Synthetic method and application of dapagliflozin intermediate
By using BTC as the acid chloride reagent and NaBH4/AlCl3 system for carbonyl reduction, the production cost and "three wastes" of dapagliflozin intermediate synthesis were successfully reduced, and the problem of high price of oxalyl chloride in the existing methods was solved, and efficient and economical intermediate synthesis was achieved.
Patent Information
- Application Number
- CN202510297917.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-13
- Publication Date
- 2025-06-17
AI Technical Summary
In the existing synthesis methods of dapagliflozin intermediates, the use of higher-priced oxalyl chloride as the acid chloride reagent, resulting in high production costs and urgently needs to improve the synthesis method.
Bis(trichloromethyl)carbonate (BTC) was used as the acyl chloride reagent, and the carbonyl reduction of the NaBH4/AlCl3 system was successfully synthesized by the acyl chloride and Fuke acylation reaction.
It reduces the cost of reagents, reduces the amount of NaBH4 and AlCl3, reduces the amount of "three wastes" in the industry, improves the yield and purity of the synthesis route, and lays the foundation for the industrial production of dapagliflozin.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of preparation of dapagliflozin intermediates, and specifically to a method for synthesizing and applying a dapagliflozin intermediate. Background Art
[0002] With the in-depth study of the pathology of diabetes, researchers have found that by highly selectively inhibiting SGLT2 (sodium-glucose cotransporter 2) on renal tubules, the reabsorption of glucose can be effectively inhibited, thereby balancing the intake and metabolism of glucose, achieving the effect of effectively controlling blood sugar, with few side effects and safe to take. Currently, SGLT2 inhibitors sold on the market include canagliflozin, dapagliflozin, ipragliflozin, empagliflozin, luseogliflozin, and tofogliflozin, etc. SGLT2 inhibitors have set off a new research upsurge at home and abroad with their unique and effective mechanism of action and have broad market prospects. Dapagliflozin is the world's first approved SGLT2 inhibitor, and other marketed SGLT2 inhibitors are basically developed from it as a lead compound through structural modification research.
[0003] Dapagliflozin is a C-aryl glycoside SGLT2 inhibitor jointly developed by Bristol-Myers Squibb Company and AstraZeneca Company, with CAS number 461432-26-8, molecular formula C 21 H 25 ClO6, relative molecular mass 408.9, and chemical name (2R,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
[0004] Many raw materials are used in the synthesis of dapagliflozin. 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene is the key intermediate for synthesizing dapagliflozin. However, in the existing method for synthesizing 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene, expensive oxalyl chloride is used as an acyl chlorination reagent, resulting in high production costs and an urgent need to improve the synthesis method of 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene. Summary of the Invention
[0005] The purpose of the present invention is to provide a method for synthesizing a dapagliflozin intermediate to solve the problems raised in the above background art.
[0006] To achieve the above purpose, the present invention provides the following technical solutions:
[0007] A method for synthesizing a dapagliflozin intermediate, the specific steps are as follows:
[0008] Synthesis of 2-chloro-5-bromobenzoyl chloride: 0.2 - 0.24 mol of 2-chloro-5-bromobenzoic acid, 140 - 160 mL of 1,2-dichloroethane, 60 - 67 g of bis(trichloromethyl) carbonate (BTC) and a catalyst were heated to reflux for 2.5 - 3.5 hours. After the reaction was completed, it was naturally cooled to obtain a yellow 2-chloro-5-bromobenzoyl chloride solution;
[0009] Synthesis of 2-chloro-5-bromo-4'-ethoxydibenzoyl ketone: 16 - 17 g of phenetole and 90 - 110 mL of 1,2-dichloroethane were mixed evenly. At room temperature, 62 - 62.5 g of aluminum trichloride was added thereto, and the mixture was stirred and 2-chloro-5-bromobenzoyl chloride solution was added dropwise. After the reaction was completed, it was poured into ice water for quenching. The organic solvent was recovered by atmospheric distillation, then extracted with dichloromethane, and the dichloromethane was recovered by atmospheric distillation. The residue was crystallized with an aqueous methanol solution to obtain white solid 2-chloro-5-bromo-4'-ethoxydibenzoyl ketone;
[0010] Synthesis of 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene: 140 - 160 mL of tetrahydrofuran (THF), 27 - 28 g of aluminum trichloride, 12 - 12.5 g of sodium borohydride and 48 - 53 g of 2-chloro-5-bromo-4'-ethoxydibenzoyl ketone were added at 0 °C. The mixture was stirred and heated to reflux for 1.6 - 2.5 hours. After the reaction was completed, hydrochloric acid was added to quench the reaction. The organic solvent was recovered by atmospheric distillation, then extracted with ethyl acetate, and the ethyl acetate was recovered by atmospheric distillation. The residue was crystallized with an aqueous methanol solution to obtain white solid 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene.
