CN104119324A - Preparation method of canagliflozin - Google Patents
Preparation method of canagliflozin Download PDFInfo
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Abstract
The invention discloses a preparation method of canagliflozin. The method comprises the following steps: (1) by using DMF (N,N-dimethylformamide) as a solvent, carrying out protective reaction on the main raw material SM1 by using benzoyl chloride to obtain an intermediate I; (2) by using acetonitrile as a solvent, removing methoxy group from the intermediate I under the action of trimethyl phosphite to obtain an intermediate II; and (3) by using tetrahydrofuran and anhydrous ethanol or methanol as solvents, removing benzoyl protection from the intermediate II under the action of sodium methoxide to obtain the canagliflozin. The purity of the product is at least 99.9%, and the yield is at least 81.6%. The method has the advantages of mild reaction conditions, high yield and high product quality, is economical and environment-friendly, and can easily implement industrial production.
Description
Technical field
The present invention relates to the clean preparation method of a kind of Ka Gelie, belong to medical technical field.
Background technology
Ka Gelie is clean, chinesization formal name used at school: (1S)-1,5-dehydrogenation-1-{3-[(5-(4-fluorophenyl)-2-thienyl) methyl]-4-aminomethyl phenyl }-D-Glucose alcohol, structural formula:
Ka Gelie is New type of S GLT-2 inhibitor only, is used for the treatment of the type ii diabetes of adult patients.Developed jointly by the Mitsubishi's pharmacy of day Honda limit and Johnson & Johnson's pharmacy.On March 29th, 2013, the approval Ka Gelie of FDA (Food and Drug Adminstration) (FDA) is only for improving the glycemic control of type ii diabetes adult patient, this product is the first SGLT-2 inhibitor of FDA approval, on November 25th, 2013, obtain EU Committee (EC) approval, for the treatment of diabetes B adult patient, to improve glycemic control.
SGLT is a kind of glucose transporter, and having two kinds of hypotypes is SGLT-1 and SGLT-2, is distributed in respectively mucous membrane of small intestine and uriniferous tubules, glucose transport can be entered to blood.Ka Gelie net energy suppresses SGLT-2, glucose in uriniferous tubules can not heavily be absorbed smoothly enter blood and discharges with urine, thereby reduce blood sugar concentration.
The clean synthetic method of Ka Gelie of report mainly contains following four kinds at present:
Route 1 for Ka Gelie purify compound patent (application number: the method for describing 200480022007.8), concrete route is as follows:
This route is taking the bromo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) Gluconolactone of thiotolene and trimethyl silicon based protection is as initial starting material, and first under butyllithium effect, to Gluconolactone, attack obtains compound 3 to compound 1; Compound 3 is etherificate under methanesulfonic acid catalyzed effect, then removes trimethyl silicane protecting group and obtains compound 4; Final compound 4 reduces and removes methoxyl group to obtain Ka Gelie clean under triethyl silicane and boron trifluoride diethyl etherate condition.
It is clean that this route efficiently succinctly can be prepared Ka Gelie through three step operations, route uses butyllithium, need 78 DEG C of low temperature (– 67 DEG C～–) nitrogen protection operation, this step reaction is strict to conditional requests such as equipment, not easy to operate, and it is large that butyllithium has explosion hazard technique usage quantity, increased danger coefficient; To produce impurity more for the reaction of this step in addition, causes in product impurity too much, difficult purifying.
The method of route 2 for describing in patent 200880106239.X, concrete synthetic method is as follows:
This route is taking the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) Gluconolactone of thiotolene and trimethyl silicon based protection is as initial starting material, and first compound 6 attack compound 2 under trimethyl silicon based lithium methide effect obtains compound 7; Compound 7 reduces and removes hydroxyl and obtain compound 5 (the clean crude product of Ka Gelie) under the effect of triethyl silicane boron trifluoride ethyl ether complex; It is clean that this compound goes to protect step to obtain pure product Ka Gelie through the ethanoyl protection of perhydroxyl radical again.
