CN103980263B - The synthesis technique of canagliflozin - Google Patents
The synthesis technique of canagliflozin Download PDFInfo
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- CN103980263B CN103980263B CN201410153116.9A CN201410153116A CN103980263B CN 103980263 B CN103980263 B CN 103980263B CN 201410153116 A CN201410153116 A CN 201410153116A CN 103980263 B CN103980263 B CN 103980263B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 synthesis technique of canagliflozin, with 2 ar-Toluic acids as initiation material, use self-control catalyst, iodic acid and Iod R to generate intermediate one, or with 2 ar-Toluic acids as initiation material, under the effect of metal reagent and catalyst, add bromine, synthetic intermediate two；Optionally intermediate one or intermediate two first carries out acylation reaction with thionyl chloride, carries out Friedel-Crafts reaction and generates intermediate three；With ALPHA D glucose as raw material, after reacting all hydroxyls of protection with pivaloyl chloride, then react generation intermediate four with zinc bromide, bromotrimethylsilane；Intermediate three and intermediate four, connect and generate intermediate five；Under last acid condition, pivaloyl group is sloughed, generate target compound.The new technique for synthesizing yield of the canagliflozin of the present invention is high, and mild condition is safe and reliable, is suitable for industrialized production, and raw material is cheap and easily-available, is conducive to controlling production cost.
Description
Technical field
The present invention relates to the new technique for synthesizing of a kind of canagliflozin.
Background technology
Canagliflozin Canagliflozin is first SGLT2 inhibitor medicaments ratified by FDA, can be by by Fructus Vitis viniferae
By the way of kidney excrete, reduce blood glucose after sugar decomposition, be used for treating adult's type 2 diabetes mellitus, have wide before
Scape.Except good glycemic control, the antiobesity action of Canagliflozin is more notable, and compared with glimepiride,
Far much less for the hypoglycemic event that canagliflozin causes.
The existing synthetic route process conditions of reported in literature are harsh, as used high-temperature hot filter, high to producing equipment requirements, work
Industry relatively costly；Owing to syntheti c route is longer, the yield of each step is relatively low, causes total recovery low, and environmental pollution is big, is unfavorable for
Industrialized production.Accordingly, it is desirable to provide a kind of new technical scheme solves the problems referred to above.
Summary of the invention
For solving the problems referred to above, the present invention provides the new technique for synthesizing of a kind of canagliflozin.
The technical solution used in the present invention:
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 0.5 ~ 1.0, and aftertreatment technology uses cold filtration after cooling,
The way of mother liquid recycle；
B or with 2-ar-Toluic acid as initiation material, under the effect of metal reagent and super acidic catalyst, addition rubs
Your multiple is the bromine of 1.05 ~ 1.5, and solvent bromine is used molecular sieve absolute pretreatment, and 5-is bromo-for synthetic intermediate two
2-ar-Toluic acid；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four-10 ~ 25 DEG C of reactions；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 76-80 degree Celsius, in self-control
Catalyst zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, it is concentrated to give crude product, then the method repeatedly pulled an oar with different solvents is progressively removed respectively
Plant impurity, obtain the purity target product higher than 98%.
In b step, metal reagent is Fe powder or ferric bromide, and super acidic catalyst is trifluoromethanesulfonic acid or p-methyl benzenesulfonic acid.
In Step d, with ALPHA-D-glucose as raw material, through reacting all hydroxyls of protection, upper protection with pivaloyl chloride
The technique of base adds a small amount of thionyl chloride.
In f step, solvent is the mixed solvent of methanol, acetic acid or methanol, acetic acid and water.
For the generation of each intermediate above-mentioned, then being explained by following chemical equation, chemical equation is:
Intermediate one
；
Intermediate two
；
Intermediate three
；
Intermediate four
；
Intermediate five
；
Product
。
The invention have the advantage that yield is high, mild condition, safe and reliable, it is suitable for industrialized production, raw material is cheap and easily-available,
Be conducive to controlling production cost.
Detailed description of the invention
Following embodiment is merely to illustrate the present invention, but can not limit protection scope of the present invention.
