CN104119324B - The preparation method that a kind of Ka Gelie is clean - Google Patents
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- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention discloses the preparation method that a kind of Ka Gelie is clean.The method is: (1) take DMF as solvent, adopts Benzoyl chloride to carry out protective reaction to the hydroxyl of main raw material SM1 and obtains intermediate compound I; (2) take acetonitrile as solvent, intermediate compound I removes methoxyl group and obtains intermediate II under trimethyl phosphite effect; (3) with tetrahydrofuran (THF) and dehydrated alcohol or methyl alcohol for solvent, intermediate II removes benzoyl protection under sodium methylate effect, and to obtain Ka Gelie clean, purity >=99.9% of product, yield >=81.6%.The reaction conditions of the method is gentle, economic environmental protection, and yield is high, good product quality, is easy to industrial production.
Description
Technical field
The present invention relates to the preparation method that a kind of Ka Gelie is clean, belong to medical art.
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, FDA (Food and Drug Adminstration) (FDA) ratifies Ka Gelie 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, has two kinds of hypotypes and SGLT-1 and SGLT-2, is distributed in mucous membrane of small intestine and uriniferous tubules respectively, glucose transport can be entered blood.Ka Gelie net energy suppresses SGLT-2, the glucose in uriniferous tubules heavily can not be absorbed smoothly and enter blood and discharge with urine, thus reduces blood sugar concentration.
The synthetic method that the Ka Gelie of current report is clean mainly contains following four kinds:
Route 1 for Ka Gelie purify conjugate patent (application number: 200480022007.8) in describe method, concrete route is as follows:
With 2-(4-fluorophenyl)-5-, [for raw starting material, first compound 1 obtains compound 3 to Gluconolactone attack to the Gluconolactone of (5-bromo-2-aminomethyl phenyl) thiotolene and trimethyl silicon based protection to this route under butyllithium effect; 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.
This route is efficiently succinct, and through three steps operations, can to prepare Ka Gelie clean, route uses butyllithium, need low temperature (– 67 DEG C～– 78 DEG C) nitrogen protection operation, the reaction of this step is strict to conditional requests such as equipment, not easy to operate, and butyllithium has explosion hazard technique usage quantity greatly, increases danger coefficient; This step reaction generation impurity is more in addition, causes impurity in product too much, difficult purifying.
Route 2 is the method described in patent 200880106239.X, and concrete synthetic method is as follows:
With 2-(4-fluorophenyl)-5-, [for raw starting material, first compound 6 attack compound 2 under trimethyl silicon based lithium methide effect obtains compound 7 to the Gluconolactone of (5-iodo-2-aminomethyl phenyl) thiotolene and trimethyl silicon based protection to this route; Compound 7 reduces eliminating hydroxide and obtains 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 protection step to obtain pure product Ka Gelie through the protection of the ethanoyl of perhydroxyl radical again.
This route advantage selects the trimethyl silicon based lithium methide of alkali of more active Yuan Cai Liao – compound 6 and milder temperature of reaction to be Shenged Gao Zhi – 40 DEG C, relaxed harsh experiment condition, and route adopts ethanoyl protection to remove protection purifying product.Shortcoming is that experiment condition still needs low temperature, operates harsher, reacts in addition and still need a large amount of alkyl lithium reagents, have larger danger.
Route 3 is the method described in patent 200980151648.6, and concrete synthetic method is as follows:
This route is identical with route 2 raw starting material, and the reagent just selected is different, and first compound 6 is prepared into corresponding Grignard reagent in this route, 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 selects grignard reaction to construct molecular skeleton, and temperature of reaction is 0 DEG C, to temperature and equipment requirements also corresponding reduction.Reaction intermediate 8 easily purifying, can effectively control intermediate purity, be easy to purifying products in addition.
Route 4 is the method described in patent WO2013068850.Concrete synthetic method is as follows:
[(the bromo-2-aminomethyl phenyl of 5-) thiotolene is for raw starting material with 2-(4-fluorophenyl)-5-for this route; first Grignard reagent is prepared; 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, and it is ingenious to construct skeleton thinking; But use butyllithium in this reaction, still need cold operation, harsh to operational requirement, reaction danger coefficient is large.
