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CN111040000A - A kind of method for preparing Liejing class hypoglycemic agent intermediate - Google Patents

A kind of method for preparing Liejing class hypoglycemic agent intermediate Download PDF

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CN111040000A
CN111040000A CN201911363040.1A CN201911363040A CN111040000A CN 111040000 A CN111040000 A CN 111040000A CN 201911363040 A CN201911363040 A CN 201911363040A CN 111040000 A CN111040000 A CN 111040000A
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methanol
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任旭红
张乐天
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Shenyang Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract

本发明属于药物合成技术领域，涉及一种制备列净类降糖药关键中间体的新方法，具体涉及卡格列净(Canagliflozin)、达格列净(Dapagliflozin)和恩格列净(Empagliflozin)的关键中间体(C‑1、D‑1和E‑1)的制备方法。所述的方法包括：1)在共溶剂的存在下，原料芳基溴2与有机锂试剂发生卤素金属交换得到芳基锂试剂3，再与TMS保护的葡萄糖酸内酯4发生亲核加成反应得到过渡态产物5；2)5先脱去TMS保护基，再将半缩酮转化为缩酮即得构型单一的关键中间体1。本方法能够立体选择性的合成卡格列净、达格列净和恩格列净的关键中间体(C‑1、D‑1和E‑1)，反应收率较高(>75％)，产物纯度高(HPLC纯度95％左右)，有利于下一步的还原制备终产物。

Figure DDA0002337706580000011
The invention belongs to the technical field of drug synthesis, and relates to a new method for preparing key intermediates of the hypoglycemic drugs of Liejing, in particular to Canagliflozin, Dapagliflozin and Empagliflozin. The preparation method of the key intermediates (C-1, D-1 and E-1). The method comprises: 1) in the presence of a co-solvent, the raw material aryl bromide 2 and the organolithium reagent undergo halogen metal exchange to obtain the aryl lithium reagent 3, and then undergo nucleophilic addition with the TMS-protected gluconolactone 4; The reaction obtains the transition state product 5; 2) 5 first removes the TMS protecting group, and then converts the hemiketal into a ketal to obtain the key intermediate 1 with a single configuration. This method can stereoselectively synthesize key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin, and the reaction yield is high (>75%) , the product has high purity (about 95% HPLC purity), which is beneficial to the next step of reduction to prepare the final product.
Figure DDA0002337706580000011

Description

Method for preparing intermediate of gliflozin hypoglycemic drug
The technical field is as follows:
the invention belongs to the technical field of drug synthesis, and relates to a novel method for preparing key intermediates of a gliflozin hypoglycemic drug, in particular to a preparation method of key intermediates (C-1, D-1 and E-1) of Canagliflozin (Canagliflozin), Dapagliflozin (Dapagliflozin) and Empagliflozin (Empagliflozin).
Background art:
canagliflozin (Canagliflozin), trade name:
Figure BDA0002337706570000011
research and development companies: the first three ingredients of Mirabilitum pratense,Yang Sen. Canagliflozin received marketing approval by the united states Food and Drug Administration (FDA) on 29 th 3 th 2013, european pharmaceutical administration (EMA) on 15 th 11 th 2013, japanese pharmaceutical and medical instrumentation complex (PMDA) on 4 th 7 th 2014, and Chinese Food and Drug Administration (CFDA) on 29 th 9 th 2017.
Dapagliflozin (Dapagliflozin), trade name:
Figure BDA0002337706570000012
research and development companies: aslikang, Baishimei Guibao. Dapagliflozin received a marketing approval from the European Medicines Agency (EMA) on day 11-12 in 2012, the united states Food and Drug Administration (FDA) on day 1-8 in 2014, the japanese pharmaceutical and medical device integrated agency (PMDA) on day 3-24 in 2014, and the Chinese Food and Drug Administration (CFDA) on day 3-13 in 2017.