Embodiment 1
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 0.5, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically, specific as follows: reaction temperature is down to 20 degrees Celsius, a large amount of solids separate out, and will be mixed with catalysis at this temperature
The product of agent filters, and mother solution is applied mechanically next time, can connected set 5 times, after filter cake dissolves with ethyl acrylate, room temperature filters, by catalyst
Leach and apply mechanically next time, can apply mechanically 5 times, after filtrate precipitation, the crude product ethyl acrylate recrystallization of 2.5 times of weight, obtain white product
Product obtain product, yield more than 88%；
B or with 2-ar-Toluic acid as initiation material, in metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid
Under effect, adding mol times is the bromine of 1.05, and solvent bromine is used molecular sieve absolute pretreatment, synthetic mesophase
Body two 5-bromo-2-ar-Toluic acid, yield is more than 85%；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three, yield 78%；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four-10 DEG C of reactions, adds a small amount of thionyl chloride, make pivaloyl chloride in the technique of upper protection group
Consumption reduces half, and yield is without impact, and two step yields are all more than 82%, and total recovery is more than 67%；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 76 degrees Celsius, urge in self-control
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five, yield more than 71%；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, being concentrated to give crude product, the method that again with methanol is repeatedly pulled an oar progressively is removed various miscellaneous
Matter, obtains the purity target product higher than 98%, yield more than 85%.
Embodiment 2
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 0.7, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically, specific as follows: reaction temperature is down to 18 degrees Celsius, a large amount of solids separate out, and will be mixed with catalysis at this temperature
The product of agent filters, and mother solution is applied mechanically next time, can connected set 3 times, after filter cake dissolves with ethyl acrylate, room temperature filters, by catalyst
Leach and apply mechanically next time, can apply mechanically 3 times, after filtrate precipitation, the crude product ethyl acrylate recrystallization of 2.5 times of weight, obtain white product
Product obtain product, yield more than 88%；
B or with 2-ar-Toluic acid as initiation material, at metal reagent ferric bromide and super acidic catalyst p-methyl benzenesulfonic acid
Effect under, add mol times be the bromine of 1.25, and to solvent bromine use molecular sieve absolute pretreatment, in synthesis
Mesosome two 5-bromo-2-ar-Toluic acid, yield is more than 85%；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three, yield 78-80%；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four 10 DEG C of reactions, uses the way adding a small amount of thionyl chloride in the technique of upper protection group,
Making pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is more than 67%；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 78 degrees Celsius, urge in self-control
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five, yield more than 71%；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, it is concentrated to give crude product, then the method repeatedly pulled an oar with acetic acid is progressively removed various miscellaneous
Matter, obtains the purity target product higher than 98%, yield more than 85%.
Embodiment 3
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 1.0, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically, specific as follows: reaction temperature is down to 22 degrees Celsius, a large amount of solids separate out, and will be mixed with catalysis at this temperature
The product of agent filters, and mother solution is applied mechanically next time, can connected set 4 times, after filter cake dissolves with ethyl acrylate, room temperature filters, by catalyst
Leach and apply mechanically next time, can apply mechanically 4 times, after filtrate precipitation, the crude product ethyl acrylate recrystallization of 2.5 times of weight, obtain white product
Product obtain product, yield more than 88%；
B or with 2-ar-Toluic acid as initiation material, in metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid
Under effect, adding mol times is the bromine of 1.5, and solvent bromine is used molecular sieve absolute pretreatment, synthetic mesophase
Body two 5-bromo-2-ar-Toluic acid, yield is more than 85%；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three, yield 80%；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four 25 DEG C of reactions, uses the way adding a small amount of thionyl chloride in the technique of upper protection group,
Making pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is more than 67%；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 80 degrees Celsius, urge in self-control
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five, yield more than 71%；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, be concentrated to give method that crude product, again with methanol and water mixed solvent repeatedly pull an oar by
Step removes various impurity, obtains the purity target product higher than 98%, yield more than 85%.