To be the trimethyl silicon based lithium methide of alkali of selecting more active Yuan Cai Liao – compound 6 and milder Sheng 40 DEG C of Gao Zhi – by temperature of reaction to this route advantage, relaxed harsh experiment condition, and route adopts ethanoyl protection to remove to protect purifying product.Shortcoming is that experiment condition still needs low temperature, operate harsher, in addition reaction still need a large amount of alkyl lithium reagents, there is larger danger.
Route 3 is the method for describing in patent 200980151648.6, and concrete synthetic method is as follows:
This route is identical with the initial starting material of route 2, and the reagent difference of just selecting, is first prepared into corresponding Grignard reagent by compound 6 in this route, and then attack compound 2, constructs skeleton by grignard reaction; Methyl-etherified under methylsulfonic acid condition, de-trimethyl silicon based protection obtains compound 4; Compound 4 obtains compound 10 through ethanoyl protection again; Then under triethyl silicane boron trifluoride diethyl etherate condition, reduction removes methoxyl group and obtains compound 8; It is clean that final compound 8 obtains Ka Gelie in lithium hydroxide Water Under solution.
The advantage of this route is to select grignard reaction to construct molecular skeleton, and temperature of reaction is 0 DEG C, to temperature and also corresponding reduction of equipment requirements.The easy purifying of reaction intermediate 8, can effectively control intermediate purity in addition, is easy to purifying products.
The method of route 4 for describing in patent WO2013068850.Concrete synthetic method is as follows:
This route is taking the bromo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) thiotolene is as initial starting material; first prepare Grignard reagent; then with compound 12, grignard reaction occurs and prepare intermediate 13, under tetrabutyl ammonium fluoride condition, removing the silica-based protection of tert-butyl diphenyl, to obtain product Ka Gelie clean.This route advantage is succinct for reaction, constructs skeleton thinking ingenious; But in this reaction, use butyllithium, still need cold operation, to operational requirement harshness, reaction danger coefficient is large.
To sum up, in 4 above-mentioned synthetic routes, the temperature of reaction of synthetic route 3 is low, relatively adapts to the carrying out of industrialization reaction.But compound 10 reduction removes obtaining in compound 4 processes of methoxyl group in this reaction, used relatively large boron trifluoride diethyl etherate (see in the embodiment 13 of patent 200980151648.6, usage quantity be compound 10 quality 66%).Boron trifluoride diethyl etherate is filbert colourless fuming liquid, inflammable, poisonous.There is strong impulse and strong corrosion; be unfavorable for the carrying out of industrialization reaction; and this compound chance water both decomposed; reaction times, the long protecting group (methoxyl group) that can slough gradually reactant was unfavorable for the refining and edulcoration in later stage; end product quality also can be poor, and in route 3, technologic yield is 65.6%.
Summary of the invention
Some shortcomings that exist for existing technology of preparing, the invention provides a kind of reaction conditions gentleness, economic environmental protection, and yield is high, and good product quality, is easy to the clean preparation method of industrial Ka Gelie.
Technical characterictic of the present invention is: the preparation method that a kind of Ka Gelie is clean, it is characterized in that,
(1), taking DMF as solvent, adopt Benzoyl chloride to carry out protective reaction to the hydroxyl of main raw material SM1 and obtain intermediate compound I;
(2), taking acetonitrile as solvent, intermediate compound I removes methoxyl group and obtains intermediate II under trimethyl phosphite effect;
(3), taking tetrahydrofuran (THF) and dehydrated alcohol or methyl alcohol as solvent, intermediate II removes benzoyl protection under sodium methylate effect, and to obtain Ka Gelie clean.
Remarks:
SM1: methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside.The preparation of raw material SM1 can be with reference to patent 200980151648.6.
Intermediate compound I: (2S, 3S, 4R; 5R; 6R)-6-(benzoyl methyl)-3,4,5-tri-base tri-benzoyl-2-{3-[(5-(4-fluorophenyl)-2-thienyl) methyl]-4-aminomethyl phenyl }-2-methoxyl group tetrahydrochysene-2H-glucopyranoside.
Intermediate II: (2S, 3S, 4R; 5R; 6R)-6-(benzoyl methyl)-3,4,5-tri-base tri-benzoyl-2-{3-[(5-(4-fluorophenyl)-2-thienyl) methyl]-4-aminomethyl phenyl }-2H-glucopyranoside.
