CN109336875A - A kind of synthetic method of canagliflozin - Google Patents
A kind of synthetic method of canagliflozin Download PDFInfo
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- CN109336875A CN109336875A CN201710697872.1A CN201710697872A CN109336875A CN 109336875 A CN109336875 A CN 109336875A CN 201710697872 A CN201710697872 A CN 201710697872A CN 109336875 A CN109336875 A CN 109336875A
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- 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 present invention relates to a kind of synthetic methods of canagliflozin, using 4- fluorobenzoic boric acid as starting material and 2- methyl -5- bromothiophene coupling synthesis 2- methyl -5- (4- fluorophenyl) thiophene, then bromo, 2-(2- methyl -5- bromobenzyl is synthesized through paying a gram alkylated reaction with 4- toluene bromide) -5-(4- fluorophenyl) thiophene, then with 2,3,4, tetra--O- trimethyl silicon substrate of 6--D-Glucose acid lactone is condensed, and etherificate, demethoxylation obtains antidiabetic drug canagliflozin.The present invention has the advantages that synthesis technology of the present invention, compared with existing synthetic method, using 4- fluorobenzoic boric acid as starting material, cost of material is cheap and easily-available, technique industrialization easy to accomplish, synthetic route is short, easy to operate；And in synthesis process, do not need to can reduce the danger level of technique using bromine or twice using butyl lithium；In addition, synthetic method through the invention, can be improved the yield of canagliflozin product, yield be can be improved to 70% or more.
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular to a kind of synthetic method of canagliflozin.
Background technique
Canagliflozin (canagliflozin, 1), entitled (1S) -1,5- dehydrogenation -1-C- [3- [[5- (the 4- fluorobenzene of chemistry
Base) -2- thienyl] methyl] -4- aminomethyl phenyl]-D-Glucose alcohol hydrate (2: 1) is by Mitsubishi Tanabe
A kind of oral 2 type of C- glycoside sodium dependent glucose that Pharma company original is ground cotransports body inhibitor.It can be close by blocking
Distal convoluted tubule is discharged the glucose of filtration from urine the re-absorption of glucose, to reach hypoglycemic purpose.In March, 2013 head
It is secondary to ratify to list through U.S. FDA, it is clinically used for treatment diabetes B, trade name Invokana.
Its synthetic method of canagliflozin is mainly the following, and a kind of scheme is with the bromo- 2- methyl benzoic acid of 5- for starting
Raw material is paid with 2- p-fluorophenyl thiophene and gram is acylated, then restore through chloride, then with 2,3,4,6- tetra--O- trimethyl silicanes
Canagliflozin is made in ester condensation in alkyl-D- glucopyra saccharic acid -1,5-, methyl-etherified, reduction de-methoxy；Such as document: PCT
Int. Appl.,2016098016；PCT Int.Appl., 2016016852, synthetic route is as follows:
Program route is shorter, but starting material synthesis difficulty is big, at high cost, expensive.
Another synthetic schemes is using 5- nitro -2- methyl benzoyl chloride as starting material, with the bromo- 5- thienyl boric acid coupling of 2-
Reaction is closed, then pays and gram is acylated with 2- p-fluorophenyl thiophene, nitro reduction, diazotising bromo, then with 2,3,4,6- tetra--O-
Canagliflozin is made in trimethylsilyl-D- glucopyra saccharic acid 1, ester condensation in 5-, methyl-etherified, reduction de-methoxy；As specially
Benefit: CN104311532, synthetic route are as follows:
The synthetic schemes route is long, and yield is low.
The third scheme is equally to pass through fourth with 2- p-fluorophenyl thiophene using 2- methyl -5- bromobenzaldehyde as starting material
The reaction of base lithium, reduction, then with 2, ester condensation in 3,4,6- tetra--O- trimethylsilyl-D- glucopyra saccharic acids -1,5-, first
Etherificate restores de-methoxy, and canagliflozin is made；Such as patent: CN104987320, synthetic route are as follows:
The raw materials technology is expensive, uses butyl lithium twice, and process dangerous is higher.