To sum up, in 4 above-mentioned synthetic routes, the temperature of reaction of synthetic route 3 is low, compares the carrying out adapting to industrialization reaction.But what in this reaction, compound 10 reduction removed methoxyl group obtains in compound 4 process, employs relatively large boron trifluoride diethyl etherate (see in the embodiment 13 of patent 200980151648.6, usage quantity is 66% of compound 10 quality).Boron trifluoride diethyl etherate is filbert colourless fuming liquid, inflammable, poisonous.There is strong impulse and aggressive; be unfavorable for the carrying out that industrialization is reacted; and this compound chance water both decomposed; reaction times, the long protecting group (methoxyl group) sloughing reactant was gradually 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
For some shortcomings that existing technology of preparing exists, the invention provides a kind of reaction conditions gentle, economic environmental protection, and yield is high, good product quality, is easy to the clean preparation method of industrial Ka Gelie.
Technical characteristic of the present invention is: the preparation method that a kind of Ka Gelie is clean, it is characterized in that,
(1) take 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) take acetonitrile as solvent, intermediate compound I removes methoxyl group and obtains intermediate II under trimethyl phosphite effect;
(3) with tetrahydrofuran (THF) and dehydrated alcohol or methyl alcohol for 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 with reference to patent 200980151648.6.
Intermediate compound I: (2S; 3S; 4R; 5R; 6R)-6-(benzoylmethyl)-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-(benzoylmethyl)-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) add DMF and main raw material SM1 in reaction vessel, stirring and dissolving, to feed clarification, slowly adds Benzoyl chloride after feed clarification, room temperature reaction 3 ~ 5h; Add extraction solvent and water after completion of the reaction and stir extraction, organic phase is washed through salt, dry and subtract to steam obtain intermediate compound I after dry;
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/gSM1, is preferably 7.0 ~ 8.0ml/gSM1;
(2) after intermediate compound I being dissolved by acetonitrile, slowly add trimethyl phosphite, after finishing, be warming up to backflow, insulation reaction 6 ~ 10h; Add extraction solvent and water stirring extraction after completion of the reaction, organic phase is washed through salt, dry and subtract to steam add methyl alcohol after dry, stir to be warming up to and reflux and be incubated 1.5 ~ 2.5 hours, be then cooled to 5 ~ 15 DEG C and carry out insulation crystallization 3 ~ 6h, suction filtration, dries and obtains intermediate II;
The mol ratio of described step (2) phosphorous acid trimethyl and intermediate compound I is 1.5 ~ 3:1, is preferably 2 ~ 3:1;
(3) step (2) gained intermediate II, with after tetrahydrofuran (THF) and dehydrated alcohol or dissolve with methanol, is added sodium methylate, 30 ~ 50 DEG C of stirring reaction 2 ~ 4h; Add extraction solvent and water stirring extraction after completion of the reaction, organic phase is washed through salt, dry and subtract steam to obtaining crude product Ka Gelie after dry clean, this crude product drops in purified water by after 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 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 the extraction solvent wherein 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) trimethyl phosphite that the present invention adopts security higher replaces boron trifluoride diethyl etherate, and usage quantity decreases 60% simultaneously, and reduce the security risk because using boron trifluoride diethyl etherate to bring in production process, production process is safety and environmental protection more.
(2) compared to existing technology, the raw material used 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 more simple, on the basis of improving dust removal rate, reduce further the complicacy of technological operation.