[0011] As a further scheme of the present invention: The catalyst is DMF (N,N-dimethylformamide), and the mass of DMF is 4 g.
[0012] As a further scheme of the present invention: The synthesis of 2-chloro-5-bromobenzoyl chloride is carried out in a 250 mL three-necked flask, and the syntheses of 2-chloro-5-bromo-4'-ethoxydibenzoyl ketone and 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene are both carried out in a 500 mL three-necked flask.
[0013] As a further scheme of the present invention: TLC detection is used to determine the completion of the reaction. TLC detection is thin layer chromatography, which is a very important experimental technique for the rapid separation and qualitative analysis of small amounts of substances and is also used to track the reaction process.
[0014] As a further scheme of the present invention: The concentration of hydrochloric acid during the quenching reaction is 3 mol / L.
[0015] As a further scheme of the present invention: The mass fraction of the aqueous methanol solution is 50%.
[0016] The present invention also relates to the use of the intermediate of dapagliflozin obtained by the above synthesis method for protecting dapagliflozin in the synthesis process.
[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: In the existing methods, oxalyl chloride is used as the acyl chlorination reagent for 2-chloro-5-bromobenzoic acid. However, for industrial production, although the operation using oxalyl chloride is relatively simple, its price is relatively expensive. The present invention uses inexpensive BTC as the acyl chlorination reagent, which greatly reduces the reagent cost. At the same time, the usage amounts of NaBH4 and AlCl3 in the carbonyl reduction are reduced, further reducing the reagent cost and the amount of "three wastes" in industry, laying a foundation for the industrial production of the intermediate of dapagliflozin. The reaction in each step has a relatively high yield, reducing the production cost of enterprises. Detailed implementation mode
[0018] The technical solutions of this patent will be further described in detail below in conjunction with the specific implementation modes.
[0019] The present invention uses 2-chloro-5-bromobenzoic acid as the starting material. After acyl chlorination and subsequent Friedel-Crafts acylation reaction with phenetole, 2-chloro-5-bromo-4'-ethoxydiphenyl ketone is obtained. The carbonyl group of 2-chloro-5-bromo-4'-ethoxydiphenyl ketone is reduced using the NaBH4 / AlCl3 system to obtain the target product 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene.
