CN104945332B - The preparation method of Erlotinib - Google Patents
The preparation method of Erlotinib Download PDFInfo
- Publication number
- CN104945332B CN104945332B CN201410127452.6A CN201410127452A CN104945332B CN 104945332 B CN104945332 B CN 104945332B CN 201410127452 A CN201410127452 A CN 201410127452A CN 104945332 B CN104945332 B CN 104945332B
- Authority
- CN
- China
- Prior art keywords
- preparation
- erlotinib
- bis
- methoxy ethoxies
- quinazoline
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention discloses a kind of preparation method of Erlotinib, belong to field of medicine preparing technology.In the preparation method, with 4,5 two（2 methoxy ethoxies）2 p-nitriles are raw material, through reduction, the amido 4,5 two of intermediate 2 obtained by hydrolysis（2 methoxy ethoxies）Benzamide directly obtains Erlotinib key intermediate 6,7 2 with triethyl orthoformate cyclization（2 methoxy ethoxies）The ketone of 3H quinazolines 4, the chloro-product of the quinazoline and an amido phenylacetylene react, and obtain Erlotinib.The preparation method of the present invention, not only overcomes nitro reduction in prior synthesizing method and uses expensive catalyst, and temperature higher defect during cyclization, also avoid, by carbonamidine intermediate, shortening reactions steps, reduce reaction cost, improve yield.And all reaction conditions are very gentle in the preparation method, are particularly suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine preparing technology, more particularly to a kind of preparation method of Erlotinib.
Background technology
Erlotinib（Erlotinib）, trade name Erlotinib（Tarceva）, it is the one of Osi Pharm Inc. of U.S. research and development
Plant EGF EGFR EGFR-TK type small molecular inhibitor cancer therapy drugs.Listed first in the U.S. within 2004, mainly
For treating non-small cell lung cancer.The chemical name of Erlotinib is N- (3- acetylene phenyl) (2- methoxyl group ethoxies of -6,7- two
Base) -4- quinazoline amine, mechanism of action is to be combined suppression EGFR phosphorylations with substrate competition in the cell, blocks tumour cell letter
Number transduction, so as to suppress the growth of tumour cell, induce its dead.The structure of Erlotinib is shown as a formula V.
Key step is related to key intermediate 6 in Erlotinib synthetic method, and 7- is double-（2- methoxy ethoxies）- 3H- quinolines
The synthesis of oxazoline -4- ketone.In the prior art, have in the document report synthetic method of the intermediate, these methods and mainly deposit
The problem of be that nitrification yield and purity are relatively low, nitro reduction uses expensive catalyst, and temperature is higher etc. during cyclization.These
Factor have impact on the yield and purity of Erlotinib, be unfavorable for industrialized production.
In view of the above-mentioned problems, also document report uses 4,5- double（2- methoxy ethoxies）- 2- nitrobenzonitriles are
Raw material, through palladium charcoal/hydrazine hydrate reduction nitro, cyan-hydrolysis obtains 4,5- pairs simultaneously（2- methoxy ethoxies）- 2- aminobenzoyls
Amine intermediate, the intermediate obtains carbonamidine intermediate with DMF-DMA additions, then obtains Erlotinib key intermediate 6 through cyclization,
7- pairs-（2- methoxy ethoxies）- 3H- quinazoline-4-ones.Synthetic route is as follows：
This method synthesis 6,7- pairs-（2- methoxy ethoxies）Though -3H- quinazoline-4-ones can carry out industrialized production,
Cyclization need to pass through carbonamidine intermediate, and reactions steps are long, add reaction cost, while also influenceing the yield of Erlotinib.
The content of the invention
Based on this, it is an object of the invention to overcome the defect of prior art there is provided a kind of preparation method of Erlotinib,
The characteristics of this method has short synthetic reaction step, low cost and high yield.
