CN107200683A - A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate - Google Patents
A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate Download PDFInfo
- Publication number
- CN107200683A CN107200683A CN201710638927.1A CN201710638927A CN107200683A CN 107200683 A CN107200683 A CN 107200683A CN 201710638927 A CN201710638927 A CN 201710638927A CN 107200683 A CN107200683 A CN 107200683A
- Authority
- CN
- China
- Prior art keywords
- bromo
- preparation
- chloride
- dapagliflozin
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
Abstract
The invention discloses a kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate, wherein, the preparation method comprises the following steps：1) under DMF catalysis, the chlorobenzoic acid of 5 bromine 2 and oxalyl chloride haptoreaction in anhydrous methylene chloride are obtained into the chlorobenzoyl chloride of 5 bromine 2；2) in the presence of tert-butyl chloro-silicane, by step 1) the obtained chlorobenzoyl chloride of 5 bromine 2 carries out reacting under ferric trichloride catalytic and obtains the oxethyl-diphenyl-ketone of 5 bromine of Dapagliflozin intermediate, 2 chlorine 4 ' with phenetole.The preparation method for the Dapagliflozin intermediate that the present invention is provided will not produce ortho position accessory substance, and target product yield is high, and providing good material storage for Dapagliflozin supports.And the preparation method mild condition, the reaction time is short, it is adapted to industrialized production and promotes.
Description
Technical field
The present invention relates to the preparation field of medical compounds, in particular it relates to which a kind of be used to treat type II diabetes up to lattice
Arrange the preparation method of net intermediate.
Background technology
Diabetes are a kind of metabolic diseases being characterized with hyperglycaemia.Hyperglycaemia be due to then defect of insulin secretion or
Its biological agent is damaged, or both have concurrently and cause.Long-standing hyperglycaemia during diabetes, cause various tissues, particularly eye,
Kidney, heart, blood vessel, the chronic lesion of nerve, dysfunction.Therefore, Remedies for diabetes is always the focus of medicament research and development.
EU Committee have approved what Bristol Myers Squibb and AstraZeneca were developed jointly on November 14th, 2012
Forxiga (dapagliflozin, Dapagliflozin) is used to treat diabetes B, and the medicine is with sodium glucose co-transporter 2
(Sodium glucose co-transporters, referred to as SGLT-2) is first medicine of action target spot in vain.Da Gelie
Glycosyl is connected with aryl side chains by β-C- aryl glycoside keys in net chemical constitution, and concrete structure formula is as follows：
The synthetic method on the side chain mainly has following several method in the prior art, for example：Patent WO03099836
The intermediate compound I a of report preparation method, specific circuit is as follows, and this method is using the bromo- 2- chlorobenzoic acids of 5- as raw material, with oxalyl chloride
The bromo- 2- chlorobenzoyl chlorides of intermediate 5- are made in reaction, then chloro- through the bromo- 2- of the obtained intermediate 5- of Fu Ke acylation reactions with phenetole
4 '-oxethyl-diphenyl-ketone, is then made intermediate I with triethyl silicane and BFEE reduction.The defect of this method
It is when preparing the chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of intermediate 5-, to be sent out by the bromo- 2- chlorobenzoyl chlorides of intermediate 5- and phenetole
There is phenetole contraposition and the competitive reaction at ortho position in raw Fu Ke acylation reactions, and occur the ortho isomer by-product obtained at ortho position
Thing content is up to more than 12%, because accessory substance and target product property are close, causes the accessory substance to be difficult to purify, and can introduce
In subsequent reactions, the application of this method is constrained.
Therefore, this area needs a kind of high income, the chloro- 4 '-ethyoxyls of the bromo- 2- of Dapagliflozin intermediate 5- of no coupling product badly
The preparation method of benzophenone.
The content of the invention
It is an object of the invention to overcome existing to prepare the chloro- 4 '-ethoxy diphenyl first of the bromo- 2- of Dapagliflozin intermediate 5-
Exist during ketone accessory substance it is excessive and be difficult to the defect that purifies there is provided a kind of suitable industrialized production, selectivity it is good and
The preparation method of the Dapagliflozin intermediate of high income.