[0020] Example 1
[0021] A method for synthesizing the intermediate of dapagliflozin, the specific steps are as follows: Synthesis of 2-chloro-5-bromobenzoyl chloride: Take a 250 mL three-necked flask, and successively add 0.212 mol of 2-chloro-5-bromobenzoic acid, 150 mL of 1,2-dichloroethane, 63 g of bis(trichloromethyl) carbonate, and 4 g of the catalyst DMF. Heat to reflux for 3 hours. After detecting the reaction is complete by TLC, cool naturally to obtain a yellow solution of 2-chloro-5-bromobenzoyl chloride. The synthesis route is as follows:
[0022] Synthesis of 2-chloro-5-bromo-4'-ethoxydiphenyl ketone: Take a 500 mL three-necked flask, and successively add 16.5 g of phenetole and 100 mL of 1,2-dichloroethane. Stir mechanically to make the mixture uniform. At room temperature, add 62.2 g of aluminum trichloride thereto, stir and dropwise add the 2-chloro-5-bromobenzoyl chloride solution. After detecting the reaction is complete by TLC, pour it into ice water for quenching. Recover the organic solvent by atmospheric distillation, then extract with dichloromethane, recover dichloromethane by atmospheric distillation, and crystallize the residue with a 50% methanol aqueous solution to obtain white solid 2-chloro-5-bromo-4'-ethoxydiphenyl ketone, with a weight of 54.3 g and a yield of 75.0%. The synthesis route is as follows:
[0023] Synthesis of 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene: Take a 500 mL three-necked flask, add 150 mL of tetrahydrofuran (THF), 27.4 g of aluminum trichloride, 12.2 g of sodium borohydride, and 50 g of 2-chloro-5-bromo-4'-ethoxydibenzophenone at 0 °C, stir and heat to reflux for 2 hours. After detecting the completion of the reaction by TLC, quench the reaction with 3 mol / L hydrochloric acid, recover the organic solvent by atmospheric distillation, then extract with ethyl acetate, recover ethyl acetate by atmospheric distillation, and crystallize the residue with a 50% methanol aqueous solution to obtain 42.3 g of white solid 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene, with a yield of 86.8%. The synthesis route is as follows:
[0024] When synthesizing 2-chloro-5-bromobenzoyl chloride, all the reported literatures currently use oxalyl chloride as the acyl chlorination reagent for 2-chloro-5-bromobenzoic acid. However, for industrial production, although the operation with oxalyl chloride is relatively simple, its price is relatively expensive. To reduce the production cost of enterprises, in this paper, inexpensive BTC is used as the acyl chlorination reagent, and the reaction also has a high yield. At the same time, the solvent and temperature are also explored.
[0025] 1.1 Influence of reaction solvent on the reaction
[0026] Using 2-chloro-5-bromobenzoic acid as the starting material, taking 1.0 equivalent of the acyl chlorination reagent bis(trichloromethyl) carbonate (BTC) and 20% molar ratio of the catalyst DMF as the reference dosage, explore the influence of different solvents on the reaction results at the reflux temperature, and screen out the optimal reaction solvent. The reaction results are shown in Table 1.
[0027] Table 1 Influence of reaction solvent on the reaction
[0028]
[0029] It can be seen from Table 1 that BTC is an acyl chlorination reagent that requires a high activation energy, so a relatively high temperature is required for the reaction to be complete. Dichloromethane is a low-boiling solvent (boiling point 39.8 °C), and the reaction rate is slow, resulting in too long reaction time. Toluene, chlorobenzene, and 1,2-dichloroethane have higher boiling points, and the reactions can all be completed in a relatively short time. However, it is very difficult to remove toluene completely when recovering the solvent toluene in the acyl chlorination reaction involving toluene, resulting in side products involving toluene in the Friedel-Crafts acylation reaction, reducing the yield, and the side products are difficult to separate, resulting in a decrease in the purity of the product; at the same time, both toluene and chlorobenzene are high-boiling solvents, and compared with 1,2-dichloroethane, the energy consumption is larger during recovery. Considering the above factors, 1,2-dichloroethane is selected as the preferred solvent for this step of the reaction.
[0030] 1.2 Influence of Reaction Temperature on the Reaction
[0031] Using 2-chloro-5-bromobenzoic acid as the raw material, 1,2-dichloroethane as the solvent, 1.0 equivalent of the acyl chlorination reagent BTC, and 20% molar ratio of the catalyst DMF as the reference dosage, the influence of different temperatures on the reaction was explored, and the reaction results are shown in Table 2.
