CN108530408A - The method for preparing Dapagliflozin - Google Patents
The method for preparing Dapagliflozin Download PDFInfo
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- CN108530408A CN108530408A CN201810328325.0A CN201810328325A CN108530408A CN 108530408 A CN108530408 A CN 108530408A CN 201810328325 A CN201810328325 A CN 201810328325A CN 108530408 A CN108530408 A CN 108530408A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
A kind of shorter, the more effective method for synthesizing Dapagliflozin that the purpose of the present invention is to provide steps.This method is using 5 bromine, 2 chlorine, 4 ' oxethyl-diphenyl-ketone as starting material; ketal protection is completed through strong acid catalyst; the glucolactone that the diaryl ketal compound of acquisition is protected after being handled with magnesium with trimethylsilyl reacts, and the preparation of Dapagliflozin can be completed in the hemiketal compound reduction that diluted acid obtains after being quenched.
Description
Technical field
The invention belongs to bulk pharmaceutical chemicals preparation method fields, and in particular to the preparation of bulk pharmaceutical chemicals Dapagliflozin.
Background technology
Dapagliflozin propylene glycol monohydrate (dapagliflozin Propanediol Monohydrate) is a kind of
Sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor, by Bristol Myers Squibb (Bristol-Myers-Squibb, BMS)
It is researched and developed jointly with AstraZeneca (AstraZeneca, AZ), obtains European drug administration (EMA) on November 12nd, 2012 first
Approval is that first, the whole world obtains SGLT2 inhibitor of the listing for treating diabetes B.U.S.'s food and medicine supervision and management
Office (FDA) announces that the treatment of diabetes B is used it in approval on January 8th, 2014.Based in 9,400 many cases, 2 type glycosuria
16 clinical tests carried out in patient the results show that the drug therapy can improve glycosated Hb A 1c.Its oral medicine
The mechanism of action of object is by the SGLT2 for inhibiting to be expressed in kidney, to reduce the glucose reabsorption of kidney, increase Portugal in urine
The excretion of grape sugar, to reduce plasma glucose levels in the case where not increasing insulin secretion.On March 13rd, 2017, Ah
Si Likang China announces, the treating diabetes under Chinese food pharmaceuticals administration general bureau (CFDA) official approval AstraZeneca
New medicine Dapagliflozin propylene glycol monohydrate can be used as single therapy, improve glycemic control for diabetes B adult patient,
Thus the drug becomes first 2 inhibitor of sodium-glucose co-transporter listed in China.The listing of the drug at home,
Diabetes B patient for China brings new selection, and more people is enable therefrom to benefit, to further improve Chinese 2 types
The control rate of diabetes and Clinical Outcome.In March, 2018, AstraZeneca (AstraZeneca) are even more to announce, EMA, which has been accepted, to be reached
Lattice arrange the listing license modification application (MAV) of net propylene glycol monohydrate, and this time MAV seeks to ratify one water of Dapagliflozin propylene glycol
Close a kind of oral adjuvant therapy medicaments of the object as insulinization, for receive insulin therapy but blood glucose level control it is bad
Type 1 diabetes adult patient, improve its glycemic control.If granted, Dapagliflozin propylene glycol monohydrate is expected to become Europe
The first selective SGLT2 inhibitor of continent approval treatment type 1 diabetes, while having therapeutic effect to 1 type and diabetes B,
Application market is huge.