The present inventor has been surprisingly found that under study for action, reacts and makes with oxalyl chloride by raw material of the bromo- 2- chlorobenzoic acids of 5-
The bromo- 2- chlorobenzoyl chlorides of intermediate 5- are obtained, by introducing a small amount of tert-butyl chloro-silicane in then being reacted again with phenetole,
So that reaction avoids the reaction of ortho position acylation, so as to substantially increase the yield of reaction and avoid extra intermediate
Purification process.
To achieve these goals, the present invention provides a kind of preparation for being used to treat type II diabetes Dapagliflozin intermediate
Method, wherein, the preparation method comprises the following steps：
1) under DMF catalysis, the bromo- 2- chlorobenzoic acids of 5- and oxalyl chloride haptoreaction in anhydrous methylene chloride are obtained into 5-
Bromo- 2- chlorobenzoyl chlorides；
2) in the presence of tert-butyl chloro-silicane, by step 1) the obtained bromo- 2- chlorobenzoyl chlorides of 5- and phenetole
Under ferric trichloride catalytic react obtaining the chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of Dapagliflozin intermediate 5-.
In the present invention, it is preferred in the case of, the preparation method more specifically comprises the following steps：
1) under DMF catalysis, by the bromo- 2- chlorobenzoic acids of 5- and oxalyl chloride room temperature haptoreaction 1 in anhydrous methylene chloride
~2 hours, removal of solvent under reduced pressure and unreacted oxalyl chloride obtained the bromo- 2- chlorobenzoyl chlorides of 5-；
2) 0~10 DEG C, first by tert-butyl chloro-silicane and step 1) obtained bromo- 2- chlorobenzoyl chlorides of 5- are anhydrous
20~30min is mixed in dichloromethane, then phenetole and ferric trichloride are added in reaction system by keeping temperature successively, are stirred
Mix reaction 2~5 hours, reaction terminates, be poured into frozen water and reaction is quenched, dichloromethane extraction, washing is concentrated to give Dapagliflozin
The chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of intermediate 5-.
In the present invention, in step 1) in, DMF is as catalyst amount, catalysis as well known to those skilled in the art
The implication of amount, the weight for example fed intake relative to raw material, catalytic amount can be 2~10% that raw material feed intake.Under preferable case,
Step 1) in, the mol ratio of the bromo- 2- chlorobenzoic acids of 5- and oxalyl chloride is 1：2~4.The step 1 of the present invention) react and terminate without special
Do not post-process, next step reaction is can be used to after reduced pressure treatment, without subsequent reactions are produced with obvious influence.
In the present invention, step 2) using addition reaction promoter tert-butyl chloro-silicane and using weaker tri-chlorination
Iron makees catalyst combination, so as to reach the purpose of control selecting response.Why selectivity, tert-butyl chloro-silicane are produced
It can combine electrophilic to phenyl ring with acyl group positive oxygen ion, due to its steric hindrance, limit the generation of ortho-product.Preferable case
Under, in step 2) in, relative to the bromo- 2- chlorobenzoyl chlorides of every g 5-, the consumption of tert-butyl chloro-silicane for 0.02~
0.15g；The mol ratio of the bromo- 2- chlorobenzoyl chlorides of 5- and phenetole, ferric trichloride is 1：1~1.5：1~1.2.
In the case of further preferably, in step 2) in, relative to the bromo- 2- chlorobenzoyl chlorides of every g 5-, fert-butyidimethylsilyl
The consumption of chlorosilane is 0.08~0.1g；The mol ratio of the bromo- 2- chlorobenzoyl chlorides of 5- and phenetole, ferric trichloride is 1：1.1~
1.2：1.1~1.2.Tert-butyl chloro-silicane, phenetole, the consumption of ferric trichloride are with the bromo- 2- chlorobenzoyls of preferable 5-
What chlorine yield (100%) was calculated, actually step 1) the bromo- 2- chlorobenzoyl chlorides yields of 5- are also close to 100%.
In order to reduce influence of the external environment such as empty gas and water to reaction, in the present invention, it is preferred in the case of, step 1) and
Step 2) reaction carried out in the presence of protective gas.The protective gas can be used for synthetic reaction for this area routine
In protective gas, such as nitrogen, argon gas or helium.
