CN103242244B - Canertinib preparation method - Google Patents
Canertinib preparation method Download PDFInfo
- Publication number
- CN103242244B CN103242244B CN201310180647.2A CN201310180647A CN103242244B CN 103242244 B CN103242244 B CN 103242244B CN 201310180647 A CN201310180647 A CN 201310180647A CN 103242244 B CN103242244 B CN 103242244B
- Authority
- CN
- China
- Prior art keywords
- morpholinyl
- dihydroquinazoline
- ketone
- propoxyl group
- preparation
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a Canertinib (I) preparation method which comprises the following steps: performing etherification reaction on 6-amino-7-hydroxy-3,4-dihydroquinazoline-4-one (II) and 3-(4-morpholinyl)-1-propanol to generate 6-amino-7-[3-(4-morpholinyl)propoxy]-3,4-dihydroquinazoline-4-one (III); performing acylation reaction on the compound (III) and propenoic acid or acryloyl chloride to generate 7-[3-(4-morpholinyl)propoxy]-6-acrylamido-3,4-dihydroquinazoline-4-one (IV); and performing condensation on the compound (IV) and 4-fluoro-3-chloroaniline to obtain Canertinib (I). The preparation method is simple, economic and environment-friendly in process, and meets the requirements for large-scale industrialization.
Description
Patent of the present invention other its name of submitting on the same day of REFERENCE TO RELATED people can be called the application for a patent for invention of " 6-amino-7-hydroxyl-3,4-dihydroquinazoline-4-ketone ".
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of card is how for the preparation method of Buddhist nun.
Background technology
How card is for Buddhist nun (Canertinib, I), chemistry 4-(the chloro-4-fluoroanilino of 3-)-7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido quinazoline by name, it is the irreversible EGF-R ELISA of one (pan-ErbB) selective depressant by Pfizer Inc. and Warner Lambert AG Safnern cooperative research and development, it can be attached to the atriphos binding site on ErbB family all member cells's films surface, thus suppresses activation and the downstream mitosis signal transduction pathway thereof of these acceptors.Clinical research shows that this product has good tolerance, can effectively treat the kinds of tumors such as recurrent metastatic breast cancer in its, oophoroma, cervical carcinoma, all can show synergy with multiple antineoplastic coupling.
No. CN1160338Cth, Chinese patent, No. CN1438994A and No. CN1745073A report card how for the preparation method of Buddhist nun: with parent nucleus 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-nitro-7-Fluquinconazole quinoline (VIII) for initiation material, there is the substitution reaction of 7-position with 3-(4-morpholinyl)-1-propyl alcohol under alkali condition, generate 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-nitro-7-[3-(4-morpholinyl)-1-propoxyl group] quinazoline (IX); Intermediate (IX) nitroreduction through 6-position, obtains corresponding amino-compound (X); How amino-compound (X) and acrylic acid or acryloyl chloride generation acylation reaction obtain card for Buddhist nun (I).
In addition, " Shandong medicine thing " 30 volumes the 10th phase in 2011 the 559th page and " Chinese Journal of Pharmaceuticals " 41 volumes the 6th phase in 2010 the 404th page also report improving one's methods to above-mentioned preparation, and have studied the method preparing intermediate (VIII) from 7-Fluquinconazole quinoline-3-ketone (V) through reactions such as nitrated, chloro and condensations.
Find out thus, the at present preparation of card how for Buddhist nun mainly carries out 4-position respectively by intermediate (VII), the sense of 6-position and 7-position is converted realizes.Because intermediate (VII) is fluorochemical, raw material not easily obtains, and step is more, and many steps need to carry out abstraction and purification by column chromatography, are thus not suitable for industrialized requirement.
Summary of the invention
The object of the invention is to seek new prepare approach, according to the Atom economy synthesis theory of Green Chemistry, a kind of card of improvement is provided how to replace the preparation method of Buddhist nun, its raw material is easy to get, concise in technology, economic environmental protection, is conducive to the suitability for industrialized production of this medicine, promotes the development of the economic technology of this bulk drug.