Dapagliflozin propylene glycol monohydrate, trade name:Farxiga (Anda Tang), is containing a molecular water and a molecule
The chemical name of the cocrystalization compound of S-1,2- propylene glycol, eutectic object Dapagliflozin is 2- chloro- 5- (2,3,4,6- tetra--hydroxyls
Base-β-D- glucopyranose -1- bases) -4 '-ethoxy diphenyl methane, shown in chemical structural formula following (Formulas I):
Synthetic method about Dapagliflozin (Formulas I) has many document reports, Sebastien Lemaire etc. report with
α-anhydrous grape sugar ester is the method (Org.Lett.2012,14,1480-1483) of starting material, and starting material is protected through pivaloyl group
After five hydroxyls, pyrans bromo-derivative is generated under hydrogen bromide acetic acid solution effect, the chloro- 4 '-ethyoxyl of bromide and the bromo- 2- of 5- two
The arylzinc reagent reaction that phenylmethane (Formula V) generates under magnesium lithium reagent and zinc bromide effect, most afterwards through sodium methoxide removing spy penta
Acyl group is protected to obtain Formulas I, and reaction route is as follows:
WO2013068850 is disclosed with 1,6- dehydration-β-D- glucopyranoses for starting material, through tert-butyl diphenyl silicon
Base protects hydroxyl, then with the aryl grignard reagent by chloro- 4 '-ethoxy diphenyl methane (Formula V) preparations of the bromo- 2- of 5- in alchlor
The lower reaction of catalysis, the method that last tetrabutyl ammonium fluoride (TBAF) removing silicon protecting group obtains Formulas I, route are as follows:
The main policies of another kind of synthesis Formulas I are glucolactone methods, which is anti-using cheap D-Glucose acid lactone
Answer object.Method as the patent WO2004063209A3 of BMS is reported is as follows:
The chloro- 4 '-ethoxy diphenyl methane (Formula V) of the bromo- 2- of 5- are by the bromo- 2- chlorobenzoic acids of 5- in oxalyl chloride in the route
Switch to acyl chlorides under effect, friedel-crafts acylation, the chloro- 4 '-ethoxy diphenyl first of the bromo- 2- of 5- of gained then occurs with phenetole
What ketone (Formula II) was obtained through reduction again.The chloro- 4 '-ethoxy diphenyl methane (Formula V) of the bromo- 2- of 5- are converted into virtue under butyl lithium effect
Base lithium reagent, after the maltonic acid lactone reaction of lithium reagent and trimethylsilyl protection, using hydrogen chloride/methanol or methanesulfonic acid/
Methyl alcohol process is converted into ketal compound, most afterwards through triethylsilane/boron trifluoride reduction system up to Formulas I, the purifying of product
It is to be recrystallized by the hydroxyacetyl protection at Formulas I to realize.
It is as follows that WO201002313A3 also reports similar synthetic route:
The route is substantially consistent with WO2004063209A3 strategies, mainly in the reduction chloro- 4 '-ethoxy diphenyls of the bromo- 2- of 5-
Innovated on the way of purification of the go back original reagent and product (Formulas I) that are selected when ketone (Formula II), use Formulas I and proline at
The method of eutectic object crystallization purifying.
In conclusion the method for synthesis Formulas I is all to use the chloro- 4 '-ethoxy diphenyl methane (Formula V) of the bromo- 2- of 5- as pass
Key intermediate reacts respectively with pyrylium compound or glucolactone to complete.In contrast, the side of glucolactone
Method is more cheap and easily-available on the material used, is not related to the stench pivaloyl chloride of such as pyrans method, extremely strong corrosive bromine
Change hydrogen/acetum, expensive tert-butyl diphenyl chlorosilane, tetrabutyl ammonium fluoride etc., the condition in the formation of glycosidic bond
Also more mild, can be realized using simple aryl lithium or Grignard Reagent, and in pyrylium compound method, need to add bromine
Change the additional reagents such as zinc, lithium chloride, Dibutyltin oxide, alchlor to assist completing.However, in existing gluconic acid
Ester method, reaction step is long, and the hemiacetal compound of acid labile is handled using strong acid/methanol system, is easy to happen side reaction,
Both processing step is increased, also inevitably will produce alkyl halide or sulfonic acid esters genotoxicity impurity, the step is from finished product
Separating step is close, this is very unfavorable for the control of base poison impurity in bulk pharmaceutical chemicals, it is necessary to which development procedure is shorter more
The method of effective synthesis Dapagliflozin Formulas I, generates the present invention is based on solving these problems.
Invention content
A kind of method for shorter, more effective synthesis Dapagliflozin Formulas I that the purpose of the present invention is to provide steps.The present invention
Synthetic route it is as follows:
The route, for starting material, ketal is completed through strong acid catalyst with the chloro- 4 '-oxethyl-diphenyl-ketones (Formula II) of the bromo- 2- of 5-
Protection, the diaryl ketal compound (formula III) of acquisition are anti-with the glucolactone of trimethylsilyl protection after being handled with magnesium
It answers, hemiketal compound (formula IV) reduction after diluted acid is quenched can be obtained Dapagliflozin (Formulas I).