Engelizin (Empagliflozin), trade name:
Figure BDA0002337706570000013
research and development companies: boringer Yiger, Li Lai. Engelizin received marketing approval from the European Medicines Agency (EMA) on 5/22 days 2014, the united states Food and Drug Administration (FDA) on 8/1 days 2014, the japanese pharmaceutical and medical device complex (PMDA) on 12/26 days 2014, and the Chinese Food and Drug Administration (CFDA) on 9/20 days 2017.
The gliflozin antidiabetic is a sodium-glucose cotransporter 2(SGLT2) inhibitor. 90% of renal glucose reabsorption is accomplished by SGLT2 protein (SGLT1 is responsible for the remaining 10%). The glimpuride hypoglycemic agent reduces the reabsorption of filtered glucose and lowers the renal glucose threshold, thereby increasing the excretion of urine glucose. The composition can be used for assisting diet control and exercise to improve blood sugar control of adult type II diabetes.
Figure BDA0002337706570000021
The key for preparing the glijing hypoglycemic agent is C (sp)2)-C(sp3) The construction of the glucoside bond, hereinafter, the advantages and disadvantages of the existing synthetic method are described by taking canagliflozin as an example:
Figure BDA0002337706570000022
currently, canagliflozin C (sp)2)-C(sp3) The synthesis of the glucoside bond has a plurality of literature reports at home and abroad, and most of the synthesis adopts organic lithium reagents. Firstly, preparing aryl lithium, then adding hydroxyl protected gluconolactone at-78 ℃ to carry out nucleophilic addition reaction to construct a glycosidic bond. The obtained compound can be converted into a ketal key intermediate C-1 by removing the protecting group of the glycosyl part, and the key intermediate can be separated and purified by beating. Finally, the ketal compound C-1 is passed through a reducing agent (e.g., Et)3SiH/BF3·Et2O) reducing to obtain the final product canagliflozin.
Construction of C (sp) for Canagliflozin2)-C(sp3) Glucosidic linkages, synthetic routes reported in patents WO2005012326a1, WO2017071813a1 and in documents j.med.chem.2010,53,6355-:
Figure BDA0002337706570000031
a)n-BuLi,THF,Tol,-78℃；b)MsOH,MeOH,-78℃tor.t.
the advantages are that: the raw materials of the intermediates C-2 and C-4 are cheap and easy to obtain, and the preparation is simple.
The disadvantages are as follows: in the process of generating the key intermediate C-1, a byproduct C-1a is inevitably generated, the purity of the product is not high, and the product is oily and is not easy to separate and purify.
Construction of C (sp) for Canagliflozin2)-C(sp3) The glucoside linkage, the synthetic route reported in patent US20100099883a1, is as follows:
Figure BDA0002337706570000032
the advantages are that: the reaction temperature is increased.
The disadvantages are as follows: the iodobenzene intermediate is high in price; the reaction yield is not high, and the product is oily and is not easy to separate and purify.
Construction of C (sp) for Canagliflozin2)-C(sp3) The optimized synthetic routes reported in patent WO2012140120A1 and in the literature Organic Letters,2012,14(6),1480-1483 are as follows:
Figure BDA0002337706570000041
the advantages are that: the intermediates are all solid and are easy to transfer and post-treat.
The disadvantages are as follows: the reaction temperature span is large, and the product needs column chromatography purification, so that the requirement on reaction equipment is high; pivaloyl chloride is relatively smelly and has strong irritation and corrosivity.
The prior synthesis route reported by the literature has the defects of process conditions. If the raw materials are expensive, the production cost is higher; if column chromatography purification is needed, the requirements on production equipment are high. Therefore, it is urgently needed to provide a new process condition to solve the above problems.