[0032] Table 2 Influence of Reaction Temperature on the Reaction
[0033]
[0034] As can be seen from Table 2, the reaction time gradually shortens with the increase of the reaction temperature. When the temperature rises to 78 °C, the reaction time is the shortest, and further increasing the temperature has no obvious effect on the reaction time. Therefore, 78 °C is selected as the preferred temperature for this step of the reaction.
[0035] When synthesizing 2-chloro-5-bromo-4'-ethoxydibenzoyl ketone, a large amount of experimental data shows that when 2-chloro-5-bromobenzoyl chloride undergoes a Friedel-Crafts acylation reaction with phenetole, affected by thermodynamic factors, both the para-substituted product 2-chloro-5-bromo-4'-ethoxydibenzoyl ketone and the ortho-substituted product will be formed simultaneously. The reaction formula is as follows: In the reaction formula, 13 is the para-substituted product and 33 is the ortho-substituted product. In the present invention, the influence of three factors, namely the type of catalyst, reaction temperature, and crystallization solvent, on the reaction yield will be investigated.
[0036] 2.1 Influence of Catalyst Type on the Reaction
[0037] The yield of the Friedel-Crafts acylation reaction is affected by various factors. Next, this article will explore the influence of different catalysts on the reaction results, and the reaction results are shown in Table 3.
[0038] Table 3 Influence of Different Catalysts on the Reaction
[0039]
[0040] As can be seen from Table 3, when using iron(III) chloride and zinc trifluoromethanesulfonate to replace aluminum chloride to catalyze the Friedel-Crafts acylation reaction, the yield is even lower. Moreover, zinc trifluoromethanesulfonate requires a higher reaction temperature to produce products, and new impurities will also be generated. Therefore, it is more appropriate to use AlCl3 as the catalyst here.
[0041] 2.2 Influence of Reaction Temperature on Selectivity and Yield
[0042] Since the ortho-para selectivity of the Friedel-Crafts acylation reaction product is greatly affected by thermodynamic factors, the influence of reaction temperature on selectivity and yield will be explored here, and the reaction results are shown in Table 4.
[0043] Table 4 Effects of reaction temperature on selectivity and yield
[0044]
[0045] a: Ratio of ortho- and para-products (determined by HPLC); b: Crystallized and purified with 50% aqueous methanol solution by mass
[0046] As can be seen from Table 4, with the continuous decrease of the reaction temperature, the proportion of the para-product in the Friedel-Crafts acylation reaction increases continuously, and the yield also increases continuously. However, when the temperature rises from 5 °C to 20 °C, the reaction selectivity improves. Further increasing the temperature has little effect on the selectivity and yield. Considering the energy consumption problem in enterprise production, 25 °C is selected as the optimal temperature for this reaction.
[0047] 2.3 Effects of crystallization solvent on yield and purity
[0048] Controlled the mass ratio of the crystallization solvent to 2-chloro-5-bromo-4'-ethoxydibenzophenone to be 1:1, and explored the effect of the crystallization solvent on the reaction yield. The reaction results are shown in Table 5.
[0049] Table 5 Effects of crystallization solvent on product yield and purity
[0050]
[0051] a: Ratio of ortho- and para-products (determined by HPLC); b: Crystallized and purified with 50% aqueous methanol solution by mass
[0052] As can be seen from Table 5, the product has relatively high solubility in both ethanol and methanol. Using them directly as the crystallization solvent will cause a large amount of loss. In comparison, methanol has a slight advantage over ethanol. According to the detection, the product has poor solubility in water. Therefore, it is considered to mix methanol and water in different ratios as the crystallization solvent. The experimental results show that the crystallization effect of 50% aqueous methanol solution by mass is the best, and the yield and purity of the product are relatively high, 67.9% and 98.9% respectively. With the continuous decrease of the methanol content, although the yield can be slightly increased, the purity decreases significantly. Therefore, 50% aqueous methanol solution by mass is selected as the ideal crystallization solvent here.
