chloride; The solvent C is one of dichloromethane and chloroform; The amount of solvent C used is 10 to 15 times the mass of 1-benzyl-4-ethoxybenzene.
10. The method for preparing a key intermediate of dapagliflozin according to claim 1, characterized in that, The bromination reaction described in step 5: the reaction temperature is controlled at 0~5℃; the molar ratio of 4-ethoxy-2'-chlorodiphenylmethane, the brominating reagent, and the catalyst is 1:(0.54~1.1):(0.03~0.08); The catalyst C is one of aluminum chloride and ferric chloride; The solvent D is one of dichloromethane and chloroform; The amount of solvent D used is 10 to 15 times the mass of 4-ethoxy-2'-chlorodiphenylmethane.