To achieve the above object, the present invention takes following technical scheme：
A kind of preparation method of Erlotinib, comprises the following steps：
1）With 4,5- bis-（2- methoxy ethoxies）- 2- p-nitriles are raw material, in the presence of reducing agent, through reducing,
Hydrolysis obtains 2- amidos -4,5- two（2- methoxy ethoxies）Benzamide；
2）2- amidos-the 4,5- two that above-mentioned steps are obtained（2- methoxy ethoxies）Benzamide and triethyl orthoformate
Reacted under lewis acidic catalysis, direct cyclization obtains intermediate 6,7- bis-（2- methoxy ethoxies）- 3H- quinoline azoles
Quinoline -4- ketone；
3）The 6,7- bis- that above-mentioned steps are obtained（2- methoxy ethoxies）- 3H- quinazoline-4-ones are carried out with POCl3
Reaction, obtains 6,7- bis-（2- methoxy ethoxies）- quinazoline -4- chlorine；
4）6, the 7- bis- that above-mentioned steps are obtained（2- methoxy ethoxies）- quinazoline -4- chlorine and an amido phenylacetylene are anti-
Should, obtain Erlotinib.
The preparation method of the Erlotinib of the present invention, with 4,5- bis-（2- methoxy ethoxies）- 2- p-nitriles are raw material,
Through reduction, intermediate 2- amidos -4,5- bis- obtained by hydrolysis（2- methoxy ethoxies）Benzamide directly with orthoformic acid three
Ethyl ester cyclization obtains Erlotinib key intermediate 6,7- bis-（2- methoxy ethoxies）- 3H- quinazoline-4-ones, the quinazoline
Chloro-product and amido phenylacetylene react, obtain Erlotinib.The preparation method avoids, by carbonamidine intermediate, shortening
Reactions steps, reduce reaction cost, and improve yield.
In wherein some embodiments, step 1）In, reaction dissolvent is water, water-dioxane or water-ethanol；Reducing agent
For sodium dithionite, iron, zinc, palladium carbon or Raney Ni- hydrazine hydrates；Reaction temperature is 0 DEG C -40 DEG C.Wherein, Raney Ni are
Raney's nickel, is a kind of machine metallic compound as hydrogen activity catalytic reducer；Above-mentioned water-dioxane represents water and dioxy six
The mixed solvent of ring；Equally, water-ethanol represents the mixed solvent of water and ethanol；Raney Ni- hydrazine hydrates represent Raney Ni and
The mixing reducing agent of hydrazine hydrate.Using above-mentioned process conditions, overcome nitro reduction in prior synthesizing method and use expensive catalysis
Agent, and the defect such as temperature is higher during reaction.
In wherein some embodiments, step 1）In, reaction dissolvent is water；Reducing agent is Raney Ni- hydrazine hydrates；Reaction
Temperature is 20 DEG C -40 DEG C.
In wherein some embodiments, step 2）In, the lewis acid is trifluoroacetic acid or BFEE；Reaction
Solvent is ethyl acetate, dichloromethane, ethanol, at least one of methanol.Ethyl acetate.
In wherein some embodiments, step 2）In, the 2- amidos -4,5- bis-（2- methoxy ethoxies）Benzoyl
Amine, triethyl orthoformate, lewis acidic consumption mol ratio is 1:1-1.5:0.05-0.15, preferably 1:1.2:01；Reaction temperature
For 70-80 DEG C, preferably 77 DEG C.Under the above-described reaction conditions, the progress that reacts fully can be promoted, the wave to raw material can be avoided again
Take, meanwhile, the reaction condition is gentle, is particularly suitable for industrialized production.
In wherein some embodiments, step 3）In, reaction dissolvent is ethyl acetate, dichloromethane, in dioxane
It is at least one.Ethyl acetate.
In wherein some embodiments, step 3）In, 6, the 7- bis-（2- methoxy ethoxies）- 3H- quinazoline-4-ones
Consumption mol ratio with POCl3 is 1:2-4, preferably 1:3；Reaction temperature is 60-80 DEG C, preferably 70 DEG C.In above-mentioned reaction bar
Under part, the progress that reacts fully can be promoted, the waste to raw material can be avoided again.