In the present invention, room temperature refers to 25 ± 3 DEG C.
In the present invention, the anhydrous methylene chloride used is referred to this area conventional technology and handled, example
Such as flowed back with calcium hydride, benzophenone makees indicator, when solution becomes navy blue, steams and uses.
In the present invention, can be monitored tracking to reaction using the conventional method in this area, such as TLC, LCMS,
GCMS etc., reaction completion refer to TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than
2%.
The preparation method for the Dapagliflozin intermediate that the present invention is provided will not produce ortho position accessory substance, target product yield
Height, provides good material storage for Dapagliflozin and supports.And the preparation method mild condition, the reaction time is short, it is adapted to
Industrialized production is promoted.
Other features and advantages of the present invention will be described in detail in subsequent embodiment part..
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without
It is the further restriction to protection scope of the present invention.
Embodiment 1
A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate, comprises the following steps：
1) under nitrogen protection, by the bromo- 2- chlorobenzoic acids 235.5g (1mol) of 5-, oxalyl chloride 380.9g (3mol) and catalysis
The DMF (2ml) of amount is added to room temperature haptoreaction 1~2 hour in 1500ml anhydrous methylene chlorides, removal of solvent under reduced pressure and not anti-
Oxalyl chloride is answered to obtain the bromo- 2- chlorobenzoyl chlorides of 5-；
2) under nitrogen protection, 0~10 DEG C, first by tert-butyl chloro-silicane 25g and step 1) the obtained bromo- 2- chlorine of 5-
Chlorobenzoyl chloride mixes 30min in anhydrous methylene chloride, and then keeping temperature is successively by phenetole 134.4g (1.1mol) and three
Iron chloride 194.6g (1.2mol) is added in reaction system, stirring reaction 3 hours, and reaction terminates, and is poured into frozen water and is quenched instead
Should, dichloromethane extraction, washing is concentrated to give Dapagliflozin intermediate the 5- chloro- 4 '-oxethyl-diphenyl-ketone 304.6g of bromo- 2-,
Yield：89.7%, HPLC purity：99.76%.
MS(m/z)-ESI：338.96[M+1]+、340.95[M+3]+。
1HNMR (400MHz, CDCl3)：δ 7.81~7.74 (d, 2H), 7.55~7.51 (dd, 1H), 7.46 (d, 1H),
7.34~7.30 (d, 1H), 6.95~6.93 (d, 2H), 4.12~4.05 (q, 2H), 1.45 (t, 3H).
Embodiment 2
A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate, comprises the following steps：
1) under nitrogen protection, by the bromo- 2- chlorobenzoic acids 23.6g (0.1mol) of 5-, oxalyl chloride 25.4g (0.2mol) and urge
The DMF (0.2ml) of change amount is added to room temperature haptoreaction 1~2 hour, removal of solvent under reduced pressure and unreacted in anhydrous methylene chloride
Oxalyl chloride obtains the bromo- 2- chlorobenzoyl chlorides of 5-；
2) under nitrogen protection, 0~10 DEG C, first by tert-butyl chloro-silicane 2.1g and step 1) obtained bromo- 2- of 5-
Chlorobenzoyl chloride mixes 30min in anhydrous methylene chloride, and then keeping temperature is successively by phenetole 14.7g (1.2mol) and three
Iron chloride 17.8g (1.1mol) is added in reaction system, stirring reaction 5 hours, and reaction terminates, and is poured into frozen water and is quenched instead
Should, dichloromethane extraction, washing is concentrated to give Dapagliflozin intermediate the 5- chloro- 4 '-oxethyl-diphenyl-ketone 31g of bromo- 2-, receives
Rate：91.4%, HPLC purity：99.49%.