The invention content is as follows:
in order to overcome the defects of the existing process route, the invention provides a novel method for stereoselectively synthesizing key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and engagliflozin, and the process route is as follows:
Figure BDA0002337706570000042
1)PMDTA，n-BuLi，THF，Tol，-78℃；2)i)Citricacid，MeOH，-20℃tor.t.；ii)MsOH，MeOH，r.t
the invention is realized by the following steps:
1) in the presence of a cosolvent, performing halogen metal exchange on a raw material aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and performing nucleophilic addition reaction on the aryl lithium reagent and a TMS-protected gluconolactone 4 to obtain a transition-state product 5;
2)5, removing TMS protecting group, and converting hemiketal into ketal to obtain the key intermediate 1 with single configuration.
Further, the preparation method comprises the following steps: 1) in the presence of a cosolvent, performing halogen metal exchange on aryl bromide of a raw material compound 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and performing nucleophilic addition reaction on the aryl lithium reagent and a gluconolactone 4 protected by TMS to obtain a transition state product 5;
2) adding citric acid aqueous solution into methanol, heating and stirring for reaction.
Preferably, the method comprises the following steps:
the cosolvent in the step 1) comprises one or more of hexamethylphosphoric triamide (HMPA), Pentamethyldiethylenetriamine (PMDTA), Tetramethylethylenediamine (TMEDA), 1,4,7,10, 10-Hexamethyltriethylenetetramine (HMTTA), N-Dimethylpropyleneurea (DMPU), ethylene glycol dimethyl ether (DME) and 12-Crown-4 (12-Crown-4), and the molar ratio of the compound 2 to the cosolvent is 1: 1.1-1: 2. Preferably PMDTA, and the molar ratio of the compound 2 to the PMDTA is 1: 1.1-1: 2.
The organolithium reagent in step 1) is n-butyllithium or n-hexyllithium, but is not limited to these two organolithium reagents
The molar ratio of the compound 2 to the organic lithium reagent is 1: 1.1-1: 2.
The temperature of the halogen metal exchange reaction in the step 1) is-65 to-85 ℃, preferably-75 to-80 ℃.
The reaction solvent in step 1) is tetrahydrofuran.
In the step 2), in the TMS protecting group removal of the transition state product 5, a citric acid aqueous solution is used, and the concentration of the citric acid (Citricacid) aqueous solution is 5-25%. The reaction solvent is methanol and toluene, and the amount of the methanol is 30-40% of the total volume of the reaction solvent tetrahydrofuran and toluene.
In the step 2), the amount of methanesulfonic acid used for converting the hemiketal into the ketal is 5 to 10 mol%, preferably 7 to 8 mol%, of the compound 2.
The invention has the advantages that:
the raw materials are cheap and easy to obtain, the preparation is simple and convenient, and the production cost is favorably reduced; by adopting the method, key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and engagliflozin can be stereoselectively synthesized, the reaction yield is high (> 75%), the product purity is high (about 95% of HPLC purity), and the method is favorable for preparing a final product by the next reduction; the crude product can be purified by pulping to obtain a solid product, is easy to transfer, weigh and the like, and is suitable for large-scale production.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and include, but are not limited to, examples of implementation. The present invention is described in detail below with reference to examples, but it will be understood by those skilled in the art that the present invention is not limited to these examples and the preparation method used. Furthermore, equivalent alterations, combinations, and modifications of the present invention as described herein are possible for those skilled in the art, and are intended to be included within the scope of the present invention.
Example 1: preparation of C-1
2- (2-methyl-5-bromobenzyl) -5- (4-fluorobenzene) thiophene (5.0g, 13.85mmol), tetrahydrofuran (50mL), and PMDTA (7.0mL, 1.5equiv) were sequentially added to a 500mL three-necked flask, the air in the reaction flask was replaced with nitrogen, the temperature of the cold trap was controlled to about-78 ℃, 1.6M n-butyllithium (13.0mL, 1.5equiv) was slowly dropped, and the mixture was stirred for about 1 h. Adding TMS-protected gluconolactone 4(8.5g, 1.3equiv) and toluene (50mL) into another 100mL round-bottom flask, mixing, and controlling the temperature of a cold trap to be about-78 ℃. The toluene solution of 4 was slowly dropped into a three-necked flask, and stirred for 2 hours while maintaining the temperature.