In wherein some embodiments, step 4）In, reaction dissolvent is methanol, ethanol, isopropanol, in n-butanol at least
It is a kind of.Preferred alcohol.
In wherein some embodiments, step 4）In, 6,7- bis-（2- methoxy ethoxies）- quinazoline -4- chlorine and an amine
The consumption mol ratio of base phenylacetylene is 1:1-1.3, preferably 1:1.1；Reaction temperature is 60-80 DEG C, preferably 70 DEG C.It can promote anti-
It should fully carry out, the waste to raw material can be avoided again.
In wherein some embodiments, step 4）In, using the method purifying erlotinib of recrystallization, the recrystallization
Solvent is ethanol, isopropanol, n-butanol, one kind in normal propyl alcohol.It is preferred that n-butanol.Using above-mentioned solvent, purity can be obtained
Higher recrystallization product.
Compared with prior art, the invention has the advantages that：
The preparation method of a kind of Erlotinib of the present invention, with 4,5- bis-（2- methoxy ethoxies）- 2- p-nitriles are
Raw material, through reduction, intermediate 2- amidos -4,5- bis- obtained by hydrolysis（2- methoxy ethoxies）Benzamide is directly and primitive nail
Triethylenetetraminehexaacetic acid ester cyclization obtains Erlotinib key intermediate 6,7- bis-（2- methoxy ethoxies）- 3H- quinazoline-4-ones, it is to avoid
By carbonamidine intermediate, reactions steps are shortened, reaction cost are reduced, and improve yield.
Also, the preparation method also overcomes nitro reduction in prior synthesizing method and uses expensive catalyst, and cyclization
The defect such as temperature is higher during reaction.Meanwhile, all reaction conditions are very gentle in the preparation method, are particularly suitable for industrialization
Production.
Embodiment
Describe the present invention in detail below in conjunction with specific embodiment, but any limitation is not caused to the present invention.
Following examples are with 4,5- bis-（2- methoxy ethoxies）- 2- p-nitriles are raw material, and through reduction, hydrolysis is obtained
Intermediate 2- amidos -4,5- two（2- methoxy ethoxies）Benzamide directly obtains 6,7- bis- with triethyl orthoformate cyclization
（2- methoxy ethoxies）- 3H- quinazoline-4-ones, the chloro-product of the quinazoline and an amido phenylacetylene react, and obtain angstrom sieve
For Buddhist nun.Synthetic line is as follows：
Embodiment 1
（1）Compound ii（2- amidos -4,5- two（2- methoxy ethoxies）Benzamide）Synthesis.
At 0 DEG C, by chemical compounds I（4,5- bis-（2- methoxy ethoxies）- 2- p-nitriles）214g, Raney Ni50g
It is suspended in about 2L water, mechanical agitation, the aqueous solution 500mL of the hydrazine hydrate containing 141mL is added dropwise, completion of dropping is warmed to room temperature（About
20-30℃）, 3h is reacted, TLC is monitored to reaction and finished.Adding sodium hydroxide solution adjusts Ph values between 11-12, adds about 2L
Dichloromethane is extracted 2 times, and organic phase saturated common salt washing, anhydrous sodium sulfate drying, revolving obtains the thick of 170g compound iis
Product, yield is 83%.
The characterize data of the compound ii is：1H-NMR(400MHz,DMSO-d6)：7.15(1H,s),6.40(2H,s),
6.27(1H,s),5.73(1H,s),4.01-4.03(2H,J=4.8Hz,t),3.95-3.98(2H,J=4.8Hz,t),3.64-
3.66(2H,J=4.8Hz,t),3.58-3.60(2H,J=4.8Hz,t),3.30(3H,s),3.31(3H,s)。
（2）Compound III（6,7- bis-（2- methoxy ethoxies）- 3H- quinazoline-4-ones）Synthesis.