To achieve these goals, main technical schemes provided by the present invention is as follows: how a kind of card is for Buddhist nun's (4-(the chloro-4-fluoroanilino of 3-)-7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido quinazoline, I) preparation method
It is characterized in that described preparation method comprises the steps: 6-amino-7-hydroxyl-3, 4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3, 4-dihydroquinazoline-4-ketone (III), this compound (III) carries out acylation reaction with acrylic acid or acryloyl chloride and generates 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3, 4-dihydroquinazoline-4-ketone (IV), this compound (IV) and the fluoro-3-chloroaniline of 4-carry out condensation reaction obtained the card and how to replace Buddhist nun (I).
In addition, the present invention also provides following attached technical scheme:
Raw material 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3, the 4-dihydroquinazoline-4-ketone (IV) of described condensation reaction and the molar ratio of the fluoro-3-chloroaniline of 4-are 1: 1-2, preferably 1: 1.1-1.4.
The condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1-hydroxyl-BTA (HOBt), O-BTA-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester (TBTU), O-(7-azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), preferred BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).
The alkali promoter of described condensation reaction is triethylamine (TEA), pyridine, 2, 6-lutidines, DMAP (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN), 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 4-diazabicylo [2.2.2] octane (DABCO), preferably 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) or 1, 4-diazabicylo [2.2.2] octane (DABCO).
The solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, methyl-sulfoxide, DMF or acetonitrile, preferred acetonitrile.
Described condensation reaction, is characterized in that the temperature of described reaction is 0-120 DEG C, preferred 50-60 DEG C.
Compared to prior art, how card involved in the present invention replaces the preparation method of Buddhist nun, it is by 6-amino-7-hydroxyl-3, 4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3, 4-dihydroquinazoline-4-ketone (III), this compound (III) can obtain target product by acidylate and condensation reaction again, so advantage of the present invention mainly raw material is easy to get, concise in technology, economic environmental protection, be conducive to the suitability for industrialized production of this medicine, promote the development of the economic technology of this bulk drug.
Detailed description of the invention
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
Embodiment one:
Under room temperature, in there-necked flask, add diisopropyl azo-2-carboxylic acid (3mL, 15mmol) and oxolane 5mL, under room temperature, drip the oxolane 25mL solution of triphenylphosphine (4.0g, 15mmol), keep room temperature reaction 2 hours.Under nitrogen protection; by 3-(4-morpholinyl)-1-propyl alcohol (0.49g; oxolane 5mL dropwise 3.4mmol) joins in above-mentioned reaction system; drip standby after; add 6-amino-7-hydroxyl-3; 4-dihydroquinazoline-4-ketone (II) (0.53g, 3.0mmol), stirring at room temperature reacts 4 hours.Drip the oxolane 5mL solution of 3-(4-morpholinyl)-1-propyl alcohol (0.38g, 2.6mmol), continue room temperature reaction 2 hours, TLC monitoring reaction terminates.Vacuum distillation recovered solvent, residue watery hydrochloric acid adjusts pH=5-6, is extracted with ethyl acetate, and organic phase saturated sodium carbonate adjusts pH=10-11.Separate aqueous phase, vacuum freezedrying, obtain off-white color solid 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3,4-dihydroquinazoline-4-ketone (III) 0.80g, yield is 87.7%.
Embodiment two:
6-amino-7-[3-(4-morpholinyl) propoxyl group]-3 is added in there-necked flask, 4-dihydroquinazoline-4-ketone (III) (0.76g, 2.5mmol), triethylamine (0.25g, 2.5mmol) with carrene 20mL, be warming up to 40-45 DEG C, the system that is stirred to is dissolved homogeneous.Be down to less than 10 DEG C, slowly drip the carrene 10mL solution of acryloyl chloride (0.25g, 2.8mmol), drip off rear room temperature and continue reaction 6 hours, TLC detection reaction terminates.Reactant liquor uses 10% sodium bicarbonate solution and water washing respectively, anhydrous sodium sulfate drying.Decompression and solvent recovery, residue re-crystallizing in ethyl acetate, obtains white solid 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV) 0.81g, yield 90.5%.
Embodiment three:
Under nitrogen protection; 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 100mL.Under stirring, drip 1,8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) (2.28g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 60 DEG C, continue reaction 12 hours.Decompression distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M NaOH 20mL.Separate organic phase, dry, reduced pressure concentration.Residue 100mL oxolane dissolves, and adds the chloro-3-fluoroaniline (1.89g, 13mmol) of 4-and sodium hydride (0.32g, 13mmol), is warming up to 50 DEG C, stirring reaction 5 hours, and TLC monitoring reaction terminates.With saturated aqueous common salt cancellation reaction, separate organic phase, dry, vacuum distillation recovered solvent, obtains pale solid.How obtain off-white color solid card for Buddhist nun (I) 4.05g with ethyl alcohol recrystallization, yield is 83.5%.
Embodiment four:
Under nitrogen protection; 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 100mL.Under stirring, drip 1,5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) (1.86g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 60 DEG C, continue reaction 12 hours.Decompression distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M NaOH 20mL.Separate organic phase, dry, reduced pressure concentration.Residue 100mL oxolane dissolves, and adds the chloro-3-fluoroaniline (1.89g, 13mmol) of 4-and sodium hydride (0.32g, 13mmol), is warming up to 50 DEG C, stirring reaction 5 hours, and TLC monitoring reaction terminates.With saturated aqueous common salt cancellation reaction, separate organic phase, dry, vacuum distillation recovered solvent, obtains pale solid.How obtain off-white color solid card for Buddhist nun (I) 3.85g with ethyl alcohol recrystallization, yield is 79.4%.
Embodiment five:
Under nitrogen protection; 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3 is added in there-necked flask; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g; 15mmol), the chloro-3-fluoroaniline of 4-(1.89g; 13mmol) with DMF 100mL.Under stirring, drip 1,8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) (2.28g, 15mmol), drip and finish, room temperature reaction 12 hours.Be warming up to 60 DEG C, continue reaction 12 hours.Decompression distillation, except desolventizing, adds ethyl acetate 100mL and dissolves, and wash with 2M NaOH 20mL.Separate organic phase, dry, reduced pressure concentration.Residue from ethanol is recrystallized how off-white color solid card replaces Buddhist nun (I) 2.32g, and yield is 47.8%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to Spirit Essence of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (3)
1. how card replaces a Buddhist nun's preparation method, and how described card replaces the chemistry of Buddhist nun to be called 4-(the chloro-4-fluoroanilino of 3-)-7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido quinazoline (I)
It is characterized in that described preparation method comprises the steps: 6-amino-7-hydroxyl-3,4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3,4-dihydroquinazoline-4-ketone (III), described 6-amino-7-[3-(4-morpholinyl) propoxyl group]-3,4-dihydroquinazoline-4-ketone (III) carries out acylation reaction with acrylic acid or acryloyl chloride and generates 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV), described 7-[3-(4-morpholinyl) propoxyl group]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV) and 4-fluoro-3-chloroaniline carry out condensation reaction and how obtain described card for Buddhist nun (I) under condensing agent and alkali promoter act on, raw material 7-[3-(4-morpholinyl) the propoxyl group]-6-acrylamido-3 of wherein said condensation reaction, the molar ratio of the fluoro-3-chloroaniline of 4-dihydroquinazoline-4-ketone (IV) and 4-is 1:1-2, the condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide, carbonyl dimidazoles, N, N '-DIC, 1-hydroxyl-BTA, O-BTA-N, N, N', N'-tetramethylurea tetrafluoro boric acid ester, O-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, BTA-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester or BTA-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate, the alkali promoter of described condensation reaction is triethylamine, pyridine, 2,6-lutidines, DMAP, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [the 4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-ten one-7-alkene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane.
2. block the preparation method how replacing Buddhist nun according to claim 1, it is characterized in that: the solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, methyl-sulfoxide, DMF or acetonitrile.
3. block the preparation method how replacing Buddhist nun according to claim 1, it is characterized in that: the temperature of described condensation reaction is 0-120 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310180647.2A CN103242244B (en) | 2013-05-16 | 2013-05-16 | Canertinib preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310180647.2A CN103242244B (en) | 2013-05-16 | 2013-05-16 | Canertinib preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103242244A CN103242244A (en) | 2013-08-14 |
| CN103242244B true CN103242244B (en) | 2015-03-25 |
Family
ID=48922149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310180647.2A Expired - Fee Related CN103242244B (en) | 2013-05-16 | 2013-05-16 | Canertinib preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103242244B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183560A1 (en) * | 2013-05-16 | 2014-11-20 | 苏州明锐医药科技有限公司 | Afatinib and preparation method of intermediate thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL143089A0 (en) * | 1998-11-19 | 2002-04-21 | Warner Lambert Co | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases |
| PE20040945A1 (en) * | 2003-02-05 | 2004-12-14 | Warner Lambert Co | PREPARATION OF SUBSTITUTED QUINAZOLINES |
| CN102153519B (en) * | 2011-02-18 | 2012-10-24 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
-
2013
- 2013-05-16 CN CN201310180647.2A patent/CN103242244B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN103242244A (en) | 2013-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102584795B (en) | Preparing method of crizotinib | |
| CN103288808B (en) | A kind of Ah method is for the preparation method of Buddhist nun | |
| CN105399736A (en) | Novel preparation method of brexpiprazole | |
| CN103242303B (en) | Afatinib preparation method | |
| CN103288758B (en) | Preparation method of dacomitinib (I) | |
| CN103601645B (en) | The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt | |
| CN105198821A (en) | Preparation method of Rociletinib | |
| CN104478898A (en) | Preparation method of everolimus and intermediate of everolimus | |
| CN105218445B (en) | A kind of preparation method of tyrosine kinase inhibitor Foretinib | |
| CN103012268B (en) | Novel preparation method for ivabradine | |
| CN103242244B (en) | Canertinib preparation method | |
| CN105837493A (en) | A synthetic method of Nintedanib and an intermediate of Nintedanib | |
| CN104311485A (en) | Preparation method of medicine bosutinib for treating leukemia | |
| CN103044467B (en) | Method for preparing intermediate used for synthesizing bortezomib | |
| CN104649966A (en) | Method for synthesizing organic intermediate 5-cyano-3-methylpyridine formic acid | |
| CN103788010A (en) | Febuxostat intermediate and preparation method thereof | |
| CN103265497B (en) | Intermediate compound 4-chloro-6-amino-7-hydroxyquinazoline required for synthesis of tinib antineoplastic drug and preparation method thereof | |
| CN103145636A (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN106008372B (en) | A kind of preparation method and its key intermediate for replacing Buddhist nun up to grammeter | |
| CN103275072B (en) | The preparation method of saracatinib | |
| CN103896889B (en) | Lapatinib intermediate and its preparation method and application | |
| CN105111155A (en) | Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate | |
| CN107365301B (en) | Synthesis method of crizotinib and preparation method of intermediate thereof | |
| CN102924473A (en) | Preparation method of 2-chlorine-7-iodothieno[3,2-D] pyrimidine | |
| CN103288760B (en) | Preparation method of canertinib (I) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20181127 Address after: 214425 No. 23 Huanxi Road, Zhutang Town, Jiangyin City, Jiangsu Province Patentee after: JIANGSU ADOPTION MEDICAL TECHNOLOGY CO., LTD. Address before: Room 1305, 1 Building, Lianfeng Commercial Plaza, Suzhou Industrial Park, Jiangsu Province Co-patentee before: Xu Xuenong Patentee before: Suzhou Mingyue Medical Technology Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200409 Address after: 236200 Anhui province Fuyang City Yingshang Industrial Development Zone Patentee after: ANHUI GOLDEN SUN BIOPHARMACEUTICALS Co.,Ltd. Address before: 214425 No. 23 Huanxi Road, Zhutang Town, Jiangyin City, Jiangsu Province Patentee before: Jiangsu Caina Medical Technology Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150325 Termination date: 20200516 |