While the temperature was kept constant, methanol (35mL) was slowly dropped into the three-necked flask and stirred for 20 min. Then the temperature is raised to about-20 ℃, 15 percent citric acid aqueous solution (50mL) is slowly dripped into the three-necked bottle, and the temperature is raised to the room temperature and stirred for 2h after dripping. Then, a saturated aqueous sodium bicarbonate solution (100mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 500mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a yellow oil.
The yellow oil was dissolved in methanol (50mL), transferred to a 250mL round bottom flask, methanesulfonic acid (0.7mL, 10% mol) was added slowly and the reaction stirred at room temperature for 10 h. Then, a saturated aqueous sodium bicarbonate solution (80mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 250mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a pale yellow oil. The light yellow oil was purified with ethyl acetate: pulping with n-hexane (v/v: 1/3) to obtain C-1 pure product as light yellow powder with weight of 5.0g, HPLC purity of 97.1% and yield of 75.6%.
Example 2: preparation of C-1
2- (2-methyl-5-bromobenzyl) -5- (4-fluorobenzene) thiophene (5.0g, 13.85mmol), tetrahydrofuran (50mL), and PMDTA (7.0mL, 1.5equiv) were sequentially added to a 500mL three-necked flask, the air in the reaction flask was replaced with nitrogen, the temperature of the cold trap was controlled to about-78 ℃, 2.5M n-butyllithium (8.3mL, 1.5equiv) was slowly dropped, and the mixture was stirred for about 1 h. Adding TMS-protected gluconolactone 4(8.5g, 1.3equiv) and toluene (50mL) into another 100mL round-bottom flask, mixing, and controlling the temperature of a cold trap to be about-78 ℃. The toluene solution of 4 was slowly dropped into a three-necked flask, and stirred for 2 hours while maintaining the temperature.
While the temperature was kept constant, methanol (35mL) was slowly dropped into the three-necked flask and stirred for 20 min. Then the temperature is raised to about-20 ℃, 15 percent citric acid aqueous solution (50mL) is slowly dripped into the three-necked bottle, and the temperature is raised to the room temperature and stirred for 2h after dripping. Then, a saturated aqueous sodium bicarbonate solution (100mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 500mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a yellow oil.
The yellow oil was dissolved in methanol (50mL), transferred to a 250mL round bottom flask, methanesulfonic acid (0.7mL, 10% mol) was added slowly and the reaction stirred at room temperature for 10 h. Then, a saturated aqueous sodium bicarbonate solution (80mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 250mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a pale yellow oil. The light yellow oil was purified with ethyl acetate: pulping with n-hexane (v/v: 1/3) to obtain C-1 pure product as light yellow powder with weight of 5.1g, HPLC purity of 99.3% and yield of 77.6%.
Example 3: preparation of D-1
5-bromo-2-chloro-4' -ethoxydiphenylmethane (1.0g, 3.07mmol), tetrahydrofuran (16mL), and PMDTA (1.4mL, 1.5equiv) were sequentially charged into a 250mL three-necked flask, the air in the reaction flask was replaced with nitrogen, the temperature of the cold trap was controlled to about-78 ℃, 2.5M n-butyllithium (1.8mL, 1.5equiv) was slowly added dropwise, and the mixture was stirred for about 1 hour. Adding the TMS-protected gluconolactone 4(1.7g, 1.3equiv) and toluene (16mL) into another 50mL round-bottom flask, mixing uniformly, and controlling the temperature of a cold trap to be about-78 ℃. The toluene solution of 4 was slowly dropped into a three-necked flask, and stirred for 2 hours while maintaining the temperature.