Embodiment
Embodiment 1
20g main raw material SM1 methyl 1-C-(3-{ [5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside is added in the reaction flask that 150mlDMF is housed, be stirred to feed clarification, 29.6g (5 times amount) Benzoyl chloride is slowly added, room temperature reaction 3h after feed clarification; TLC monitors after reaction completes and adds 100ml methylene dichloride and 100ml water, stir extraction, upper strata aqueous phase stirs extracting twice with 80ml, 60ml methylene dichloride more respectively, the washing of 100ml saturated aqueous common salt is added once after merging organic phase, 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 amount), finish, stirring is warming up to backflow, insulation reaction 7 hours, TLC monitors after reaction completes and adds 120ml ethyl acetate and 100ml water, stir extraction, lower floor's aqueous phase uses 100ml more respectively, 80ml extraction into ethyl acetate twice, the washing of 150ml saturated aqueous common salt is added once after merging organic phase, organic phase anhydrous sodium sulfate drying 30min, feed liquid is subtracted steam and obtain intermediate II to dry, then add the stirring of 100ml methyl alcohol and be warming up to backflow, be incubated after 2 hours, slow cooling to 5 ~ 15 DEG C, insulation crystallization 4 ~ 6h, suction filtration, 30.8g intermediate II (molecular weight 860) is obtained after oven dry, 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, 100ml ethyl acetate and 150ml water stirring extraction is added after reaction terminates, after stratification, aqueous phase uses 70ml extraction into ethyl acetate once again, organic phase is merged after layering, organic phase 100ml saturated aqueous common salt is washed once, after layering, organic subtracting each other is steamed to dry, then adding isopropyl acetate dissolving makes feed liquid gross weight be 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
20g main raw material SM1 methyl 1-C-(3-{ [5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside is added in the reaction flask that 150mlDMF is housed, be stirred to feed clarification, until feed liquid molten clear after slowly add 29.6g (5 times amount) Benzoyl chloride, room temperature reaction 3h; TLC monitors after reaction completes and adds 100ml methylene dichloride and 100ml water, stir extraction, upper strata aqueous phase stirs extracting twice with 80ml, 60ml methylene dichloride more respectively, the washing of 100ml saturated aqueous common salt is added once after merging organic phase, organic phase anhydrous sodium sulfate drying 30min, then subtracts steaming and obtains 37.6g intermediate compound I to dry by feed liquid.
After upper step gained intermediate compound I is dissolved with 120ml acetonitrile, slowly add trimethyl phosphite 11.6g (2.2 times amount), finish, stirring is warming up to backflow, insulation reaction 7 hours, TLC monitors after reaction completes and adds 120ml ethyl acetate and 100ml water, stir extraction, lower floor's aqueous phase uses 100ml more respectively, 80ml extraction into ethyl acetate twice, the washing of 150ml saturated aqueous common salt is added once after merging organic phase, organic phase anhydrous sodium sulfate drying 30min, feed liquid is subtracted steam and obtain intermediate II to dry, then add the stirring of 100ml methyl alcohol and be warming up to backflow, be incubated after 2 hours, slow cooling to 5 ~ 15 DEG C, insulation crystallization 4 ~ 6h, suction filtration, 31.2g intermediate II is obtained after oven dry, 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, 100ml ethyl acetate and 150ml water stirring extraction is added after reaction terminates, after stratification, aqueous phase uses 70ml extraction into ethyl acetate once again, organic phase is merged after layering, organic phase 100ml saturated aqueous common salt is washed once, after layering, organic subtracting each other is steamed to dry, then adding isopropyl acetate dissolving makes feed liquid gross weight be 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
20g main raw material SM1 methyl 1-C-(3-{ [5-(4-fluorophenyl)-2-thienyl] methyl }-4-aminomethyl phenyl)-D-glucopyranoside is added in the reaction flask that 150mlDMF is housed, be stirred to feed liquid clearly molten, 23.7g (4 times amount) Benzoyl chloride is slowly added, room temperature reaction 3h after feed clarification; TLC monitors after reaction completes and adds 100ml methylene dichloride and 100ml water, stir extraction, upper strata aqueous phase stirs extracting twice with 80ml, 60ml methylene dichloride more respectively, the washing of 100ml saturated aqueous common salt is added once after merging organic phase, organic phase anhydrous sodium sulfate drying 30min, then subtracts feed liquid and steams to the dry intermediate compound I obtaining 37.6g.
