CN107382679A - The preparation method of Dapagliflozin intermediate - Google Patents
The preparation method of Dapagliflozin intermediate Download PDFInfo
- Publication number
- CN107382679A CN107382679A CN201710566032.1A CN201710566032A CN107382679A CN 107382679 A CN107382679 A CN 107382679A CN 201710566032 A CN201710566032 A CN 201710566032A CN 107382679 A CN107382679 A CN 107382679A
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction
- ethyoxyl
- ethoxy
- dapagliflozin
- 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
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention proposes a kind of preparation method of Dapagliflozin intermediate, comprises the following steps：1) carry out reaction as catalyst as reaction dissolvent, inorganic base as raw material, polar solvent using 4 methylphenols and bromoethane and 4 ethyoxyl toluene are prepared；2) the 4 ethyoxyl toluene obtained using N chlorosuccinimides and step 1) are reacted to obtain 4 ethyoxyl benzyl chlorides as reaction dissolvent, dibenzoyl peroxide as raw material, non-polar solven as initiator；3) 4 ethyoxyl benzyl chlorides, 4 bromanilines for obtaining step 2) are dissolved in ethyl acetate, and are added catalyst lewis acid and reacted to obtain the amino 4' ethoxy diphenyl methane of 5 bromine 2；4) the amino 4' ethoxy diphenyls methane of 5 bromine 2 that step 3) obtains carries out diazo-reaction, and the synthesis chlorine 4' ethoxy diphenyl methane of 5 bromine 2 is then reacted with stannous chloride.This method cost is low, and environmental pressure is small, and synthetic route is short.
Description
Technical field
The invention belongs to Dapagliflozin synthesis technical field, and in particular to a kind of preparation method of Dapagliflozin intermediate.
Background technology
Dapagliflozin (Dapagliflozin) is the white 2 (Sodium-glucose of sodium glucose co-transporter 2
Cotransporter-2, SGLT2) inhibitor, C- aryl glucoside class compounds, chemistry it is entitled：(2S, 3R, 4R, 5S,
6R) -2- [3- (4- ethoxybenzenes methyl) -4- chlorphenyls] -6- methylol tetrahydrochysene -2H- pyrans -3,4,5- triols.Dapagliflozin
By suppressing kidney sodium glucose co-transporter 2 white 2, suppress the reabsorption of blood glucose, so as to adjust blood sugar level；Simultaneously can
Significantly reduce patient's glycated hemoglobin levels and body weight.Dapagliflozin is by Shi Guibao companies and AstraZeneca cooperative research and development
Second SGLT2 inhibitor of U.S. FDA approval listing, for treating diabetes B.
The chloro- 4'- ethoxy diphenyls methane of the bromo- 2- of 5- is the key intermediate for preparing Dapagliflozin, and its synthetic method is main
There are two kinds, a kind of scheme is using the bromo- 2- chlorobenzoic acids of 5- as initiation material, and through chloride, friedel-crafts acylation, reduction is made.Should
Scheme route is shorter, but initiation material synthesis difficulty is big, and cost is high, expensive.Such as patent：PCT Int.Appl.,
2010022313,PCT Int.Appl.,2009026537；Document Journal of Medicinal Chemistry, 51 (5),
1145-1149；2008.Another synthetic schemes is using o-toluidine as initiation material, through bromo, diazotising chloro, benzyl
Chloro, alkylated reaction are made.The process route is Benzylation to use AIBN, and the cyaniding of severe toxicity can be produced during the substance reaction
Thing, it is seriously polluted, such as patent CN104478670.
The content of the invention
The present invention proposes a kind of preparation method of Dapagliflozin intermediate, and this method cost is low, and environmental pressure is small, and synthesizes
Route is short.