Embodiment 3
A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate, comprises the following steps：
1) under nitrogen protection, by the bromo- 2- chlorobenzoic acids 23.6g (0.1mol) of 5-, oxalyl chloride 50.8g (0.4mol) and urge
The DMF (0.3ml) of change amount is added to room temperature haptoreaction 1~2 hour, removal of solvent under reduced pressure and unreacted in anhydrous methylene chloride
Oxalyl chloride obtains the bromo- 2- chlorobenzoyl chlorides of 5-；
2) under nitrogen protection, 0~10 DEG C, first by tert-butyl chloro-silicane 2.5g and step 1) obtained bromo- 2- of 5-
Chlorobenzoyl chloride mixes 20min in anhydrous methylene chloride, and then keeping temperature is successively by phenetole 14.7g (1.2mol) and three
Iron chloride 19.5g (1.2mol) is added in reaction system, stirring reaction 5 hours, and reaction terminates, and is poured into frozen water and is quenched instead
Should, dichloromethane extraction, washing is concentrated to give Dapagliflozin intermediate the 5- chloro- 4 '-oxethyl-diphenyl-ketone 30.3g of bromo- 2-,
Yield：89.3%, HPLC purity：99.67%.
Embodiment 4
A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate, comprises the following steps：
1) under nitrogen protection, by the bromo- 2- chlorobenzoic acids 235.5g (1mol) of 5-, oxalyl chloride 253.9g (2mol) and catalysis
The DMF (2ml) of amount is added to room temperature haptoreaction 1~2 hour in anhydrous methylene chloride, removal of solvent under reduced pressure and unreacted oxalyl
Chlorine obtains the bromo- 2- chlorobenzoyl chlorides of 5-；
2) under nitrogen protection, 0~10 DEG C, first by tert-butyl chloro-silicane 5.1g and step 1) obtained bromo- 2- of 5-
Chlorobenzoyl chloride mixes 30min in anhydrous methylene chloride, then keeping temperature successively by phenetole 158.8g (1.3mol) and
Ferric trichloride 178.4g (1.1mol) is added in reaction system, stirring reaction 4 hours, and reaction terminates, and is poured into frozen water and is quenched
Reaction, dichloromethane extraction, washing is concentrated to give Dapagliflozin intermediate the 5- chloro- 4 '-oxethyl-diphenyl-ketone 28g of bromo- 2-,
Yield：82.4%, HPLC purity：99.01%, contain the chloro- 2 '-oxethyl-diphenyl-ketones 0.52% of the bromo- 2- of accessory substance 5-.
Embodiment 5
A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate, comprises the following steps：
1) under nitrogen protection, by the bromo- 2- chlorobenzoic acids 23.6g (0.1mol) of 5-, oxalyl chloride 38.1g (0.1mol) and urge
The DMF (0.2ml) of change amount is added to room temperature haptoreaction 1~2 hour, removal of solvent under reduced pressure and unreacted in anhydrous methylene chloride
Oxalyl chloride obtains the bromo- 2- chlorobenzoyl chlorides of 5-；
2) under nitrogen protection, 0~10 DEG C, first by tert-butyl chloro-silicane 3.8g and step 1) obtained bromo- 2- of 5-
Chlorobenzoyl chloride mixes 30min in anhydrous methylene chloride, and then keeping temperature is successively by phenetole 17.1g (1.4mol) and three
Iron chloride 19.5g (1.2mol) is added in reaction system, stirring reaction 5 hours, and reaction terminates, and is poured into frozen water and is quenched instead
Should, dichloromethane extraction, washing is concentrated to give Dapagliflozin intermediate the 5- chloro- 4 '-oxethyl-diphenyl-ketone 14.47g of bromo- 2-,
Yield：83.7%, HPLC purity：99.17%.
Embodiment 6
Such as preparation method of embodiment 1, except that, tert-butyl chloro-silicane adds simultaneously with other reactants
Enter, then finally obtain concentrate HPLC analysis ortho isomers and account for 2.2%.Column chromatography (PE：EA=1:1) obtain that lattice row must be reached
Net intermediate the 5- chloro- 4 '-oxethyl-diphenyl-ketone 259.1g of bromo- 2-, yield：76.3%, HPLC purity：99.14%, contain pair
The chloro- 2 '-oxethyl-diphenyl-ketones 0.28% of the bromo- 2- of product 5-.