In f step, mixed solvent can also be the mixed solvent of acetic acid and water.
It is below the preparation process of each intermediate:
Prepare in intermediate one: 500ml reaction bulb and add, 2-methyl-benzoic acid 40g, 0.113mol iodine, 70% iodic acid water
Solution, catalyst molecule sieve load ferrum oxide, acetic acid, acetic anhydride, it is warming up to backflow, LC is controlled, crystallize of lowering the temperature, filters, mother solution
Apply mechanically.It is the most molten to product that crude product adds ethyl acrylate, is filtered to remove zeolite, is spin-dried for, the crude product acrylic acid second of 2.5 times of weight
Ester recrystallization, obtains white products 67.76g, yield 88%, purity 94%(LC).
Prepare and intermediate two: 250 ml reaction bulb adds 2-methyl-benzoic acid 40g, iron powder, trifluoromethanesulfonic acid, bromine/
Dichloromethane (through molecular sieve pretreatment), is warming up to backflow, drips 0.388mol bromine/dichloromethane solution, drips and finishes, refluxed
At night, in TLC, control terminates to reaction, and cooling drips saturated sodium sulfite and takes off to redness, separatory, water layer 30ml dichloromethane
Alkane extracts, and merges organic layer, washing, is spin-dried for obtaining crude product 53g, ethyl alcohol recrystallization, obtains product 54.09g, yield 85%, purity 95%
(LC).
Prepare addition 5-iodo-2-ar-Toluic acid 20g, dichloromethane, fumaric acid in intermediate three: 250ml four-hole boiling flask
Two formicesters, are warming up to 20 DEG C, drip thionyl chloride.Dropping is finished, and is warming up to backflow, and after 1.5h, sampling LC monitors without raw material.Cooling
To 2 DEG C, adding aluminum chloride, stir 15min, dropping 13.6g2-(is to fluorophenyl) the DCM solution of-thiophene.Dropping is finished, 20 DEG C
Lower reaction 3h, in LC, control is without raw material.It is cooled to 2 DEG C, adds aluminum chloride, stir 15min, the acetonitrile solution of dropping TMDSO, rise
Temperature is to back flow reaction 5h, and in LC, control terminates to reaction.Reactant liquor is poured in the hydrochloric acid solution of 5%, stirring, water layer dichloromethane
Alkane is extracted twice, and merges organic layer, and washing, anhydrous sodium sulfate is dried, and is spin-dried for, and with ethyl acetate and recrystallisation from isopropanol, obtains product
Product 21.75g, yield 70%, purity 98%(LC).
Prepare addition 5-bromo-2-ar-Toluic acid 800g, dichloromethane, fumaric acid two in intermediate three: 10L four-hole boiling flask
Formicester, is warming up to backflow, drips thionyl chloride, and in sampling LC, control terminates to reaction.It is cooled to 2 DEG C, adds aluminum chloride, dropping
Equimolar 2-(is to fluorophenyl) the DCM solution of-thiophene.Dropping is finished, and reacts 3 hours at 20 DEG C, and LC monitors without raw material.It is cooled to
2 DEG C, add aluminum chloride.Dropping acetonitrile, dropping is complete, and the acetonitrile solution of fast drop TMDSO is warming up to back flow reaction 5h, LC
Middle control terminates to reaction.Being poured into by reactant liquor in the hydrochloric acid solution of 10%, stir 15min, water layer 3L dichloromethane extracts, and closes
And organic layer, washing, it is spin-dried for, with ethyl acetate and recrystallisation from isopropanol, obtains product 1009.6g, yield 75%, purity 96%
(LC).
Prepare addition 384g alpha-D-glucose, pyridine, dichloromethane, 4-diformazan ammonia in four: 10L tetra-mouthful of reaction bulb of intermediate
Yl pyridines, mechanical agitation, it is heated to 48 DEG C.Close heating, add 10ml thionyl chloride.Start to drip pivaloyl chloride 1412g, 2h
Dripping complete, temperature maintains 50 DEG C of back flow reaction.HPLC detection is controlled.Reaction terminates rear negative pressure and is concentrated to dryness, and adds dichloromethane
Alkane and dilute hydrochloric acid stirring and dissolving, stratification, separatory.Anhydrous Na is used after organic facies washing2SO4It is dried, filters.Organic facies negative pressure
It is concentrated to dryness, obtains light yellow solid 1830g.Crude product dehydrated alcohol recrystallization, obtains white solid 1096g, purity 98%, yield
82%, standby.