The technical proposal of the invention is realized in this way：
A kind of preparation method of Dapagliflozin intermediate, comprises the following steps：
1) using 4- methylphenols and bromoethane as raw material, polar solvent as reaction dissolvent, inorganic base as catalyst,
Carry out reaction and 4- ethyoxyl toluene is prepared；
2) the 4- ethyoxyls toluene obtained using N- chlorosuccinimides and step 1) is used as raw material, non-polar solven conduct
Reaction dissolvent, dibenzoyl peroxide are reacted to obtain 4- ethyoxyl benzyl chlorides as initiator；
3) 4- ethyoxyls benzyl chloride that step 2) obtains, 4- bromanilines are dissolved in ethyl acetate, and add catalyst Louis
This acid is reacted to obtain the bromo- 2- amino -4'- ethoxy diphenyl methane of 5-；
4) the bromo- 2- amino -4'- ethoxy diphenyls methane of step 3) obtains 5- carries out diazo-reaction, then with chlorination
The cuprous reaction synthesis chloro- 4'- ethoxy diphenyls methane of the bromo- 2- of 5-.
Preferably, one kind in methanol, ethanol, DMF, acetone and tetrahydrofuran of the polar solvent of the step 1) or
Person is a variety of.
Preferably, the one kind of the inorganic base of the step 1) in sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate
It is or a variety of.
Preferably, the non-polar solven of the step 2) in carbon tetrachloride, chloroform, dichloromethane and petroleum ether one
Kind is a variety of.
Preferably, the lewis acid of the step 3) is one in zinc chloride, ferric trichloride, alchlor and titanium tetrachloride
Kind is a variety of.
Preferably, the diazo reaction of the step 4) is：The bromo- 2- amino -4'- ethoxy diphenyl methane of 5- is dissolved in dense salt
Reacted with natrium nitrosum to obtain diazonium product in acid, under cryogenic conditions.
Preferably, the temperature of low temperature is -5 DEG C~0 DEG C.
The synthetic route of the present invention is as follows：
Beneficial effects of the present invention：
The present invention obtains the chloro- 4'- ethoxy diphenyls first of the bromo- 2- of 5- using 4- methylphenols and bromoethane as Material synthesis
Alkane, synthetic route is short, and final products purity is high, without using hypertoxic AIBN.
Embodiment
Below by embodiment, the present invention is described further, but embodiment is not intended to limit the protection model of the present invention
Enclose.
1st, the preparation of 4- ethyoxyls toluene
Reactive chemistry formula is：
4- methylphenol 108kg are taken, are dissolved in 200kgDMF, in 50kg toluene, add potassium carbonate 150kg, under 60 °, are added dropwise
The toluene solution (bromoethane 130kg, toluene 150kg) of bromoethane, drips off, is added dropwise for 30 minutes, 60 ° of reaction 2h, reaction knot
Shu Hou, KBr and potassium carbonate being filtered to remove, solvent is recovered under reduced pressure, Liquid Residue adds 400kg water, and 400kg ethyl acetate extracts,
Anhydrous sodium sulfate drying, filtering, filtrate recycling design, residue are evaporated under reduced pressure to light yellow liquid 127.8kg, yield 94%.
2nd, the preparation of 4- ethyoxyls benzyl chloride
Reactive chemistry formula is：
4- ethyoxyl toluene 136kg are taken, are dissolved in 300kg petroleum ethers, NCS (N- chlorosuccinimides) 140kg, BPO
(dibenzoyl peroxide) 12kg, back flow reaction 8h, after reaction terminates, filtering, filtrate decompression recycling design, Liquid Residue decompression steaming
Evaporate to obtain colourless liquid 158kg, yield 93%.
3rd, the preparation of the bromo- 2- amino -4'- ethoxy diphenyl methane of 5-
Reactive chemistry formula is：
4- ethyoxyl benzyl chloride 85kg are taken, are dissolved in 150kg ethyl acetate, 4- bromaniline 90kg is added, zinc chloride 70kg, adds
Hot back flow reaction 8h, after reaction terminates, room temperature is cooled to, adds water 300kg, sodium bicarbonate solution regulation pH to 8-9, extract,
100kg is washed to neutrality, anhydrous sodium sulfate drying, filters, and filtrate recovery 80kg, crystallisation by cooling obtains yellow crystal 133kg, yield
87%.