After upper step gained intermediate compound I is dissolved with 120ml acetonitrile, slowly add trimethyl phosphite 11.6g (2.2 times amount), finish, stirring is warming up to backflow, insulation reaction 7 hours, TLC monitors after reaction completes and adds 120ml ethyl acetate and 100ml water, stir extraction, lower floor's aqueous phase uses 100ml more respectively, 80ml extraction into ethyl acetate twice, the washing of 150ml saturated aqueous common salt is added once after merging organic phase, organic phase anhydrous sodium sulfate drying 30min, feed liquid is subtracted steam and obtain intermediate II to dry, then add the stirring of 100ml methyl alcohol and be warming up to backflow, be incubated after 2 hours, slow cooling to 5 ~ 15 DEG C, insulation crystallization 4 ~ 6h, suction filtration, the intermediate II of 30.9g is obtained after oven dry, 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, 100ml ethyl acetate and 150ml water stirring extraction is added after reaction terminates, after stratification, aqueous phase uses 70ml extraction into ethyl acetate once again, organic phase is merged after layering, organic phase 100ml saturated aqueous common salt is washed once, after layering, organic subtracting each other is steamed to dry, then adding isopropyl acetate dissolving makes feed liquid gross weight be 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 (9)
1. the preparation method that Yi Zhong Ka Gelie is clean, is characterized in that,
(1) take 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) take acetonitrile as solvent, intermediate compound I removes methoxyl group and obtains intermediate II under trimethyl phosphite effect;
(3) with tetrahydrofuran (THF) and dehydrated alcohol or methyl alcohol for 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-(benzoylmethyl)-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-(benzoylmethyl)-3,4,5-tri-base tri-benzoyl-2-{3-[(5-(4-fluorophenyl)-2-thienyl) methyl]-4-aminomethyl phenyl }-2H-glucopyranoside; Specifically comprise the following steps:
(1) add solvent DMF and main raw material SM1 in reaction vessel, stirring and dissolving, to feed clarification, adds Benzoyl chloride after feed clarification, room temperature reaction 3 ~ 5h; Add extraction solvent and water after completion of the reaction and stir extraction, organic phase is washed through salt, dry and subtract to steam obtain intermediate compound I after dry; The mol ratio of described Benzoyl chloride and main raw material SM1 is 4.0 ~ 6.0:1;
(2), after intermediate compound I being dissolved with acetonitrile, add trimethyl phosphite, after finishing, be warming up to backflow, insulation reaction 6 ~ 10h; Add extraction solvent and water stirring extraction after completion of the reaction, organic phase is washed through salt, dry and subtract to steam add methyl alcohol after dry, stir to be warming up to and reflux and be incubated 1.5 ~ 2.5 hours, be then cooled to 5 ~ 15 DEG C and carry out insulation 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) step (2) gained intermediate II, with after tetrahydrofuran (THF) and dehydrated alcohol or dissolve with methanol, is added sodium methylate, 30 ~ 50 DEG C of stirring reaction 2 ~ 4h; Add extraction solvent and water stirring extraction after completion of the reaction, organic phase is washed through salt, dry and subtract steam to obtaining crude product Ka Gelie after dry clean, this crude product drops in purified water by after 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.
2. the preparation method that Ka Gelie as claimed in claim 1 is clean, is characterized in that, the mol ratio 4.5 ~ 5.5:1 of Benzoyl chloride and main raw material SM1 in described step (1).
3. the preparation method that Ka Gelie as claimed in claim 1 is clean, is characterized in that, with the use gauge of main raw material SM1 in described step (1), the consumption of DMF is 6.0 ~ 10.0ml/g.
4. the preparation method that Ka Gelie as claimed in claim 1 is clean, it is characterized in that, the mol ratio of described step (2) phosphorous acid trimethyl and intermediate compound I is 2 ~ 3:1.
5. the preparation method that Ka Gelie as claimed in claim 1 is clean, is characterized in that, in described step (3), the mol ratio of sodium methylate and intermediate II is 3 ~ 4:1.
6. the preparation method that Ka Gelie as claimed in claim 1 is clean, is characterized in that, in described step (3), the volume ratio of isopropyl acetate or acetone and purified water is 1:1 ~ 2.
7. preparation method as clean in the Ka Gelie in claim 1-6 as described in any one, it is characterized in that, the extraction solvent in described step (1)-(3) is a kind of, two or more mixed solvent in ethyl acetate, methyl acetate, butylacetate, acetonitrile, tetrahydrofuran (THF), trichloromethane, methylene dichloride, toluene, ether, diethyl ether, methyl ethyl ether, methyl ethyl ketone.
8. the preparation method that Ka Gelie as claimed in claim 7 is clean, it is characterized in that, the extraction solvent in described step (1) is methylene dichloride.
9. the preparation method that Ka Gelie as claimed in claim 7 is clean, is characterized in that, the extraction solvent in described step (2) and (3) is ethyl acetate.
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| WO2015071761A2 (en) * | 2013-11-11 | 2015-05-21 | Crystal Pharmatech Co., Ltd. | Crystalline forms b, c, and d of canagliflozin |
| CN104557895B (en) * | 2015-01-27 | 2017-10-31 | 江苏嘉逸医药有限公司 | The synthesis technique of 1 (β D glycopyranosyls) 4 methyl 3 [5 (4 fluorophenyl) 2 thienyl methyls] 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 |
| 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 |
| 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 |
| CN110698468B (en) * | 2019-09-24 | 2020-11-03 | 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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