By compound ii（2- amidos -4,5- two（2- methoxy ethoxies）Benzamide）170g, triethyl orthoformate
106.3g, trifluoroacetic acid 7g, add into about 1.7L ethyl acetate, are heated to reflux, about 4h, TLC is monitored to reaction and finished, and stop
Reaction.Reaction solution is cooled to room temperature, there are a large amount of solids to separate out, suction filtration collects solid, and vacuum drying obtains compound III and consolidated
Body 158g, carries out purity testing, purity is 99%, and yield is 90% with HPLC.
The characterize data of the compound III is：1H-NMR(400MHz,DMSO-d6)：12.02(1H,brs),7.97(1H,
s),7.46(1H,s),7.14(1H,s),4.23-4.25(2H,J=4.8Hz,t),4.17-4.20(2H,J=4.8Hz,t),
3.69-3.72(4H,J=4.8Hz,t),3.32(6H,s)。
（3）Compounds Ⅳ（6,7- bis-（2- methoxy ethoxies）- quinazoline -4- chlorine）Synthesis.
By compound III（6,7- bis-（2- methoxy ethoxies）- 3H- quinazoline-4-ones）5g is added to about 50mL acetic acid second
In ester, nitrogen protection adds about 4.7mL POCl3s, 1gDMF is added dropwise（N,N-dimethylformamide）, 70 DEG C are then heated to,
About 2h is reacted, TLC is monitored to reaction and finished.Reaction solution is cooled to room temperature, 100mL frozen water is added dropwise, point liquid, aqueous phase acetic acid second
Ester extracts 2 × 100mL, collects ethyl acetate phase, and saturated common salt washing, anhydrous sodium sulfate drying rotates ethyl acetate, and vacuum is done
It is dry, the compounds Ⅳ solid 4.4g of yellowish is obtained, yield is 83%, purity testing is carried out with HPLC, purity is 98%.
The characterize data of the compounds Ⅳ is：1H-NMR(400MHz,DMSO-d6)：8.85(1H,s),7.44(1H,s),
4.34-4.36(4H,br),3.75-3.77(4H,br),3.34(6H,s)。
（4）Erlotinib（Compound V）Synthesis.
Compounds Ⅳ 2.02g is added into 20mL absolute ethyl alcohols, 40 DEG C are heated to, homogeneous suspension is formed, it is warm herein
The lower ethanol solution 10mL for adding 3-aminophenylacetylene of degree, is to slowly warm up to after 70 DEG C, about 1h, solution clarification, after about 2h, TLC
Raw material disappearance is monitored, stops reaction.
Reaction solution is cooled to room temperature, has a large amount of solids to separate out, solid is collected by filtration, be dried in vacuo white solid about
2.6g, n-butanol recrystallization, obtains Erlotinib sterling, yield is 95.2%, and purity testing, purity 99.89% are carried out with HPLC.
Compound V characterize data is：1H-NMR(400MHz,D2O-d6)：8.43(1H,s),7.42-7.42(2H,J=
9.6Hz,d),7.34(1H,s),7.08-7.12(1H,J=6.8Hz,t),6.99-7.00(1H,J=6.8Hz,d),6.89(1H,
s),4.20-4.25(4H,m),3.86-3.88(4H,m),3.55(1H,s)3.50(6H,s)。
Embodiment described above only expresses the several embodiments of the present invention, and it describes more specific and detailed, but simultaneously
Therefore the limitation to the scope of the claims of the present invention can not be interpreted as.It should be pointed out that for one of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention
Protect scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of preparation method of Erlotinib, it is characterised in that comprise the following steps:
1) with 4,5- bis- (2- methoxy ethoxies) -2- p-nitriles for raw material, in the presence of reducing agent, while being reduced
And hydrolysis, obtain 2- amidos -4,5- bis- (2- methoxy ethoxies) benzamide；The reducing agent is hydrated for RaneyNi-
Hydrazine；
2) (2- methoxy ethoxies) benzamides of 2- amidos -4,5- two for obtaining above-mentioned steps and triethyl orthoformate are on road
Reacted under the catalysis of Lewis acid, direct cyclization obtains intermediate 6, (2- the methoxy ethoxies) -3H- quinazolines of 7- bis- -4-
Ketone；
3) (2- the methoxy ethoxies) -3H- quinazoline-4-ones of 6,7- bis- obtained above-mentioned steps carry out anti-with POCl3
Should, obtain 6,7- bis- (2- methoxy ethoxies)-quinazoline -4- chlorine；
4) obtain above-mentioned steps 6,7- bis- (2- methoxy ethoxies)-quinazoline -4- chlorine and an amido phenylacetylene react, and obtain
To Erlotinib.