While the temperature was kept constant, methanol (10mL) was slowly dropped into the three-necked flask and stirred for 20 min. Then the temperature is raised to about-20 ℃, 15 percent citric acid aqueous solution (50mL) is slowly dripped into the three-necked bottle, and the temperature is raised to the room temperature and stirred for 2h after dripping. Then, a saturated aqueous sodium bicarbonate solution (100mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 250mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a yellow oil.
The yellow oil was dissolved in methanol (20mL), transferred to a 100mL round bottom flask, methanesulfonic acid (0.1mL, 10% mol) was added slowly, and the reaction was stirred at room temperature for 10 h. Then, a saturated aqueous sodium bicarbonate solution (50mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 100mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a pale yellow oil. The light yellow oil was purified with ethyl acetate: pulping with n-hexane (v/v: 1/3) to obtain pure D-1 as white powder with weight of 1.1g, HPLC purity of 95.7% and yield of 81.4%.
Example 4: preparation of E-1
(3S) -3- [4- [ (2-chloro-5-iodophenyl) methyl ] phenoxy ] tetrahydrofuran (1.0g, 2.72mmol), tetrahydrofuran (16mL), and PMDTA (1.2mL, 1.5equiv) were sequentially charged into a 250mL three-necked flask, the air in the reaction flask was replaced with nitrogen, and then 2.5M n-butyllithium (1.6mL, 1.5equiv) was slowly added dropwise with controlling the temperature at about-78 ℃ in a cold trap, and stirred for about 1 h. Adding TMS-protected gluconolactone 4(1.5g, 1.3equiv) and toluene (16mL) into another 50mL round-bottom flask, mixing, and controlling the temperature of a cold trap to be about-78 ℃. The toluene solution of 4 was slowly dropped into a three-necked flask, and stirred for 2 hours while maintaining the temperature.
While the temperature was kept constant, methanol (10mL) was slowly dropped into the three-necked flask and stirred for 20 min. Then the temperature is raised to about-20 ℃, 15 percent citric acid aqueous solution (50mL) is slowly dripped into the three-necked bottle, and the temperature is raised to the room temperature and stirred for 2h after dripping. Then, a saturated aqueous sodium bicarbonate solution (100mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 250mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a yellow oil.
The yellow oil was dissolved in methanol (20mL), transferred to a 100mL round bottom flask, methanesulfonic acid (0.1mL, 10% mol) was added slowly, and the reaction was stirred at room temperature for 10 h. Then, a saturated aqueous sodium bicarbonate solution (50mL) was slowly dropped into the three-necked flask, and the mixture was stirred for 20min after completion of dropping. The reaction solution was transferred to a 100mL separatory funnel, allowed to stand for separation, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by rotary evaporation to give a pale yellow oil. The light yellow oil was purified with ethyl acetate: pulping with n-hexane (v/v: 1/3) to obtain pure E-1 as white powder with weight of 1.0g, HPLC purity of 93.4% and yield of 76.3%.

Claims (10)

1.一种制备列净类降糖药中间体的方法，其特征在于，1. a method for preparing a class of hypoglycemic drug intermediates of Liejing is characterized in that, 1)在共溶剂的存在下，原料芳基溴2与有机锂试剂发生卤素金属交换得到芳基锂试剂3，再与TMS保护的葡萄糖酸内酯4发生亲核加成反应得到过渡态产物5；1) In the presence of a co-solvent, the raw material aryl bromide 2 and the organolithium reagent undergo halogen metal exchange to obtain the aryllithium reagent 3, and then undergo a nucleophilic addition reaction with the TMS-protected gluconolactone 4 to obtain the transition state product 5 ; 2)5先脱去TMS保护基，再将半缩酮转化为缩酮即得构型单一的关键中间体1。2) 5 First remove the TMS protecting group, and then convert the hemiketal into a ketal to obtain the key intermediate 1 with a single configuration.