Synthetic route is as follows:
Concrete steps are as follows:
(1) in reaction vessel, add DMF and main raw material SM1, stirring and dissolving, to feed clarification, slowly adds Benzoyl chloride, room temperature reaction 3～5h after feed clarification; Add after completion of the reaction extraction solvent and water to stir extraction, organic phase is washed, is dried and subtract to steam after dry through salt and obtains intermediate compound I;
In described step (1), the mol ratio of Benzoyl chloride and main raw material SM1 is 4.0～6.0:1, is preferably 4.5～5.5:1; The usage quantity of described DMF is 6.0～10.0ml/g SM1, is preferably 7.0～8.0ml/g SM1;
(2) after intermediate compound I is dissolved by acetonitrile, slowly add trimethyl phosphite, after finishing, be warming up to backflow, insulation reaction 6～10h; Add after completion of the reaction extraction solvent and water to stir extraction, organic phase is washed, is dried and subtract to steam after dry through salt and adds methyl alcohol, stirs to be warming up to and refluxes and be incubated 1.5～2.5 hours, is then cooled to 5～15 DEG C and is incubated crystallization 3～6h, suction filtration, dries and obtains intermediate II;
In described step (2), the mol ratio of trimethyl phosphite and intermediate compound I is 1.5～3:1, is preferably 2～3:1;
(3) by step (2) gained intermediate II with tetrahydrofuran (THF) and dehydrated alcohol or dissolve with methanol after, add sodium methylate, 30～50 DEG C of stirring reaction 2～4h; Add after completion of the reaction extraction solvent and water to stir extraction, organic phase through salt wash, dry and subtract steam to obtaining crude product Ka Gelie after dry clean, this crude product drops in purified water after by isopropyl acetate or acetone solution, stirring and crystallizing 8～12h, and suction filtration obtains the clean finished product of finished product Ka Gelie;
In described step (3), the mol ratio of sodium methylate and intermediate II is 2～5:1, is preferably 3～4:1; The volume ratio of described tetrahydrofuran (THF) and dehydrated alcohol or methyl alcohol is 1:1.5～2.5; The volume ratio of described isopropyl acetate or acetone and purified water is 1:1～2.
Extraction solvent in above steps is a kind of, two or more the mixed solvent in ethyl acetate, methyl acetate, butylacetate, acetonitrile, tetrahydrofuran (THF), trichloromethane, methylene dichloride, toluene, ether, diethyl ether, methyl ethyl ether, methyl ethyl ketone, and wherein the extraction solvent in step (1) is preferably methylene dichloride; Extraction solvent in step (2) and (3) is preferably ethyl acetate.
This beneficial effect of the invention is:
(1) the present invention adopts the higher trimethyl phosphite of security to replace boron trifluoride diethyl etherate, and usage quantity has reduced 60% simultaneously, has reduced the security risk because using boron trifluoride diethyl etherate to bring in production process, and production process is safety and environmental protection more.
(2) compared to existing technology, the raw material using is simple and easy to get, is more conducive to the carrying out of industrialization reaction.
(3) quality and yield are all higher than other patents.Purity >=99.9% of product, yield >=81.6%.
(4) last handling process of the present invention is simpler, improving on the basis of dust removal rate, further reduces the complicacy of the technological operation of knowing clearly.
Embodiment
Embodiment 1
In the reaction flask of 150ml DMF, add 20g main raw material SM1 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside to being equipped with, be stirred to feed clarification, after feed clarification, slowly add 29.6g (5 times of amounts) Benzoyl chloride, room temperature reaction 3h; TLC monitoring adds 100ml methylene dichloride and 100ml water after having reacted, stir extraction, upper strata water stirs extracting twice with 80ml, 60ml methylene dichloride respectively again, after merging organic phase, add 100ml saturated aqueous common salt to wash once, organic phase anhydrous sodium sulfate drying 30min, then feed liquid is subtracted and steam to dry, obtain the intermediate compound I (molecular weight 890) of 37.6g.