In tetra-mouthfuls of reaction bulbs of 20L, it is passed through N2, add 750g Calcium Chel 330, dichloromethane, zinc bromide, stir.Instead
Answering liquid to be cooled to 10 DEG C, start the mixture dripping bromotrimethylsilane with dichloromethane, 1.5h dropping is complete.Control temperature
20-25 DEG C, stirring reaction 1.5h.HPLC detection terminates to reaction.Sucking filtration goes out zinc bromide, obtains yellow supernatant liquid.It is cooled to 0
DEG C, dripping sodium bicarbonate aqueous solution, monitoring pH value is at 7-8.Separatory obtains organic layer and adds anhydrous Na2SO4It is dried, filters.Organic layer is born
Pressure is concentrated to give lurid solid 700g, crude product purity 88%.Isopropanol is washed and starched, and obtains product 599.7g, yield 83%, purity
97.5%.Total recovery 68.06%.
Prepare intermediate five: anhydrous and oxygen-free device, 500ml reaction bulb adds intermediate three 40.8g, n-butyl ether, toluene,
Logical nitrogen, cools to-40 DEG C, drips butyl lithium, drips Bi Baowen 2h.Dropping zinc bromide lithium bromide butyl ether solution, dropping is complete,
30 DEG C of insulation 2h.The toluene solution of dropping intermediate four, is warming up to 90 DEG C of insulations, controls to reacting knot in sampling LC after dripping
Bundle.Being poured into by reactant liquor after cooling in the dilute hydrochloric acid of 500ml, separatory, water layer 120ml*3 ethyl acetate extracts, and merges organic
Layer, washing, separatory, concentration are done to obtain brown oil, are added ethyl alcohol recrystallization and obtain product 55.5g.Purity 95%, yield 71%.
The four-hole boiling flask of the preparation of canagliflozin: 2L adds 150g intermediate five, methanol, 15min is stirred at room temperature.Dropping
The methanol solution of 30% Feldalat NM, drips complete being warming up to and refluxes.LC is controlled to reacting complete.Normal pressure steams the spy being difficult to remove
After levying impurity, be concentrated to give crude product, then add methanol, method that Acetic Acid-Water, water, methanol-water equal solvent are repeatedly pulled an oar progressively is removed
Various impurity, filter, and recrystallizing methanol obtains solid 72.6g, yield 85%, purity 98%(LC) more than.
The canagliflozin new technique for synthesizing advantage specific as follows of the present invention:
1) synthesis of intermediate one, uses catalytic synthetic techniques, uses and makes the participation of molecular sieve carried ferric oxide catalyst by oneself
Reaction, makes the selectivity of 5 upper iodine increase to almost absolutely from 60%.This step yield is made to bring up to more than 88%, greatly
Improve greatly yield, reduce impurity.The step that complex fine grained high-temperature hot filters has been evaded in this external post processing,
Because this step is high to equipment requirements, temperature is slightly lower, and product just separates out from filtrate, blocks filter cloth.It is changed by this method
Become, use cold filtration after cooling, the way of mother liquid recycle.Filter cake then uses lower step solvent dissolution, contains product after filtering catalyst
Filtrate directly participates in the next step.Technique is simple to operation, greatly reduces process time and difficulty, and producing feasibility substantially carries
Height, also can improve yield, and decrease the pollution to environment.
2) synthesis of intermediate two is by groping with synthesis mechanism reaction condition, makes 3 special adaptations.One is
Want molecular sieve that reaction dissolvent is carried out pretreatment so that it is absolute；The metal examinations such as the Fe powder of two catalytic amounts to be added, ferric bromide
Agent；The super acids such as the trifluoromethanesulfonic acid of three catalytic amounts to be added thereto to, p-methyl benzenesulfonic acid, can be by original anti-almost without product
High yield should be accomplished.