Figure RE-FDA0002384887880000011
Figure RE-FDA0002384887880000011
 其中，Ar为
Figure RE-FDA0002384887880000012
Among them, Ar is
Figure RE-FDA0002384887880000012
 2.如权利要求1所述的方法，其特征在于，2. The method of claim 1, wherein 1)在共溶剂的存在下，原料化合物2芳基溴与有机锂试剂发生卤素金属交换得到芳基锂试剂3，再与TMS保护的葡萄糖酸内酯4发生亲核加成反应得到过渡态产物5；1) In the presence of a co-solvent, the raw material compound 2 aryl bromide and organolithium reagent undergo halogen metal exchange to obtain aryl lithium reagent 3, and then undergo nucleophilic addition reaction with TMS-protected gluconolactone 4 to obtain a transition state product 5; 2)在甲醇中加入柠檬酸水溶液，升温搅拌反应。2) Add citric acid aqueous solution to methanol, heat up and stir to react. 3.如权利要求1或2所述的方法，其特征在于，3. The method of claim 1 or 2, wherein 步骤1)中所述共溶剂包括六甲基磷酰三胺、五甲基二乙烯三胺、四甲基乙二胺、1,1,4,7,10,10-六甲基三亚乙基四胺、N,N-二甲基丙烯基脲、乙二醇二甲醚、12-冠醚-4中的一种或几种。The co-solvents in step 1) include hexamethylphosphoric triamide, pentamethyldiethylenetriamine, tetramethylethylenediamine, 1,1,4,7,10,10-hexamethyltriethylene One or more of tetramine, N,N-dimethylpropenyl urea, ethylene glycol dimethyl ether and 12-crown-4. 4.如权利要求1或2所述的方法，其特征在于，4. The method of claim 1 or 2, wherein 步骤1)中原料芳基溴2与共溶剂的摩尔比为1:1.1～1:2。In step 1), the molar ratio of the raw material aryl bromide 2 to the co-solvent is 1:1.1 to 1:2. 5.如权利要求1或2所述的方法，其特征在于，5. The method of claim 1 or 2, wherein 步骤1)中所述共溶剂为五甲基二乙烯三胺。The co-solvent described in step 1) is pentamethyldiethylenetriamine. 6.如权利要求1或2所述的方法，其特征在于，6. The method of claim 1 or 2, wherein 步骤1)中卤素金属交换反应的温度为-65～-85℃，优选-75～-80℃。The temperature of the halogen metal exchange reaction in step 1) is -65 to -85°C, preferably -75 to -80°C. 7.如权利要求1或2所述的方法，其特征在于，7. The method of claim 1 or 2, wherein 步骤1)中的反应溶剂为四氢呋喃。The reaction solvent in step 1) is tetrahydrofuran. 8.如权利要求1或2所述的方法，其特征在于，8. The method of claim 1 or 2, wherein 步骤2)中所述柠檬酸水溶液浓度为5％～25％。The concentration of the citric acid aqueous solution in step 2) is 5% to 25%. 9.如权利要求1或2所述的方法，其特征在于，9. The method of claim 1 or 2, wherein 步骤2)中反应溶剂为甲醇和甲苯。In step 2), the reaction solvents are methanol and toluene. 10.如权利要求1或2所述的方法，其特征在于，10. The method of claim 1 or 2, wherein 步骤2)所述甲醇量为反应溶剂四氢呋喃和甲苯总体积的30％～40％。Step 2) The amount of methanol is 30% to 40% of the total volume of the reaction solvent tetrahydrofuran and toluene.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111748004A (en) * 2020-06-30 2020-10-09 药璞(上海)医药科技有限公司 Crystal form of high-purity dapagliflozin intermediate and preparation method thereof
CN112321400A (en) * 2020-09-08 2021-02-05 乐威医药（江苏）股份有限公司 Synthetic method for improving yield of 2, 5-difluorobenzaldehyde by adopting negative ion stabilizer

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101916A1 (en) * 2013-12-30 2015-07-09 Mylan Laboratories Ltd. Process for the preparation of empagliflozin
WO2017063617A1 (en) * 2015-10-13 2017-04-20 Zentiva, K.S. Preparation of intermediates for the synthesis of canagliflozin and dapagliflozin