4th kind of scheme is reacted with 4- bromofluorobenzene, is then aoxidized using 2 thiophene carboxaldehyde as starting material, chloride, with
The reaction of 4- toluene bromide, reduction, then and with 2,3,4,6- tetra--O- trimethylsilyl-D- glucopyra saccharic acids 1, the contracting of 5- lactone
It closes, methyl-etherified, canagliflozin is made in reduction de-methoxy；Such as patent: Eur.Pat.Appl., 20152918579 synthesize road
Line is as follows:
The reaction route is longer, and yield is lower.
5th kind of synthetic schemes be using o-toluic acid as starting material, through bromo, then with 2- p-fluorophenyl thiophene
Occur friedel-crafts reaction, reduction, then and with 2,3,4,6- tetra--O- trimethylsilyl-D- glucopyra saccharic acids 1, the contracting of 5- lactone
It closes, methyl-etherified, canagliflozin is made in reduction de-methoxy；Such as patent: CN103980263, synthetic route are as follows:
The process route uses bromine, and environmental pollution is serious.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of low in cost, easy to operate, synthesis
Route is safe and can improve the synthetic method of the canagliflozin of product yield.
In order to solve the above technical problems, the technical solution of the present invention is as follows: a kind of synthetic method of canagliflozin, innovative point
It is: using 4- fluorobenzoic boric acid as starting material and 2- methyl -5- bromothiophene coupling synthesis 2- methyl -5- (4- fluorophenyl) thiophene,
Then bromo synthesizes 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene through paying a gram alkylated reaction with 4- toluene bromide,
Then with 2,3,4,6- tetra--O- trimethyl silicon substrates-D-Glucose acid lactone is condensed, and etherificate, demethoxylation obtains antidiabetic drug card
Lattice column are net；Specifically comprise the following steps:
(1) preparation (I) of 2- methyl -5- (4- fluorophenyl) thiophene: 4- fluorobenzoic boric acid and 2- methyl -5- bromothiophene are according to molar ratio
1:1.1- 1.3 is mixed, and is taken water as a solvent, and tetrabutylammonium bromide is phase transfer catalyst, acetic acid palladium chtalyst, under room temperature instead
2- methyl -5- (4- fluorophenyl) thiophene (I) should be synthesized；Specific reaction is as follows:
(2) preparation (II) of 2- bromomethyl -5- (4- fluorophenyl) thiophene: by 2- methyl -5- (4- fluorophenyl) thiophene and NBS according to
Molar ratio 1:1-1.1 is molten to react in a solvent, causes reaction synthesis 2- bromomethyl -5- (the 4- fluorine at 60-80 DEG C by initiator
Phenyl) thiophene (II)；Specific reaction is as follows:
(3) preparation (III) of 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene: 2- bromomethyl -5- (4- fluorophenyl)
Thiophene and 4- toluene bromide are dissolved in solvent according to molar ratio for 1:1.1-1.3, and catalyze and synthesize 2- (2- methyl-through lewis acid
5- bromobenzyl) -5- (4- fluorophenyl) thiophene (III)；Specific reaction is as follows:
(4) 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorophenyl) -2- thienyl] first
Base] benzene preparation (IV): 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene is dissolved in solvent, with 2,3,4,6-
The reaction of four-O- trimethyl silicon substrate-D- glucolactones, is condensed, then in methanesulfonic acid condition under the catalysis of n-BuLi
Under, the protection of trimethyl silicon substrate is taken off, prepares 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- with methanol etherification
[[5- (4- fluorophenyl) -2- thienyl] methyl] benzene (IV)；Specific reaction is as follows:
(5) preparation (V) of canagliflozin: 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorine
Phenyl) -2- thienyl] methyl] benzene is dissolved in methylene chloride/acetonitrile, and pass through Louis acid catalysis silicon hydrogen reduction agent and restores piptonychia
Oxygroup prepares canagliflozin (V)；Specific reaction is as follows:
Further, in the step (2), any one of carbon tetrachloride, chloroform or carbon disulfide, initiator is may be selected in solvent
Any one of optional BPO or AIBN.