After upper step gained intermediate compound I is dissolved with 120ml acetonitrile, slowly add trimethyl phosphite 10.5g (2 times of amounts), finish, stirring is warming up to backflow, insulation reaction 7 hours, TLC monitoring adds 120ml ethyl acetate and 100ml water after having reacted, stir extraction, lower floor's water is used respectively 100ml again, 80ml ethyl acetate extracting twice, after merging organic phase, add 150ml saturated aqueous common salt to wash once, organic phase anhydrous sodium sulfate drying 30min, feed liquid is subtracted and steamed to the dry intermediate II that obtains, then add 100ml methyl alcohol to stir and be warming up to backflow, be incubated after 2 hours, slow cooling to 5～15 DEG C, insulation crystallization 4～6h, suction filtration, after oven dry, obtain 30.8g intermediate II (molecular weight 860), the yield of two steps is 85.0%.
By upper step gained intermediate II by 40ml tetrahydrofuran (THF) and 80ml dissolve with methanol, add 7.7g sodium methylate (mol ratio is 4:1), be warming up to 40 DEG C, react starting point plate after 2 hours, after finishing, reaction add 100ml ethyl acetate and 150ml water to stir extraction, after stratification, water extracts once by 70ml ethyl acetate again, after layering, merge organic phase, organic phase is washed once with 100ml saturated aqueous common salt, after layering, organic subtracting each other steamed to dry, then add isopropyl acetate to dissolve making feed liquid gross weight is 60g, this feed liquid is slowly dropped in 1.1L water, stirring and crystallizing 10 hours, suction filtration obtains the clean finished product 15.2g of Ka Gelie.Yield is 96%, content 99.93%.
Embodiment 2
In the reaction flask of 150ml DMF, add 20g main raw material SM1 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside to being equipped with, be stirred to feed clarification, slowly add 29.6g (5 times of amounts) Benzoyl chloride, room temperature reaction 3h after clear until feed liquid is molten; TLC monitoring adds 100ml methylene dichloride and 100ml water after having reacted, stir extraction, upper strata water stirs extracting twice with 80ml, 60ml methylene dichloride respectively again, after merging organic phase, add 100ml saturated aqueous common salt to wash once, organic phase anhydrous sodium sulfate drying 30min, then subtracts feed liquid and steams to the dry 37.6g of obtaining intermediate compound I.
After upper step gained intermediate compound I is dissolved with 120ml acetonitrile, slowly add trimethyl phosphite 11.6g (2.2 times of amounts), finish, stirring is warming up to backflow, insulation reaction 7 hours, TLC monitoring adds 120ml ethyl acetate and 100ml water after having reacted, stir extraction, lower floor's water is used respectively 100ml again, 80ml ethyl acetate extracting twice, after merging organic phase, add 150ml saturated aqueous common salt to wash once, organic phase anhydrous sodium sulfate drying 30min, feed liquid is subtracted and steamed to the dry intermediate II that obtains, then add 100ml methyl alcohol to stir and be warming up to backflow, be incubated after 2 hours, slow cooling to 5～15 DEG C, insulation crystallization 4～6h, suction filtration, after oven dry, obtain 31.2g intermediate II, the yield of two steps is 86.1%.
By upper step gained intermediate II by 40ml tetrahydrofuran (THF) and 80ml dissolve with methanol, add 7.7g sodium methylate (mol ratio is 4:1), be warming up to 40 DEG C, react starting point plate after 2 hours, after finishing, reaction add 100ml ethyl acetate and 150ml water to stir extraction, after stratification, water extracts once by 70ml ethyl acetate again, after layering, merge organic phase, organic phase is washed once with 100ml saturated aqueous common salt, after layering, organic subtracting each other steamed to dry, then add isopropyl acetate to dissolve making feed liquid gross weight is 60g, this feed liquid is slowly dropped in 1.1L water, stirring and crystallizing 10 hours, suction filtration obtains the clean finished product 15.5g of Ka Gelie.The yield of product is 96%, content 99.95%.