CN107163033A (en) * 2017-06-15 2017-09-15 扬子江药业集团北京海燕药业有限公司 A kind of preparation method net high-purity Yi Palie
CN107556302A (en) * 2017-11-02 2018-01-09 中国医药集团总公司四川抗菌素工业研究所 It is a kind of to prepare the net methods of Yi Palie
CN108084130A (en) * 2017-12-15 2018-05-29 东南大学 A kind of preparation method of antidiabetic drug Dapagliflozin
CN109180662A (en) * 2018-10-17 2019-01-11 北大医药股份有限公司 A kind of preparation method of canagliflozin
CN109336875A (en) * 2017-08-15 2019-02-15 江苏工程职业技术学院 A kind of synthetic method of canagliflozin
CN109336874A (en) * 2017-08-15 2019-02-15 江苏工程职业技术学院 A kind of preparation method of canagliflozin
CN109988161A (en) * 2017-12-29 2019-07-09 徐州万邦金桥制药有限公司 A kind of preparation method that suitable industrialized production En Gelie is net
CN110396119A (en) * 2018-04-24 2019-11-01 上海迪赛诺药业股份有限公司 The preparation method of canagliflozin intermediate
CN111560004A (en) * 2020-04-30 2020-08-21 江苏德源药业股份有限公司 Preparation method of high-purity canagliflozin intermediate

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101916A1 (en) * 2013-12-30 2015-07-09 Mylan Laboratories Ltd. Process for the preparation of empagliflozin
WO2017063617A1 (en) * 2015-10-13 2017-04-20 Zentiva, K.S. Preparation of intermediates for the synthesis of canagliflozin and dapagliflozin
CN107163033A (en) * 2017-06-15 2017-09-15 扬子江药业集团北京海燕药业有限公司 A kind of preparation method net high-purity Yi Palie
CN109336875A (en) * 2017-08-15 2019-02-15 江苏工程职业技术学院 A kind of synthetic method of canagliflozin
CN109336874A (en) * 2017-08-15 2019-02-15 江苏工程职业技术学院 A kind of preparation method of canagliflozin
CN107556302A (en) * 2017-11-02 2018-01-09 中国医药集团总公司四川抗菌素工业研究所 It is a kind of to prepare the net methods of Yi Palie
CN108084130A (en) * 2017-12-15 2018-05-29 东南大学 A kind of preparation method of antidiabetic drug Dapagliflozin
CN109988161A (en) * 2017-12-29 2019-07-09 徐州万邦金桥制药有限公司 A kind of preparation method that suitable industrialized production En Gelie is net
CN110396119A (en) * 2018-04-24 2019-11-01 上海迪赛诺药业股份有限公司 The preparation method of canagliflozin intermediate
CN109180662A (en) * 2018-10-17 2019-01-11 北大医药股份有限公司 A kind of preparation method of canagliflozin
CN111560004A (en) * 2020-04-30 2020-08-21 江苏德源药业股份有限公司 Preparation method of high-purity canagliflozin intermediate

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111748004A (en) * 2020-06-30 2020-10-09 药璞(上海)医药科技有限公司 Crystal form of high-purity dapagliflozin intermediate and preparation method thereof
CN112321400A (en) * 2020-09-08 2021-02-05 乐威医药（江苏）股份有限公司 Synthetic method for improving yield of 2, 5-difluorobenzaldehyde by adopting negative ion stabilizer
CN112321400B (en) * 2020-09-08 2023-05-09 乐威医药（江苏）股份有限公司 Synthetic method for improving yield of 2, 5-difluorobenzaldehyde by adopting negative ion stabilizer

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