Further, in the step (3), any one of ethyl acetate, carbon disulfide or nitrobenzene is may be selected in solvent,
Any one of aluminum trichloride (anhydrous), zinc chloride or alchlor may be selected in lewis acid.
Further, in the step (4), solvent be may be selected in ether/toluene or tetrahydrofuran/toluene solvant system
It is any.
Further, in the step (5), appointing for zinc chloride, aluminum trichloride (anhydrous) or lithium chloride is may be selected in lewis acid
Any one of trimethyl silicane hydrogen or triethyl group silicon hydrogen may be selected in one kind, silicon hydrogen reduction agent.
The present invention has the advantages that the synthetic method of canagliflozin of the present invention, compared with existing synthetic method, with 4- fluorobenzene
Boric acid is starting material, and cost of material is cheap and easily-available, and technique industrialization easy to accomplish, synthetic route is short, easy to operate；And synthesis work
During skill, do not need to can reduce the danger level of technique using bromine or twice using butyl lithium；In addition, through the invention
Synthetic method, can be improved the yield of canagliflozin product, and yield can be improved to 70% or more；
Specific embodiment
The following examples can make professional and technical personnel that the present invention be more fully understood, but therefore not send out this
It is bright to be limited among the embodiment described range.
The synthetic method of canagliflozin of the present invention is coupled by starting material and 2- methyl -5- bromothiophene of 4- fluorobenzoic boric acid
2- methyl -5- (4- fluorophenyl) thiophene is synthesized, then bromo, synthesizes 2- (2- first through paying a gram alkylated reaction with 4- toluene bromide
Base -5- bromobenzyl) -5- (4- fluorophenyl) thiophene, then with 2,3,4,6- tetra--O- trimethyl silicon substrates-D-Glucose acid lactone warp
Condensation, takes off the protection of trimethyl silicon substrate, etherificate, and demethoxylation obtains antidiabetic drug canagliflozin；Specifically comprise the following steps:
(1) preparation (I) of 2- methyl -5- (4- fluorophenyl) thiophene: 4- fluorobenzoic boric acid and 2- methyl -5- bromothiophene are according to molar ratio
1:1.1- 1.3 is mixed, and is taken water as a solvent, and tetrabutylammonium bromide is phase transfer catalyst, acetic acid palladium chtalyst, under room temperature instead
2- methyl -5- (4- fluorophenyl) thiophene (I) should be synthesized；Specific reaction is as follows:
(2) preparation (II) of 2- bromomethyl -5- (4- fluorophenyl) thiophene: by 2- methyl -5- (4- fluorophenyl) thiophene and NBS according to
Molar ratio 1:1-1.1 is molten to react in a solvent, causes reaction synthesis 2- bromomethyl -5- (the 4- fluorine at 60-80 DEG C by initiator
Phenyl) thiophene (II)；Wherein, any one of carbon tetrachloride, chloroform or carbon disulfide may be selected in solvent, and preferably toxicity is weaker
Chloroform is as solvent；Any one of BPO or AIBN may be selected in initiator, and the preferably weaker BPO of toxicity is as initiator；Specifically
It reacts as follows:
(3) preparation (III) of 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene: 2- bromomethyl -5- (4- fluorophenyl)
Thiophene and 4- toluene bromide are dissolved in solvent according to molar ratio for 1:1.1-1.3, and catalyze and synthesize 2- (2- methyl-through lewis acid
5- bromobenzyl) -5- (4- fluorophenyl) thiophene (III)；Wherein, solvent may be selected in ethyl acetate, carbon disulfide or nitrobenzene
Any, the preferably weaker ethyl acetate of toxicity is as solvent；Aluminum trichloride (anhydrous), zinc chloride or tribromo may be selected in lewis acid