Comparative example 1
Such as preparation method of embodiment 1, except that, tert-butyl chloro-silicane is added without, then is finally obtained dense
Contracting thing HPLC analysis ortho isomers account for 9.82%.Column chromatography (PE：EA=1:1) Dapagliflozin intermediate 5- is obtained bromo-
The chloro- 4 '-oxethyl-diphenyl-ketone 196.3g of 2-, yield：57.8%, HPLC purity：98.77%, contain the bromo- 2- of accessory substance 5-
Chloro- 2 '-oxethyl-diphenyl-ketone 1.37%.
Comparative example 2
Such as preparation method of embodiment 1, except that, ferric trichloride is substituted using the alchlor of same molar,
Then finally obtain concentrate HPLC analysis ortho isomers and account for 7.65%.Column chromatography (PE：EA=1:1) Dapagliflozin is obtained
The chloro- 4 '-oxethyl-diphenyl-ketone 218g of the bromo- 2- of intermediate 5-, yield：64.2%, HPLC purity：98.96%, contain accessory substance
The chloro- 2 '-oxethyl-diphenyl-ketones 0.87% of the bromo- 2- of 5-.
To sum up, the invention provides a kind of preparation of the chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of Dapagliflozin intermediate 5-
Method, this method product yield high, it is to avoid produce ortho position accessory substance, reduce the workload of subsequent treatment, reduce intermediate
The cost of preparation, and the preparation method mild condition, the reaction time are short, are adapted to industrialized mass production.
Claims (7)
1. a kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate, it is characterised in that the preparation method bag
Include following steps：
1) under DMF catalysis, by the bromo- 2- chlorobenzoic acids of 5- with oxalyl chloride the haptoreaction in anhydrous methylene chloride to obtain 5- bromo-
2- chlorobenzoyl chlorides；
2) in the presence of tert-butyl chloro-silicane, by step 1) obtained bromo- 2- chlorobenzoyl chlorides of 5- with phenetole three
Under Ferric Chloride react obtaining the chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of Dapagliflozin intermediate 5-.
2. according to the method described in claim 1, it is characterised in that the preparation method more specifically comprises the following steps：
1) under DMF catalysis, by the bromo- 2- chlorobenzoic acids of 5-, the room temperature haptoreaction 1~2 in anhydrous methylene chloride is small with oxalyl chloride
When, removal of solvent under reduced pressure and unreacted oxalyl chloride obtain the bromo- 2- chlorobenzoyl chlorides of 5-；
2) 0~10 DEG C, first by tert-butyl chloro-silicane and step 1) obtained bromo- 2- chlorobenzoyl chlorides of 5- are in anhydrous dichloro
20~30min is mixed in methane, then phenetole and ferric trichloride are added in reaction system by keeping temperature successively, stirring is anti-
Answer 2~5 hours, reaction terminates, be poured into frozen water and reaction is quenched, dichloromethane extraction, washing is concentrated to give in the middle of Dapagliflozin
The chloro- 4 '-oxethyl-diphenyl-ketones of the bromo- 2- of body 5-.
3. preparation method according to claim 1 or 2, it is characterised in that in step 1) in, the bromo- 2- chlorobenzoic acids of 5- with
The mol ratio of oxalyl chloride is 1：2~4.
4. preparation method according to claim 1 or 2, it is characterised in that in step 2) in, relative to every bromo- 2- of g 5-
Chlorobenzoyl chloride, the consumption of tert-butyl chloro-silicane is 0.02~0.15g；The bromo- 2- chlorobenzoyl chlorides of 5- and phenetole, three
The mol ratio of iron chloride is 1：1~1.5：1~1.2.
5. preparation method according to claim 4, it is characterised in that in step 2) in, relative to the bromo- 2- chlorobenzenes of every g 5-
Formyl chloride, the consumption of tert-butyl chloro-silicane is 0.08~0.1g；The bromo- 2- chlorobenzoyl chlorides of 5- and phenetole, tri-chlorination
The mol ratio of iron is 1：1.1~1.2：1.1~1.2.
6. the preparation method according to claim 1-5, it is characterised in that step 1) and step 2) reaction in protection gas
Carried out in the presence of body.