[0053] The reaction formula for synthesizing 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene is as follows: During the experimental process, TLC detection showed that the reaction would generate the intermediate diaryl alcohol (34 in the reaction formula), but as the reaction continued, it would gradually disappear and generate 14 in the reaction formula. Next, this article will explore the feed ratio, crystallization solvent, and feeding order.
[0054] 3.1 Effects of feed ratio on yield
[0055] This process follows the synthesis method in the literature and uses the NaBH4 / AlCl3 system as the reduction system. At the reflux temperature, the diaryl ketone compound is reduced to the diarylmethane compound. However, a large amount of NaBH4 / AlCl3 was used for reduction in the literature, which would generate more three wastes. To make the synthesis process more environmentally friendly, the present invention investigated its feed ratio, and the reaction results are shown in Table 6.
[0056] Table 6 Influence of feed ratio on yield
[0057]
[0058] a: Crystallized and purified by 50% MeOH aqueous solution in mass fraction
[0059] As can be seen from Table 6, when the feed amount of AlCl3 is in the range of 0.7 - 1 equivalent, the yield has no obvious change. However, when it drops to 0.6 equivalent, the yield significantly decreases, possibly because the insufficient amount of AlCl3 causes the reaction to stay in the transition state and not convert to the product. Therefore, it is more appropriate to select 0.8 equivalent for the feed amount of AlCl3. Similarly, when the feed amount of NaBH4 is in the range of 2.0 - 2.2 equivalents, the yield has no obvious change. However, when it drops to 1.0 equivalent, there are a small amount of raw materials, intermediate diaryl alcohol, and products in the system, making it difficult to separate and purify. Therefore, here n(13):n(NaBH4):n(AlCl3) = 1:2:0.8 is selected as the preferred feed ratio.
[0060] 3.2 Influence of crystallization solvent on yield and purity
[0061] Compound 14 in the reaction formula is a low-melting compound (melting point 40.1 - 41.6 °C). Even slightly containing impurities, it appears as a colorless liquid and is difficult to crystallize. Therefore, here different crystallization solvents are considered and tried for its purification. The mass ratio of the crystallization solvent to compound 14 in the reaction formula is controlled at 1:1 to explore the influence of the crystallization solvent on the reaction yield. The reaction results are shown in Table 7.
[0062] Table 7 Influence of crystallization solvent on product yield and purity
[0063]
[0064] a: Crystallized and purified by 50% MeOH aqueous solution in mass fraction
[0065] As can be seen from Table 7, the product has relatively high solubility in both ethanol and methanol. Using them directly as crystallization solvents would cause significant losses. In comparison, methanol has a slight advantage over ethanol. According to the detection, the product has poor solubility in water. Therefore, it was considered to mix methanol and water in different ratios as the crystallization solvent. The experimental results showed that the crystallization effect of the 50% MeOH aqueous solution was the best, with relatively high yields and purities of the product, which were 88.7% and 99.1% respectively. If the proportion of methanol was further decreased, emulsification would occur in the system, making it difficult to crystallize. Therefore, the 50% MeOH aqueous solution was selected as the ideal crystallization solvent here.
[0066] 3.3 Influence of the feeding sequence on the reaction
[0067] Based on past experience, different feeding sequences may affect the reaction results. Therefore, in this paper, an attempt was made to investigate the following three feeding methods, and the reaction results are shown in Table 8.
[0068] Table 8 Influence of the feeding sequence on the reaction time and yield
[0069]
[0070] As can be seen from Table 8, from the perspective of the yield, there is no obvious difference among the three feeding sequences. However, the reaction time of the second feeding method is slightly shorter, probably because when AlCl3 and NaBH4 come into contact, a part of Al(BH4)3 with stronger reducing ability is formed, which has a slightly accelerating effect on the reaction.