Change any one of aluminium, preferably anhydrous aluminum chloride；Specific reaction is as follows:
(4) 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorophenyl) -2- thienyl] first
Base] benzene preparation (IV): 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene is dissolved in solvent, with 2,3,4,6-
The reaction of four-O- trimethyl silicon substrate-D- glucolactones, is condensed, then in methanesulfonic acid condition under the catalysis of n-BuLi
Under, the protection of trimethyl silicon substrate is taken off, prepares 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- with methanol etherification
[[5- (4- fluorophenyl) -2- thienyl] methyl] benzene (IV)；Wherein, ether/toluene or tetrahydrofuran/toluene may be selected in solvent
Dicyandiamide solution, since ether boiling point is lower, preferred tetrahydrofuran/toluene system is as solvent；Specific reaction is as follows:
(5) preparation (V) of canagliflozin: 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorine
Phenyl) -2- thienyl] methyl] benzene is dissolved in methylene chloride/acetonitrile, and pass through Louis acid catalysis silicon hydrogen reduction agent and restores piptonychia
Oxygroup prepares canagliflozin (V)；Wherein, any one of zinc chloride, aluminum trichloride (anhydrous) or lithium chloride may be selected in lewis acid,
Zinc chloride catalytic performance is weaker, and the reaction time is longer, and lithium chloride is more toxic, therefore preferred aluminum trichloride (anhydrous)；Silicon hydrogen reduction
Any one of trimethyl silicane hydrogen or triethyl group silicon hydrogen, preferably triethyl group silicon hydrogen may be selected in agent；Specific reaction is as follows:
Below by specific embodiment to the synthetic method of canagliflozin of the present invention, it is described in detail:
The preparation (I) of embodiment 1 2- methyl -5- (4- fluorophenyl) thiophene
Take 4- fluorobenzoic boric acid 140g, 2- methyl -5- bromothiophene 176g, tetrabutylammonium bromide 325g, acid chloride 2.24g, potassium carbonate
2000 grams of deionized water, reaction 2h is stirred at room temperature in 300g, and after reaction, 400 milliliters of ethyl acetate extractions dry, filter,
Ethyl acetate is recovered under reduced pressure, 70% ethyl alcohol recrystallization obtains white crystal 178.5g, yield 93%.
The preparation (II) of embodiment 2 2- bromomethyl -5- (4- fluorophenyl) thiophene
Take 2- methyl -5- (4- fluorophenyl) thiophene 96g, N- bromo-succinimide 100g, chloroform 200ml, BPO2.4 grams, 70 DEG C
6h is reacted, after reaction, system is cooled to room temperature, filtering, filtrate saturated common salt water washing, and washing dries, filters, and is depressurized
Recycling design, residue petroleum ether: ethyl acetate (1:1) recrystallizes to obtain light yellow solid 129.6g, yield 96%.
The preparation (III) of 3 2- of embodiment (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene
2- bromomethyl -5- (4- fluorophenyl) thiophene 134g, 4- toluene bromide 90g is taken, is dissolved in 400ml ethyl acetate, under ice bath, in batches
Aluminum trichloride (anhydrous) 70g is added, 30min adds, then the reaction was continued under reaction solution ice bath 30min, is then to slowly warm up to room
Temperature reaction 1h, is continuously heating to 80 DEG C of reaction 7h and is cooled to room temperature after reaction, ice dilute hydrochloric acid is added into reaction system
400 milliliters, liquid separation, organic layer is washed, and anhydrous sodium sulfate dries, filters, and filtrate decompression recycles to obtain crude product, is tied again with 95% ethyl alcohol
It is brilliant to obtain white solid 141g, yield 83%.