Wherein, formula III is first ketal or second ketal, the generation of first, second ketal be with corresponding orthoformate methanesulfonic acid,
Under the strong acid catalysts such as trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, sulfuric acid, corresponding alcohol or alcohol and toluene, nitromethane, acetonitrile, tetrahydrochysene
Reaction is completed under two or more mixed solvents such as furans, dioxane;
Directly diluted acid is quenched i.e. after the Grignard Reagent prepared by formula III is reacted with the glucolactone that trimethylsilyl is protected
Formula IV is obtained, hemiketal formula IV no longer needs to be converted into corresponding ketal using strong acid/methyl alcohol process, directly uses triethylsilane/tri-
Fluorination borate ether system processing can be reduced to obtain target product Formulas I.
As discussed above, have method and all inevitably use the chloro- 4 '-ethoxy diphenyl methane (formulas of the bromo- 2- of 5-
V critical component, Formula V) is used as to be obtained by chloro- 4 '-oxethyl-diphenyl-ketone (Formula II) reduction of the bromo- 2- of its precursor 5-, and
Ketal is restored in glucolactone method is also inevitable step.The present invention cleverly uses the chloro- 4 '-second of the bromo- 2- of 5-
The chloro- 4 '-oxethyl-diphenyl-ketones (Formula II) of the bromo- 2- of precursor 5- of oxygroup diphenyl-methane (Formula V) are starting material, and ketone carbonyl is restored
It is completed in one step with ketal reduction design.In addition, the hemiketal (formula IV) after Grignard Reagent is docked with lactone can be straight
It connects and is reduced, without being restored after being ketal with strong acid/methyl alcohol process, both shorten reaction step, in turn avoid close
The generation of finished product step genotoxicity impurity.
In short, the synthetic route of the present invention is short, with the chloro- 4 '-oxethyl-diphenyl-ketone (formulas of the bromo- 2- of the 5- of cheaper
II) it is starting material, only 3 steps, which are reacted, can be obtained compound of formula I, and the reagent used is all easy to be commercialized a large amount of buyings, technique behaviour
Make simply, to be more suitable for Dapagliflozin industrial amplification production.This method is succinct, efficient, it is also possible to be applied to other similar
In the synthesis for arranging net class drug.
Specific implementation mode
It can more specifically understand the present invention by the following examples, but it illustrates rather than the limitation present invention
Range, those skilled in the art are to the simple replacement done of the present invention and improve etc. and to be all contained in what the present invention was protected
Within technical solution.
Embodiment one:The preparation (formula III, R=Et) of the bromo- 1- of 4- chloro- 2 [(4- ethyoxyls-phenyl)-diethoxy-methyl] benzene
The chloro- 4 '-ethyoxyls of the bromo- 2- of 5- are successively added in 500mL four-necked bottle frame magnetic agitations, thermometer and reflux condensing tube
Benzophenone (Formula II, 33.96g, 100mmol), triethyl orthoformate (22.2g, 150mmol), a hydration p-methyl benzenesulfonic acid
(1.9g, 10mmol) and absolute ethyl alcohol (200mL), is warming up to 60+5 DEG C of insulation reaction 6 hours under stirring, be cooled to room temperature, add
Enter triethylamine (2.0g) and adjust pH to alkalinity, decompression steams ethyl alcohol.Toluene (150mL) is added and dissolves residue, washing layering (2
× 60mL) twice, heptane mashing processing is added in organic layer after being concentrated under reduced pressure again, filtering obtains white mark after obtained solid drying
Inscribe compound (formula III, R=Et, 32.5g, yield 78.6%).