[0071] The present invention designs a method for synthesizing 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene. Starting from 2-chloro-5-bromobenzoic acid, through BTC acyl chlorination, Friedel-Crafts acylation reaction with phenetole, and then carbonyl reduction, 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene can be obtained. The synthesis reaction formula is as follows: 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene then undergoes butyllithium bromine exchange, nucleophilic addition with hydroxy-protected D-glucono-1,5-lactone, followed by hydroxy methyl etherification and dehydroxy protection reaction, demethoxy reduction, and finally co-crystallization with (S)-propylene glycol to obtain dapagliflozin. The synthesis reaction formula is as follows: The total yield of dapagliflozin reaches 30.8%, and the HPLC purity can reach 99.8%. This process does not require chiral resolution, shortening the reaction steps; using BTC to replace the relatively expensive oxalyl chloride as the acyl chlorination reagent greatly reduces the reagent cost. At the same time, the usage amounts of NaBH4 and AlCl3 in the carbonyl reduction are reduced, further reducing the reagent cost and the amount of "three wastes" in industry, laying a foundation for the industrial production of dapagliflozin.
[0072] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-mentioned exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention.
[0073] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
1. A method for synthesizing a dapagliflozin intermediate, characterized in that: The specific steps are as follows: Synthesis of 2-chloro-5-bromobenzoyl chloride: 0.2-0.24 mol of 2-chloro-5-bromobenzoic acid, 140-160 mL of 1,2-dichloroethane, 60-67 g of bis(trichloromethyl) carbonate and a catalyst are heated to reflux for reaction for 2.5-3.5 hours, and cooled naturally after the reaction is completed to obtain a yellow 2-chloro-5-bromobenzoyl chloride solution; Synthesis of 2-chloro-5-bromo-4'-ethoxybenzophenone: 16-17 g of phenethyl ether and 90-110 mL of 1,2-dichloroethane were mixed evenly, 62-62.5 g of aluminum chloride was added thereto at room temperature, the mixture was stirred and a 2-chloro-5-bromobenzoyl chloride solution was added dropwise, after the reaction was completed, the mixture was poured into ice water for quenching, the organic solvent was recovered by atmospheric distillation, and then the mixture was extracted with dichloromethane, and the dichloromethane was recovered by atmospheric distillation. The residue was crystallized with a methanol aqueous solution to obtain 2-chloro-5-bromo-4'-ethoxybenzophenone as a white solid; Synthesis of 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene: 140-160 mL of tetrahydrofuran (THF), 27-28 g of aluminum chloride, 12-12.5 g of sodium borohydride and 48-53 g of 2-chloro-5-bromo-4'-ethoxybenzophenone were added at 0 degrees Celsius, stirred and refluxed at high temperature for 1.6-2.5 hours, and after the reaction was completed, hydrochloric acid was added to quench the reaction, and the organic solvent was recovered by atmospheric distillation, and then extracted with ethyl acetate, and ethyl acetate was recovered by atmospheric distillation. The residue was crystallized with methanol aqueous solution to obtain 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene as a white solid.
2. The method for synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The catalyst is DMF, and the mass of DMF is 4 g.
3. The method for synthesizing a dapagliflozin intermediate according to claim 1 or 2, characterized in that: The synthesis of 2-chloro-5-bromobenzoyl chloride was carried out in a 250 mL three-necked flask, and the synthesis of 2-chloro-5-bromo-4'-ethoxybenzophenone and the synthesis of 4-bromo-2-chloro-2-(4-ethoxybenzyl)benzene were both carried out in a 500 mL three-necked flask.
4. The method for synthesizing a dapagliflozin intermediate according to claim 1, characterized in that: The completion of the reaction was confirmed by TLC detection.
5. The method for synthesizing a dapagliflozin intermediate according to claim 1 or 4, characterized in that: The concentration of hydrochloric acid during the quenching reaction is 3 mol / L.
6. The method for synthesizing a dapagliflozin intermediate according to claim 2, characterized in that: The mass fraction of the methanol aqueous solution is 50%.
7. Use of a dapagliflozin intermediate obtained by the method for synthesizing a dapagliflozin intermediate according to any one of claims 1 to 6 in synthesizing dapagliflozin.