3) upper pivaloyl group one step during synthetic intermediate four, adds a small amount of thionyl chloride, can in the case of yield does not drops
The consumption of pivaloyl chloride is reduced 50%, reduces the pollution to environment.
4), during synthetic intermediate five, reduction dehydroxylation after traditional TMS protection glucose docks has been evaded with intermediate three
Method, with 2,3,4,6-O-tetra-pivaloyl group-ALPHA-D-bromo Glucopyranose .s dock with intermediate three, can avoid deshydroxy
Base, improves total recovery, is greatly saved cost.And to connecting the homemade bridge joint catalyst of employing so that yield carried than originally
High by 20%.
Claims (3)
1. the synthesis technique of canagliflozin, it is characterised in that comprise the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mol times be
The Iod R of 0.5 ~ 1.0 generates intermediate one 5-iodo-2-ar-Toluic acid, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically；
B or with 2-ar-Toluic acid as initiation material, under the effect of metal reagent and super acidic catalyst, adds mole times
Number is the bromine of 1.05 ~ 1.5, and solvent bromine is used molecular sieve absolute pretreatment, synthetic intermediate two 5-bromo-2-first
Yl benzoic acid；
C, optional intermediate one or intermediate two carry out acylation reaction as the first thionyl chloride with 1.1 equivalents of fragment, then exist
With the 2-(of equimolar ratio to fluorophenyl under the effect of catalyst aluminum chloride)-thiophene carries out Friedel-Crafts reaction and generates intermediate three；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, trimethyl
Bromo-silicane generates intermediate four-10 ~ 25 DEG C of reactions；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 76-80 degree Celsius, in self-control catalysis
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, and first normal pressure steams
After going out the feature impurity being difficult to remove, it is concentrated to give crude product, then the method repeatedly pulled an oar with different solvents is progressively removed various miscellaneous
Matter, obtains the purity target product higher than 98%；
In b step, metal reagent is Fe powder or ferric bromide, and super acidic catalyst is trifluoromethanesulfonic acid or p-methyl benzenesulfonic acid.
The synthesis technique of canagliflozin the most according to claim 1, it is characterised in that: in Step d, with ALPHA-D-Portugal
Grape sugar is raw material, through reacting all hydroxyls of protection with pivaloyl chloride, adds a small amount of thionyl chloride in the technique of upper protection group.
The synthesis technique of canagliflozin the most according to claim 1, it is characterised in that: in f step, solvent is methanol, vinegar
The mixed solvent of acid, methanol and water, acetic acid and the one in the mixed solvent of water.
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| CN104311532B (en) * | 2014-10-31 | 2016-04-20 | 山东大学 | The preparation method of 2-(4-fluorophenyl)-5-[(the bromo-2-aminomethyl phenyl of 5-) methyl] thiophene |
| 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 |
| CN104744449B (en) * | 2015-03-21 | 2018-02-09 | 北京工业大学 | A kind of preparation method of canagliflozin semihydrate and its monocrystalline |
| US10370365B2 (en) | 2015-09-16 | 2019-08-06 | Optimus Drugs (P) Limited | Process for the preparation of Canagliflozin |
| CN105399735A (en) * | 2015-12-29 | 2016-03-16 | 上海应用技术学院 | Empagliflozin intermediate, and preparation method and application thereof |
| CN108017612B (en) * | 2017-11-29 | 2020-06-09 | 南通常佑药业科技有限公司 | Preparation method of canagliflozin intermediate |
| CN114591313A (en) * | 2020-12-04 | 2022-06-07 | 南京圣鼎医药科技有限公司 | Preparation method of canagliflozin |
| CN113149828A (en) * | 2021-03-31 | 2021-07-23 | 山东寿光增瑞化工有限公司 | Preparation method of 5-bromo-2-methylbenzoic acid |
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