Embodiment two:The preparation (formula III, R=Me) of the bromo- 1- of 4- chloro- 2 [(4- ethyoxyls-phenyl)-dimethoxy-methyl] benzene
The chloro- 4 '-ethyoxyls of the bromo- 2- of 5- are successively added in 250mL four-necked bottle frame magnetic agitations, thermometer and reflux condensing tube
Benzophenone (Formula II, 16.98g, 50mmol), trimethyl orthoformate (15.92g, 150mmol), methanesulfonic acid (0.96g,
10mmol), absolute methanol (40mL) and toluene (120mL), are warming up to 60+5 DEG C of insulation reaction 10 hours under stirring, be cooled to room
Temperature is added triethylamine (1.5g) and adjusts pH to alkalinity, and twice, heptan is added after being concentrated under reduced pressure in organic layer for washing layering (2 × 100mL)
Alkane mashing is handled, filtering, and white title compound (formula III, R=Me, 15.9g, yield 82.4%) is obtained after obtained solid drying.
Embodiment three:(4- ethyoxyls-phenyl)-[3- (2,3,4,5- tetrahydroxys -6- methylols-ttetrahydro-pyran -2- bases)-benzene
Base]-ketone (formula IV) preparation
250mL four-necked bottle frame magnetic agitations, thermometer, constant pressure funnel and reflux condensing tube, under positive pressure of nitrogen protection
Chloro- 2 [(4- ethyoxyls-phenyl)-dimethoxy-methyl] benzene of the bromo- 1- of priority addition 4- (formula III, R=Me, 3.86g,
10mmol), anhydrous THF (20mL) and magnesium chips (25.2,100mmol), are warming up to 50 DEG C under stirring, persistently stir and wait for that reaction causes
After stabilization, start the bromo- 1- of 4- chloro- 2 [(4- ethyoxyls-phenyl)-dimethoxy-methyl] that configured in advance in constant pressure funnel is added dropwise
Benzene (formula III, R=Me, 34.7g, 90mmol) is dissolved in the solution of anhydrous THF (160mL), and heat release is apparent, controls dropwise addition process
Interior temperature is between 40-55 DEG C, after being added dropwise to complete, keeps the temperature 40-55 DEG C and reacts 1 hour, obtain grey grignard reagent solution, nitrogen is protected
It is spare under shield.Tetra--O- trimethylsilyl-D gluconic acid -1,5- lactones of 2,3,4,6- are added in the four-necked bottle of another 500mL
(46.7g, 100mmol) and toluene (180mL) is cooled to -20 DEG C after stirring dissolved clarification, by the Grignard Reagent of above-mentioned preparation under temperature control
Solution is slowly added dropwise in the 500mL reaction bulbs, adds -20 DEG C of heat preservation and reacts 2 hours, reaction solution is poured into the dilute hydrochloric acid of 1N
It is quenched 30 minutes, then with being layered after saturated sodium bicarbonate solution regulation system pH value big 7.Organic layer is washed with water (2 × 90mL)
Twice, then with saturated common salt water washing it is layered, it is formula IV compound that sticky oil object is obtained after organic concentration, is directly used in next step
Reaction.
Example IV:(4- ethyoxyls-phenyl)-[3- (2,3,4,5- tetrahydroxys -6- methylols-ttetrahydro-pyran -2- bases)-benzene
Base]-ketone (formula IV) preparation
250mL four-necked bottle frame magnetic agitations, thermometer, constant pressure funnel and reflux condensing tube, under positive pressure of nitrogen protection
Chloro- 2 [(4- ethyoxyls-phenyl)-diethoxy-methyl] benzene of the bromo- 1- of priority addition 4- (formula III, R=Et, 2.07g,
5mmol), anhydrous THF (10mL) and magnesium chips (12.6g, 50mmol), are warming up to 50 DEG C under stirring, persistently stir and wait for that reaction causes
After stabilization, start the bromo- 1- of 4- chloro- 2 [(4- ethyoxyls-phenyl)-diethoxy-methyl] that configured in advance in constant pressure funnel is added dropwise
Benzene (formula III, R=Et, 18.62g, 45mmol) is dissolved in the solution of anhydrous THF (80mL), and heat release is apparent, controls dropwise addition process
Interior temperature is between 40-55 DEG C, after being added dropwise to complete, keeps the temperature 40-55 DEG C and reacts 1 hour, obtain grey grignard reagent solution, nitrogen is protected
It is spare under shield.Tetra--O- trimethylsilyl-D gluconic acid -1,5- lactones of 2,3,4,6- are added in the four-necked bottle of another 250mL
(90mL is cooled to -20 DEG C after stirring dissolved clarification, under temperature control that the Grignard Reagent of above-mentioned preparation is molten for (23.4g, 50mmol) and toluene
Liquid is slowly added dropwise in the 250mL reaction bulbs, adds -20 DEG C of heat preservation and reacts 2 hours, reaction solution is poured into the dilute hydrochloric acid of 1N and is quenched
It goes out 30 minutes, then with being layered after saturated sodium bicarbonate solution regulation system pH value big 7.Organic layer washs two with water (2 × 50mL)
It is secondary, then be layered with saturated common salt water washing, it is formula IV compound that sticky oil object is obtained after organic concentration, is directly used in anti-in next step
It answers.