4th, the preparation of the chloro- 4'- ethoxy diphenyls methane of the bromo- 2- of 5-
Reactive chemistry formula is：
The bromo- 2- amino -4'- ethoxy diphenyls methane 153kg of 5- are taken, are dissolved in 400kg concentrated hydrochloric acids, are cooled to -5 °, are added dropwise
The aqueous solution (35kg natrium nitrosums, water 60kg) of natrium nitrosum, temperature is no more than 0 °, after being added dropwise during dropwise addition, continues
3h is reacted, is then added to the hydrochloric acid solution (stannous chloride 50kg, 100kg 3mol/L hydrochloric acid) of stannous chloride, addition finishes
Afterwards, 2h is reacted at room temperature, is warming up to 80 ° of reaction 1h, after reaction terminates, the extraction of 250kg ethyl acetate is added, during extract is washed to
Property, anhydrous sodium sulfate drying, filtering, filtrate recovery 100kg, then addition petroleum ether 100kg, crystallisation by cooling obtain faint yellow solid
128kg, yield 79%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
God any modification, equivalent substitution and improvements made etc., should be included in the scope of the protection with principle.
Claims (7)
1. a kind of preparation method of Dapagliflozin intermediate, it is characterised in that comprise the following steps：
1) carried out using 4- methylphenols and bromoethane as raw material, polar solvent as reaction dissolvent, inorganic base as catalyst
4- ethyoxyl toluene is prepared in reaction；
2) using the 4- ethyoxyls toluene that N- chlorosuccinimides and step 1) obtain as raw material, non-polar solven is as reaction
Solvent, dibenzoyl peroxide are reacted to obtain 4- ethyoxyl benzyl chlorides as initiator；
3) 4- ethyoxyls benzyl chloride that step 2) obtains, 4- bromanilines are dissolved in ethyl acetate, and add catalyst lewis acid
Reacted to obtain the bromo- 2- amino -4'- ethoxy diphenyl methane of 5-；
4) the bromo- 2- amino -4'- ethoxy diphenyls methane of step 3) obtains 5- carries out diazo-reaction, then with stannous chloride
The reaction synthesis chloro- 4'- ethoxy diphenyls methane of the bromo- 2- of 5-.
2. the preparation method of Dapagliflozin intermediate according to claim 1, it is characterised in that the polarity of the step 1)
One or more of the solvent in methanol, ethanol, DMF, acetone and tetrahydrofuran.
3. the preparation method of Dapagliflozin intermediate according to claim 1, it is characterised in that the step 1) it is inorganic
One or more of the alkali in sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate.
4. the preparation method of Dapagliflozin intermediate according to claim 1, it is characterised in that the non-pole of the step 2)
One or more of the property solvent in carbon tetrachloride, chloroform, dichloromethane and petroleum ether.
5. the preparation method of Dapagliflozin intermediate according to claim 1, it is characterised in that the Louis of the step 3)
This acid is the one or more in zinc chloride, ferric trichloride, alchlor and titanium tetrachloride.
6. the preparation method of Dapagliflozin intermediate according to claim 1, it is characterised in that the diazonium of the step 4)
React and be：The bromo- 2- amino -4'- ethoxy diphenyl methane of 5- is dissolved in concentrated hydrochloric acid, carried out instead with natrium nitrosum under cryogenic conditions
Diazonium product should be obtained.