2. the preparation method of Erlotinib according to claim 1, it is characterised in that step 1) in, reaction dissolvent is water,
Water-dioxane or water-ethanol；Reaction temperature is 0 DEG C -40 DEG C.
3. the preparation method of Erlotinib according to claim 2, it is characterised in that step 1) in, reaction dissolvent is water；
Reaction temperature is 20 DEG C -40 DEG C.
4. the preparation method of Erlotinib according to claim 1, it is characterised in that step 2) in, the lewis acid
For trifluoroacetic acid or BFEE；Reaction dissolvent is ethyl acetate, dichloromethane, ethanol, at least one of methanol.
5. the preparation method of Erlotinib according to claim 1, it is characterised in that step 2) in, 2- amido -4,
5- bis- (2- methoxy ethoxies) benzamide, triethyl orthoformate, lewis acidic consumption mol ratio is 1:1-1.5:0.05-
0.15；Reaction temperature is 70-80 DEG C.
6. the preparation method of Erlotinib according to claim 1, it is characterised in that step 3) in, reaction dissolvent is second
At least one of acetoacetic ester, dichloromethane, dioxane.
7. the preparation method of Erlotinib according to claim 1, it is characterised in that step 3) in, (the 2- of 6,7- bis-
Methoxy ethoxy) the consumption mol ratio of -3H- quinazoline-4-ones and POCl3 is 1:2-4；Reaction temperature is 60-80 DEG C.
8. the preparation method of Erlotinib according to claim 1, it is characterised in that step 4) in, reaction dissolvent is first
At least one of alcohol, ethanol, isopropanol, n-butanol.
9. the preparation method of Erlotinib according to claim 1, it is characterised in that step 4) in, 6,7- bis- (2- methoxies
Base oxethyl) the consumption mol ratio of-quinazoline -4- chlorine and an amido phenylacetylene is 1:1-1.3；Reaction temperature is 60-80 DEG C.
10. the preparation method of Erlotinib according to claim 1, it is characterised in that step 4) in, using recrystallization
Method purifying erlotinib, the solvent of the recrystallization is ethanol, isopropanol, n-butanol, one kind in normal propyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410127452.6A CN104945332B (en) | 2014-03-31 | 2014-03-31 | The preparation method of Erlotinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410127452.6A CN104945332B (en) | 2014-03-31 | 2014-03-31 | The preparation method of Erlotinib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104945332A CN104945332A (en) | 2015-09-30 |
| CN104945332B true CN104945332B (en) | 2017-10-17 |
Family
ID=54160463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410127452.6A Expired - Fee Related CN104945332B (en) | 2014-03-31 | 2014-03-31 | The preparation method of Erlotinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104945332B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646374B (en) * | 2015-12-31 | 2018-11-27 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of erlotinib Hydrochloride |
| CN107337648B (en) * | 2016-05-03 | 2020-04-17 | 南京理工大学 | Method for synthesizing erlotinib |
| CN106279585A (en) * | 2016-08-26 | 2017-01-04 | 宁波圣达精工智能科技有限公司 | A kind of preparation method of fire-retardant intelligent compact bookshelf |
| CN106361007A (en) * | 2016-08-26 | 2017-02-01 | 宁波圣达精工智能科技有限公司 | Smart compact bookshelf |
| CN108047144A (en) * | 2018-01-26 | 2018-05-18 | 中国科学院化学研究所 | The preparation method of Tarceva |
| CN113603650B (en) * | 2021-08-03 | 2023-03-10 | 杭州职业技术学院 | Catalytic cyclization preparation method and application of erlotinib key intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999067202A1 (en) * | 1998-06-19 | 1999-12-29 | Syngenta Participations Ag . | Process for preparation of pyrimidinone derivatives |