4 1- of embodiment (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorophenyl) -2- thiophene
Pheno base] methyl] benzene preparation (IV)
Take 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene 68g, anhydrous tetrahydro furan/toluene 150g (1:4) mixing
Solvent is added to through in the dry 500ml reaction flask of nitrogen, liquid nitrogen is cooled to -78 DEG C, and 1.6molL is slowly added dropwise-1N-BuLi
Hexane solution 35ml maintains to be stirred to react 1h at a temperature of this；- 78 DEG C of tetra- Portugal-O- trimethyl silicon substrate-D- 2,3,4,6- will be cooled to
The toluene solution 250g of grape saccharic acid lactone (100g) is slowly added dropwise into above-mentioned reaction solution, -78 DEG C of the reaction was continued 3h, end of reaction
Afterwards, the methanol solution (methanesulfonic acid 90g+ methanol 110g) of 200g methanesulfonic acid is added at such a temperature；It is warming up to 0 DEG C and continues stirring instead
4h is answered, 40 DEG C is then heated to and is stirred to react 6h；After reaction, 5molL is used-1Sodium hydrate aqueous solution adjust reaction
The pH to 7-8 of liquid；Stir 30min, with ethyl acetate (300ml × 2) extract, organic phase with saturated salt solution aqueous solution wash to
Then neutrality is added anhydrous sodium sulfate and dries, filters, filtrate decompression recycling design obtains faint yellow sticky oil object 70g, yield
77%.
The preparation (V) of 5 canagliflozin of embodiment
Take 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorophenyl) -2- thienyl] methyl]
Benzene 45g, methylene chloride 60ml and acetonitrile 180ml are added in 500ml reaction flask, stir evenly；Reaction solution is cooled to -5 DEG C, is added
3g aluminum trichloride (anhydrous) stirs 30min, keeps the temperature that 66g Et is added dropwise3SiH, drop finish, and system is to slowly warm up to 10 DEG C, instead
Answer 2h；End of reaction, system are cooled to -5 DEG C, and saturated sodium bicarbonate solution is added dropwise and adjusts pH to 6-7；With ethyl acetate (200g
× 2) it extracting, organic phase successively uses saturated sodium chloride solution, water washing to neutrality, and anhydrous sodium sulfate is then added and dries, filters,
The mixed solution of 150g methanol and acetone (1:1), stirring is added in filtrate decompression concentration and recovery ethyl acetate, and a large amount of solids are precipitated,
Cooling and stirring 30min；Filtering, cold ethanol washing solid, 50 DEG C are dried in vacuum overnight, and obtain white solid 31.4g, yield 74%,
Purity 99.23%.
Basic principles and main features and advantages of the present invention of the invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (5)
1. a kind of synthetic method of canagliflozin, it is characterised in that: using 4- fluorobenzoic boric acid as starting material and 2- methyl -5- bromine thiophene
Pheno coupling synthesis 2- methyl -5- (4- fluorophenyl) thiophene, then bromo, synthesizes 2- through paying a gram alkylated reaction with 4- toluene bromide
(2- methyl -5- bromobenzyl) -5-(4- fluorophenyl) thiophene, then with 2, in 3,4,6- tetra--O- trimethyl silicon substrates-maltonic acid
Ester is condensed, and etherificate, demethoxylation obtains antidiabetic drug canagliflozin；Specifically comprise the following steps:
(1) preparation (I) of 2- methyl -5- (4- fluorophenyl) thiophene: 4- fluorobenzoic boric acid and 2- methyl -5- bromothiophene are according to molar ratio
1:1.1-1.3 mixing, takes water as a solvent, tetrabutylammonium bromide is phase transfer catalyst, and acetic acid palladium chtalyst reacts under room temperature
Synthesize 2- methyl -5-(4- fluorophenyl) thiophene (I)；Specific reaction is as follows:
(2) 2- bromomethyl -5-(4- fluorophenyl) thiophene preparation (II): by 2- methyl -5-(4- fluorophenyl) thiophene and NBS according to
Molar ratio 1:1-1.1 is molten to react in a solvent, causes the reaction synthesis 2- bromomethyl -5-(4- fluorine at 60-80 DEG C by initiator
Phenyl) thiophene (II)；Specific reaction is as follows:
(3) preparation (III) of 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene: 2- bromomethyl -5- (4- fluorophenyl)
Thiophene and 4- toluene bromide are dissolved in solvent according to molar ratio for 1:1.1-1.3, and catalyze and synthesize 2-(2- methyl-through lewis acid
5- bromobenzyl) -5- (4- fluorophenyl) thiophene (III)；Specific reaction is as follows:
(4) 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorophenyl) -2- thienyl] first
Base] benzene preparation (IV): 2- (2- methyl -5- bromobenzyl) -5- (4- fluorophenyl) thiophene is dissolved in solvent, with 2,3,4,6-
Four-O- trimethyl silicon substrates-maltonic acid lactone reaction, are condensed under the catalysis of n-BuLi, then under the conditions of methanesulfonic acid,
De- trimethyl silicon substrate protection, prepares 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- with methanol etherification
(4- fluorophenyl) -2- thienyl] methyl] benzene (IV)；Specific reaction is as follows:
IV
(5) preparation (V) of canagliflozin: 1- (1-O- methyl-β-D- glucopyranose -1- base) -4- methyl -3- [[5- (4- fluorine
Phenyl) -2- thienyl] methyl] benzene is dissolved in methylene chloride/acetonitrile, and pass through Louis acid catalysis silicon hydrogen reduction agent and restores piptonychia
Oxygroup prepares canagliflozin (V)；Specific reaction is as follows:
。
2. the synthetic method of canagliflozin according to claim 1, it is characterised in that: in the step (2), solvent is optional
Select any one of any one of carbon tetrachloride, chloroform or carbon disulfide, initiator optional BPO or AIBN.
3. the synthetic method of canagliflozin according to claim 1, it is characterised in that: in the step (3), solvent is optional
Any one of ethyl acetate, carbon disulfide or nitrobenzene are selected, aluminum trichloride (anhydrous), zinc chloride or tribromo may be selected in lewis acid
Change any one of aluminium.
4. the synthetic method of canagliflozin according to claim 1, it is characterised in that: in the step (4), solvent is optional
Select any one of ether/toluene or tetrahydrofuran/toluene solvant system.
5. the synthetic method of canagliflozin according to claim 1, it is characterised in that: in the step (5), lewis acid
Any of zinc chloride, aluminum trichloride (anhydrous) or lithium chloride may be selected, trimethyl silicane hydrogen or triethyl group may be selected in silicon hydrogen reduction agent
Any one of silicon hydrogen.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110845469A (en) * | 2019-12-11 | 2020-02-28 | 台州学院 | Preparation method of canagliflozin intermediate |
| CN110950833A (en) * | 2019-12-11 | 2020-04-03 | 台州学院 | Preparation method of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene |
| CN111040000A (en) * | 2019-12-26 | 2020-04-21 | 沈阳药科大学 | Method for preparing intermediate of gliflozin hypoglycemic drug |
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| JP2016017040A (en) * | 2014-07-07 | 2016-02-01 | ＴＡＫ−Ｃｉｒｃｕｌａｔｏｒ株式会社 | Hydroxamic acid derivatives and hdac8 inhibitors |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110845469A (en) * | 2019-12-11 | 2020-02-28 | 台州学院 | Preparation method of canagliflozin intermediate |
| CN110950833A (en) * | 2019-12-11 | 2020-04-03 | 台州学院 | Preparation method of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene |
| CN111040000A (en) * | 2019-12-26 | 2020-04-21 | 沈阳药科大学 | Method for preparing intermediate of gliflozin hypoglycemic drug |
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