Embodiment five:The preparation of Dapagliflozin (Formulas I)
500mL four-necked bottle restocking magnetic agitations, low-reading thermometer, constant pressure funnel and positive pressure of nitrogen protect system, nitrogen
The formula IV compound (theory is 50mmol) that example IV obtains, acetonitrile (110mL), dichloromethane are successively added after gas displacement
(110mL) and triethylsilane (14.5g, 125mmol) is cooled to -25 DEG C, three in constant pressure funnel is added dropwise under temperature control under stirring
It is fluorinated diethyl etherate (17.8g, 125mmol), is stirred to react 4 hours, rises again to 30-40 at -20~-25 DEG C after adding
DEG C, after adding triethylsilane (11.6g, 100mmol), 35-40 DEG C of temperature control is added dropwise to boron trifluoride etherate again
(14.2g, 100mmol) adds 35-40 DEG C of heat preservation and reacts 6 hours, reaction is quenched with saturated sodium bicarbonate aqueous solution after cooling
Object, reduced pressure steam acetonitrile and dichloromethane, ethyl acetate (200mL) extracting and demixing are added, organic layer, which is washed with water, washs two
Secondary (2 × 50mL) is layered after organic layer salt water washing, and organic layer concentration is dry to obtain grease, is dissolved in a small amount of toluene and heptan is added
Alkane crystallization, it is Dapagliflozin (Formulas I, 11.3g, yield 55.3%, in terms of formula III) to cool down, faint yellow solid powder is obtained by filtration.
Claims (7)
1. a kind of method preparing Dapagliflozin (Formulas I) has following synthetic route:
2. the compound with formula III chemical constitution shown in claim 1.
3. formula III compound shown in claim 2 is by Formula II compound in trimethyl orthoformate or triethyl orthoformate
In the presence of carry out ketal and protect, R therein is methyl or ethyl.
4. catalyst used in first step reaction is methanesulfonic acid, trifluoromethanesulfonic acid, p-methyl benzenesulfonic acid, sulfuric acid in claim 1
Equal strong acid, the solvent used are two kinds of methanol, ethyl alcohol or alcohol and toluene, nitromethane, acetonitrile, tetrahydrofuran, dioxane etc.
Or a variety of mixed solvent.
5. the compound with formula IV chemical constitution shown in claim 1.
6. formula IV compound shown in claim 5 is the Grignard Reagent and tetra--O- front threes of 2,3,4,6- by formula III compound
Base silane base-D gluconic acid -1,5- lactones are condensed to yield, and used solvent is the mixed solvent of tetrahydrofuran and toluene.