Embodiment 3
In the reaction flask of 150ml DMF, add 20g main raw material SM1 methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside to being equipped with, be stirred to feed liquid molten clear, after feed clarification, slowly add 23.7g (4 times of amounts) Benzoyl chloride, room temperature reaction 3h; TLC monitoring adds 100ml methylene dichloride and 100ml water after having reacted, stir extraction, upper strata water stirs extracting twice with 80ml, 60ml methylene dichloride respectively again, after merging organic phase, add 100ml saturated aqueous common salt to wash once, organic phase anhydrous sodium sulfate drying 30min, then subtracts feed liquid the intermediate compound I of steaming to the dry 37.6g of obtaining.
After upper step gained intermediate compound I is dissolved with 120ml acetonitrile, slowly add trimethyl phosphite 11.6g (2.2 times of amounts), finish, stirring is warming up to backflow, insulation reaction 7 hours, TLC monitoring adds 120ml ethyl acetate and 100ml water after having reacted, stir extraction, lower floor's water is used respectively 100ml again, 80ml ethyl acetate extracting twice, after merging organic phase, add 150ml saturated aqueous common salt to wash once, organic phase anhydrous sodium sulfate drying 30min, feed liquid is subtracted and steamed to the dry intermediate II that obtains, then add 100ml methyl alcohol to stir and be warming up to backflow, be incubated after 2 hours, slow cooling to 5～15 DEG C, insulation crystallization 4～6h, suction filtration, after oven dry, obtain the intermediate II of 30.9g, two-step reaction yield is 85.5%.
By upper step gained intermediate II by 40ml tetrahydrofuran (THF) and 80ml dissolve with methanol, add 7.7g sodium methylate (mol ratio is 4:1), be warming up to 40 DEG C, react starting point plate after 2 hours, after finishing, reaction add 100ml ethyl acetate and 150ml water to stir extraction, after stratification, water extracts once by 70ml ethyl acetate again, after layering, merge organic phase, organic phase is washed once with 100ml saturated aqueous common salt, after layering, organic subtracting each other steamed to dry, then add isopropyl acetate to dissolve making feed liquid gross weight is 60g, this feed liquid is slowly dropped in 1.1L water, stirring and crystallizing 10 hours, suction filtration obtains the clean finished product 15.3g of Ka Gelie.Yield is 95.4%.Content 99.90%.
Claims (10)
1. the clean preparation method of Yi Zhong Ka Gelie, is characterized in that,
(1), taking DMF as solvent, adopt Benzoyl chloride to carry out protective reaction to the hydroxyl of main raw material SM1 and obtain intermediate compound I;
(2), taking acetonitrile as solvent, intermediate compound I removes methoxyl group and obtains intermediate II under trimethyl phosphite effect;
(3), taking tetrahydrofuran (THF) and dehydrated alcohol or methyl alcohol as solvent, intermediate II removes benzoyl protection under sodium methylate effect, and to obtain Ka Gelie clean;
Wherein, SM1 is methyl 1-C-(3-{[5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside; Intermediate compound I is (2S, 3S, 4R, 5R, 6R)-6-(benzoyl methyl)-3,4,5-tri-base tri-benzoyl-2-{3-[(5-(4-fluorophenyl)-2-thienyl) methyl]-4-aminomethyl phenyl }-2-methoxyl group tetrahydrochysene-2H-glucopyranoside; Intermediate II is (2S, 3S, 4R; 5R; 6R)-6-(benzoyl methyl)-3,4,5-tri-base tri-benzoyl-2-{3-[(5-(4-fluorophenyl)-2-thienyl) methyl]-4-aminomethyl phenyl }-2H-glucopyranoside.