7. preparation method according to claim 6, it is characterised in that the protective gas is nitrogen, argon gas or helium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710638927.1A CN107200683A (en) | 2017-07-31 | 2017-07-31 | A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710638927.1A CN107200683A (en) | 2017-07-31 | 2017-07-31 | A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107200683A true CN107200683A (en) | 2017-09-26 |
Family
ID=59912192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710638927.1A Pending CN107200683A (en) | 2017-07-31 | 2017-07-31 | A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107200683A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456177A (en) * | 2018-11-26 | 2019-03-12 | 深圳市第二人民医院 | The synthetic method of the bromo- 2- chlorobenzoyl chloride of Dapagliflozin intermediate 5- |
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104059041A (en) * | 2013-03-20 | 2014-09-24 | 爱康药业有限公司 | Preparation method of antidiabetic dapagliflozin intermediate |
| CN104478839A (en) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | Synthesis method of dapagliflozin |
| CN104961715A (en) * | 2015-07-10 | 2015-10-07 | 浙江美诺华药物化学有限公司 | Preparation method for Dapagliflozin |
-
2017
- 2017-07-31 CN CN201710638927.1A patent/CN107200683A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104059041A (en) * | 2013-03-20 | 2014-09-24 | 爱康药业有限公司 | Preparation method of antidiabetic dapagliflozin intermediate |
| CN104478839A (en) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | Synthesis method of dapagliflozin |
| CN104961715A (en) * | 2015-07-10 | 2015-10-07 | 浙江美诺华药物化学有限公司 | Preparation method for Dapagliflozin |
Non-Patent Citations (2)
| Title |
|---|
| 张帅阳等: "达格列净合成路线图解", 《中国医药工业杂志》 * |
| 罗六保等: "二甲基叔丁基氯硅烷的合成方法及应用", 《罗六保等》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456177A (en) * | 2018-11-26 | 2019-03-12 | 深圳市第二人民医院 | The synthetic method of the bromo- 2- chlorobenzoyl chloride of Dapagliflozin intermediate 5- |
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN111995507B (en) * | 2020-09-23 | 2022-07-22 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107200683A (en) | A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate | |
| CN101153012B (en) | Novel method of producing dronedarone key intermediate | |
| CN105541844B (en) | Simple preparation method of high-purity linagliptin | |
| CN105254589B (en) | A method of preparing heart failure drugs intermediate | |
| CN110590541A (en) | Preparation method of 5-bromo-2-chlorobenzoic acid | |
| CN106117148B (en) | A kind of preparation and purification technique of Lopinavir | |
| CN109232470A (en) | A kind of new process synthesizing ainothiazoly loximate | |
| CN109553513A (en) | A kind of preparation method of metoprolol intermediate | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN112047820B (en) | Preparation method and application of fluorocalcitol intermediate | |
| CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
| CN108892659A (en) | A kind of canagliflozin impurity and preparation method thereof | |
| CN109897064A (en) | A kind of 3- indyl -3-(p diethylaminobenzoic acid ester group) Oxoindole compound preparation method | |
| CN109761868B (en) | Synthesis method of optically pure chlorprostenol | |
| CN107674016B (en) | Preparation method of telaprevir intermediate and intermediate thereof | |
| CN106518865A (en) | Method for preparing 1-alkenyl indolizine derivative | |
| CN110256234B (en) | Preparation method of calcium gluconate | |
| CN108794479A (en) | A kind of synthetic method of 4- chloropyrrolo [2,3-ds | |
| CN106831783A (en) | A kind of synthetic method of phosphoric acid sitagliptin intermediate | |
| CN104860881A (en) | Methods for synthesizing 8-(nitro methyl) quinoline compounds and 8-methylamino tetrahydroquinoline compounds | |
| KR20190129416A (en) | A synthesis method of gliflozin using continuous process | |
| CN105801490B (en) | A method of preparing Egelieting intermediate | |
| CN107473988B (en) | The preparation method of the intermediate of Ao Gelieting | |
| CN107304171A (en) | A kind of synthetic method of Oseltamivir | |
| CN110551027B (en) | Synthetic method of 3-hydroxy-2-phenylpropionic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170926 |