7. Dapagliflozin shown in claim 1 is catalyzed in boron trifluoride ether by formula IV compound triethylsilane
What lower direct-reduction obtained, used solvent is the mixed solvent of dichloromethane and acetonitrile.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109705075A (en) * | 2018-12-13 | 2019-05-03 | 江苏苏中药业集团股份有限公司 | Purification method of dapagliflozin |
CN110305118A (en) * | 2019-06-20 | 2019-10-08 | 四川科伦药物研究院有限公司 | A kind of synthetic method that suitable industrial production En Gelie is net |
CN110396040A (en) * | 2019-09-09 | 2019-11-01 | 东南大学 | A kind of method of one pot process diaryl first ketal |
WO2021172955A1 (en) * | 2020-02-27 | 2021-09-02 | 주식회사 대웅제약 | Intermediate useful for synthesis of sglt inhibitor and method for preparing sglt inhibitor using same |
RU2802443C1 (en) * | 2020-02-27 | 2023-08-29 | Тэвун Фармасьютикал Ко., Лтд. | Intermediate used for synthesis of sglt inhibitor and method for producing sglt inhibitor using this intermediate |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1756759A (en) * | 2003-01-03 | 2006-04-05 | 布里斯托尔-迈尔斯斯奎布公司 | Methods of producing C-aryl glucoside SGLT2 inhibitors |
CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
CN105294624A (en) * | 2015-11-16 | 2016-02-03 | 山东罗欣药业集团股份有限公司 | Preparation method for dapagliflozin |
US20170240520A1 (en) * | 2016-02-19 | 2017-08-24 | Scinopharm Taiwan, Ltd. | Process for preparing sglt2 inhibitors and intermediates thereof |
-
2018
- 2018-04-13 CN CN201810328325.0A patent/CN108530408A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1756759A (en) * | 2003-01-03 | 2006-04-05 | 布里斯托尔-迈尔斯斯奎布公司 | Methods of producing C-aryl glucoside SGLT2 inhibitors |
CN105061373A (en) * | 2015-09-06 | 2015-11-18 | 合肥华方医药科技有限公司 | Synthesis method of dapagliflozin isomer impurity |
CN105294624A (en) * | 2015-11-16 | 2016-02-03 | 山东罗欣药业集团股份有限公司 | Preparation method for dapagliflozin |
US20170240520A1 (en) * | 2016-02-19 | 2017-08-24 | Scinopharm Taiwan, Ltd. | Process for preparing sglt2 inhibitors and intermediates thereof |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109705075A (en) * | 2018-12-13 | 2019-05-03 | 江苏苏中药业集团股份有限公司 | Purification method of dapagliflozin |
CN109705075B (en) * | 2018-12-13 | 2022-12-23 | 苏中药业集团股份有限公司 | Purification method of dapagliflozin |
CN110305118A (en) * | 2019-06-20 | 2019-10-08 | 四川科伦药物研究院有限公司 | A kind of synthetic method that suitable industrial production En Gelie is net |
CN110305118B (en) * | 2019-06-20 | 2024-04-02 | 四川科伦药物研究院有限公司 | Synthetic method suitable for industrial production of enggliflozin |
CN110396040A (en) * | 2019-09-09 | 2019-11-01 | 东南大学 | A kind of method of one pot process diaryl first ketal |
CN110396040B (en) * | 2019-09-09 | 2020-12-15 | 东南大学 | Method for synthesizing diaryl methyl ketal by one-pot method |
WO2021172955A1 (en) * | 2020-02-27 | 2021-09-02 | 주식회사 대웅제약 | Intermediate useful for synthesis of sglt inhibitor and method for preparing sglt inhibitor using same |
KR20210109476A (en) * | 2020-02-27 | 2021-09-06 | 주식회사 대웅제약 | Intermediates useful for the synthesis of SGLT inhibitors and a method of preparing SGLT inhibitors using the same |
CN115087649A (en) * | 2020-02-27 | 2022-09-20 | 株式会社大熊制药 | Intermediate for synthesizing SGLT inhibitor and method for preparing SGLT inhibitor by using intermediate |
RU2802443C1 (en) * | 2020-02-27 | 2023-08-29 | Тэвун Фармасьютикал Ко., Лтд. | Intermediate used for synthesis of sglt inhibitor and method for producing sglt inhibitor using this intermediate |
KR102572714B1 (en) | 2020-02-27 | 2023-08-31 | 주식회사 대웅제약 | Intermediates useful for the synthesis of SGLT inhibitors and a method of preparing SGLT inhibitors using the same |
JP7442663B2 (en) | 2020-02-27 | 2024-03-04 | デーウン ファーマシューティカル カンパニー リミテッド | Intermediates useful for the synthesis of SGLT inhibitors and methods for producing SGLT inhibitors using the same |
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