2. the clean preparation method of Ka Gelie as claimed in claim 1, is characterized in that,
(1) in reaction vessel, add solvent DMF and main raw material SM1, stirring and dissolving, to feed clarification, adds Benzoyl chloride after feed clarification, room temperature reaction 3～5h; Add after completion of the reaction extraction solvent and water to stir extraction, organic phase is washed, is dried and subtract to steam after dry through salt and obtains intermediate compound I; The mol ratio of described Benzoyl chloride and main raw material SM1 is 4.0～6.0:1;
(2) after intermediate compound I is dissolved with acetonitrile, add trimethyl phosphite, after finishing, be warming up to backflow, insulation reaction 6～10h; Add after completion of the reaction extraction solvent and water to stir extraction, organic phase is washed, is dried and subtract to steam after dry through salt and adds methyl alcohol, stirs to be warming up to and refluxes and be incubated 1.5～2.5 hours, is then cooled to 5～15 DEG C and is incubated crystallization 3～6h, suction filtration, dries and obtains intermediate II; The mol ratio of described trimethyl phosphite and intermediate compound I is 1.5～3:1;
(3) by step (2) gained intermediate II with tetrahydrofuran (THF) and dehydrated alcohol or dissolve with methanol after, add sodium methylate, 30～50 DEG C of stirring reaction 2～4h; Add after completion of the reaction extraction solvent and water to stir extraction, organic phase through salt wash, dry and subtract steam to obtaining crude product Ka Gelie after dry clean, this crude product drops in purified water after by isopropyl acetate or acetone solution, stirring and crystallizing 8～12h, and suction filtration obtains the clean finished product of finished product Ka Gelie; The mol ratio of described sodium methylate and intermediate II is 2～5:1; The volume ratio of described tetrahydrofuran (THF) and dehydrated alcohol or methyl alcohol is 1:1.5～2.5.
3. the clean preparation method of Ka Gelie as claimed in claim 2, is characterized in that, mol ratio 4.5～5.5:1 of Benzoyl chloride and main raw material SM1 in described step (1).
4. the clean preparation method of Ka Gelie as claimed in claim 2, is characterized in that, in described step (1), in the consumption of main raw material SM1, the consumption of DMF is 6.0～10.0ml/g.
5. the clean preparation method of Ka Gelie as claimed in claim 2, is characterized in that, in described step (2), the mol ratio of trimethyl phosphite and intermediate compound I is 2～3:1.
6. the clean preparation method of Ka Gelie as claimed in claim 2, is characterized in that, in described step (3), the mol ratio of sodium methylate and intermediate II is 3～4:1.
7. the clean preparation method of Ka Gelie as claimed in claim 2, is characterized in that, in described step (3), the volume ratio of isopropyl acetate or acetone and purified water is 1:1～2.
8. the clean preparation method of Ka Gelie as described in any one in claim 2-7, it is characterized in that, the extraction solvent in described step (1)-(3) is a kind of, two or more the mixed solvent in ethyl acetate, methyl acetate, butylacetate, acetonitrile, tetrahydrofuran (THF), trichloromethane, methylene dichloride, toluene, ether, diethyl ether, methyl ethyl ether, methyl ethyl ketone.
9. the clean preparation method of Ka Gelie as claimed in claim 8, is characterized in that, the extraction solvent in described step (1) is methylene dichloride.
10. the clean preparation method of Ka Gelie as claimed in claim 8, is characterized in that, the extraction solvent in described step (2) and (3) is ethyl acetate.
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| EP3068779A4 (en) * | 2013-11-11 | 2017-06-28 | Crystal Pharmatech Co. Ltd. | Crystalline forms b, c, and d of canagliflozin |
| CN104557895A (en) * | 2015-01-27 | 2015-04-29 | 江苏嘉逸医药有限公司 | Synthesis process of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene |
| CN105503845A (en) * | 2015-12-01 | 2016-04-20 | 北京普德康利医药科技发展有限公司 | Defluorinated canagliflozin compound, and preparation method and application thereof |
| CN105541815A (en) * | 2015-12-24 | 2016-05-04 | 寿光富康制药有限公司 | Preparation method for canagliflozin |
| CN105541815B (en) * | 2015-12-24 | 2018-07-13 | 寿光富康制药有限公司 | A kind of preparation method of canagliflozin |
| CN106117192A (en) * | 2016-06-23 | 2016-11-16 | 甘肃成纪生物药业有限公司 | The synthetic method that a kind of En Gelie is clean |
| CN106117192B (en) * | 2016-06-23 | 2018-11-23 | 甘肃成纪生物药业有限公司 | A kind of synthetic method that En Gelie is net |
| CN110698468A (en) * | 2019-09-24 | 2020-01-17 | 杭州华东医药集团新药研究院有限公司 | Preparation method of canagliflozin |
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