7. the preparation method of Dapagliflozin intermediate according to claim 6, it is characterised in that the temperature of low temperature is -5 DEG C
~0 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710566032.1A CN107382679A (en) | 2017-07-12 | 2017-07-12 | The preparation method of Dapagliflozin intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710566032.1A CN107382679A (en) | 2017-07-12 | 2017-07-12 | The preparation method of Dapagliflozin intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107382679A true CN107382679A (en) | 2017-11-24 |
Family
ID=60339513
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710566032.1A Pending CN107382679A (en) | 2017-07-12 | 2017-07-12 | The preparation method of Dapagliflozin intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107382679A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110683998A (en) * | 2019-11-20 | 2020-01-14 | 杭州华东医药集团浙江华义制药有限公司 | Preparation method of empagliflozin intermediate |
| US11565990B2 (en) | 2020-12-04 | 2023-01-31 | Wisdom Pharmaceutical Co., Ltd | Preparation of 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene |
| CN116332733A (en) * | 2023-03-30 | 2023-06-27 | 江苏阿尔法药业股份有限公司 | Synthesis process of dapagliflozin intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101405286A (en) * | 2006-01-17 | 2009-04-08 | 先灵公司 | Hydantoin derivatives for the treatment of inflammatory diseases |
| CN103172593A (en) * | 2013-03-19 | 2013-06-26 | 珠海保税区丽珠合成制药有限公司 | Preparation technology of cinnarizine |
| 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 |
| CN104860793A (en) * | 2014-02-20 | 2015-08-26 | 天津药物研究院 | Preparation method of a class of phenyl C-glucoside derivative intermediates |
-
2017
- 2017-07-12 CN CN201710566032.1A patent/CN107382679A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101405286A (en) * | 2006-01-17 | 2009-04-08 | 先灵公司 | Hydantoin derivatives for the treatment of inflammatory diseases |
| CN103172593A (en) * | 2013-03-19 | 2013-06-26 | 珠海保税区丽珠合成制药有限公司 | Preparation technology of cinnarizine |
| CN104860793A (en) * | 2014-02-20 | 2015-08-26 | 天津药物研究院 | Preparation method of a class of phenyl C-glucoside derivative intermediates |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| CYRIL HERBIVO ET AL.: "Synthesis of 5-aryl-5’-formyl-2,2’-bithiophenes as new precursors for nonlinear optical (NLO) materials", 《TETRAHEDRON》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110683998A (en) * | 2019-11-20 | 2020-01-14 | 杭州华东医药集团浙江华义制药有限公司 | Preparation method of empagliflozin intermediate |
| US11565990B2 (en) | 2020-12-04 | 2023-01-31 | Wisdom Pharmaceutical Co., Ltd | Preparation of 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene |
| CN116332733A (en) * | 2023-03-30 | 2023-06-27 | 江苏阿尔法药业股份有限公司 | Synthesis process of dapagliflozin intermediate |
| CN116332733B (en) * | 2023-03-30 | 2025-02-11 | 江苏阿尔法药业股份有限公司 | A synthesis process of dapagliflozin intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2775962C (en) | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives | |
| CN107382679A (en) | The preparation method of Dapagliflozin intermediate | |
| CN107311962A (en) | The preparation method of the net intermediates of Yi Palie | |
| JPH0347163A (en) | Anthraquinone derivative and production thereof | |
| CN101941963A (en) | Synthesis method of erdosteine | |
| CN105503878A (en) | Synthesis method of anagliptin | |
| CN107652278A (en) | A kind of synthesis technique net Yi Palie | |
| CN103420937A (en) | Synthesis method of tianeptine sodium | |
| CN101362786A (en) | Method for preparing ivermectin | |
| CN107540648A (en) | A kind of preparation method of Dapagliflozin | |
| CN110372641B (en) | Process for producing hexahydrofurofuranol derivative, intermediate therefor, and process for producing the intermediate | |
| CN107365310A (en) | The preparation method of new farnesyl transferase inhibitor with pyridone structure | |
| CN109867617A (en) | A kind of preparation method of 4- methoxypyrrole intermediate | |
| CN107652276A (en) | A kind of preparation method net SGLT2 inhibitor Yi Palie | |
| CN107311847A (en) | The preparation method of the chlorine 4` ethoxy diphenyl methane of 5 bromine 2 | |
| CN107573311A (en) | A kind of synthetic method of Dapagliflozin | |
| CN107652277A (en) | A kind of preparation method net Yi Palie | |
| CN107574158A (en) | The enzyme process of chiral indenes alcohol compound prepares and its draws more applications in lucky synthesis in chiral drug | |
| CN109748902A (en) | A kind of hydrochloric acid peace sieve replaces the preparation method of Buddhist nun | |
| CN108707115B (en) | Synthetic method of acrylic acid derivative | |
| CN105061327A (en) | Synthetic method of long-acting sulfonamide | |
| CN105461640A (en) | Preparation method of tyrosine kinase inhibitor | |
| WO2023138099A1 (en) | Preparation method for miglittol | |
| US20080194842A1 (en) | Transition Metal Catalyzed Cross-Coupling Of 1-Halo-1-Haloalkene Compounds | |
| CN107304194A (en) | The method for preparing Dapagliflozin |
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: 20171124 |