| WO2003064377A1 (en) * | 2002-01-29 | 2003-08-07 | Ube Industries, Ltd. | 4,5-substituted-2-formylaminobenzamides and processes for their production and conversion |
| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| CN102659629A (en) * | 2012-02-14 | 2012-09-12 | 杭州华东医药集团生物工程研究所有限公司 | Compound and application thereof in preparing erlotinib |
| CN103145629A (en) * | 2013-04-02 | 2013-06-12 | 朱志成 | Synthetic process of tandutinib for treating solid tumors |
-
2014
- 2014-03-31 CN CN201410127452.6A patent/CN104945332B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999067202A1 (en) * | 1998-06-19 | 1999-12-29 | Syngenta Participations Ag . | Process for preparation of pyrimidinone derivatives |
| WO2003064377A1 (en) * | 2002-01-29 | 2003-08-07 | Ube Industries, Ltd. | 4,5-substituted-2-formylaminobenzamides and processes for their production and conversion |
| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| CN102659629A (en) * | 2012-02-14 | 2012-09-12 | 杭州华东医药集团生物工程研究所有限公司 | Compound and application thereof in preparing erlotinib |
| CN103145629A (en) * | 2013-04-02 | 2013-06-12 | 朱志成 | Synthetic process of tandutinib for treating solid tumors |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104945332A (en) | 2015-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104945332B (en) | The preparation method of Erlotinib | |
| CN101163698B (en) | Method for the production of 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide | |
| CN109020881B (en) | Preparation method of apatinib | |
| CN103570633B (en) | The preparation method of Gefitinib | |
| CN102557977A (en) | Synthesis intermediate of erlotinib and preparation method thereof | |
| CN105837502A (en) | Synthesis method of Vadadustat | |
| CN109053625A (en) | A kind of preparation method replacing benzothiazole C2 alkyl derivative | |
| CN109206317B (en) | Preparation process of amantadine nitrate derivative | |
| CN103304492B (en) | The synthetic method of a kind of EGFR inhibitor Dacomitinib | |
| WO2022088573A1 (en) | Method for preparing pyrotinib | |
| CN109928890B (en) | Preparation method of tolvaptan intermediate 2-methyl-4-N- (2-methylbenzoyl) benzoic acid | |
| CN111333543B (en) | Synthesis method of rilpivirine intermediate | |
| CN101463011B (en) | Process for synthesizing 3,4-dihydropyrimidine-2-keto | |
| CN101367767B (en) | Room temperature solvent-free synthesis of 3,4-dihydropyrimidine-2-ketone | |
| CN103773360B (en) | Schiff base fluorescent polymer and preparation method thereof | |
| CN102153518B (en) | Preparation method of Gefitinib | |
| JP2017503020A (en) | Process for the preparation of (E) -4-N, N-dialkylaminocrotonic acid in the form of an HX salt and its use for the synthesis of EGFR tyrosine kinase inhibitors | |
| CN100378073C (en) | Dindoly methylane and preparation process thereof | |
| CN103804373A (en) | Synthesis process of azasetron hydrochloride | |
| CN111533742A (en) | Method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as raw material | |
| CN105175400A (en) | Preparation method of Afatinib intermediate | |
| CN102584636A (en) | Synthetic method of kreatine | |
| CN106883185B (en) | Preparation method of 4-chloro-2-trifluoromethylpyrimidine | |
| CN109232434A (en) | A kind of new method synthesizing flibanserin | |
| CN103242244B (en) | Canertinib preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171017 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |