CN101575319B - Process for preparing lapatinib synthetic intermediate - Google Patents
Process for preparing lapatinib synthetic intermediate Download PDFInfo
- Publication number
- CN101575319B CN101575319B CN2009100333278A CN200910033327A CN101575319B CN 101575319 B CN101575319 B CN 101575319B CN 2009100333278 A CN2009100333278 A CN 2009100333278A CN 200910033327 A CN200910033327 A CN 200910033327A CN 101575319 B CN101575319 B CN 101575319B
- Authority
- CN
- China
- Prior art keywords
- chloro
- iodo
- aminobenzonitrile
- dma
- dmf
- 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
Images
Abstract
The invention relates to a process for preparing a lapatinib synthetic intermediate, which is characterized by comprising the following process steps: mixing 5-iodo-2-aminobenzonitrile and DMF-DMA; heating and refluxing the mixture at a temperature of between 90 and 100 DEG C for 1 to 2 hours, and performing reduced pressure distillation at a pressure of 0.1 MPa and at a temperature of between 70 and 80 DEG C for 10 to 30 minutes to remove excessive DMF-DMA; adding glacial acetic acid and 3-chloro-4-(3-fluorophenyl-methoxy) aniline; heating and refluxing the mixture at a temperature of between90 and 100 DEG C for 1 hour, cooling the mixture to the room temperature, and pouring the mixture to ice water; performing vacuum filtration, and washing a filter cake with the ice water and then wit h methanol; and performing vacuum drying on the filter cake to obtain a faint yellow solid N-(3-chloro-4-(3-fluorophenylmethoxy)phenyl)-6-iodoquinazoline-4-amine. The route avoids the use of thionyl chloride or phosphorus oxychloride and reduces pollutions to the environment; besides, the process has high yield and simple operation and is suitable for industrial production.
Description
One, technical field
The invention belongs to the chemical pharmaceutical field, relate in particular to a kind of preparation technology of lapatinibditosylate synthetic intermediate.
Two, background technology
Lapatinibditosylate (Lapatinib)
Chemistry N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl) by name-two (4-toluenesulfonate) monohydrates of 6-(5-((2-(methylsulfonyl) ethylamino) methyl) furans-2-yl) quinazoline-4-amine, it is novel tyrosine kinase inhibitor by the research and development of GlaxoSmithKline PLC company, be used for the treatment of the late period or the metastatic breast cancer patient of HER-2 overexpression, gone on the market by drugs approved by FDA in March, 2007.N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine (1) is the key intermediate of synthetic lapatinibditosylate, and the CAS accession number is 231278-20-9.The preparation technology who adopts is at present: with 5-iodo-2-benzaminic acid is starting raw material, obtain 4-hydroxyl-6-iodine quinazoline through the FORMAMIDINE ACETATE cyclization, obtain 4-chloro-6-iodine quinazoline through sulfur oxychloride or phosphorus oxychloride chlorination, obtain 1 (accompanying drawing 1, route 1) with 3-chloro-4-(3-fluorobenzene methoxyl group) aniline condensation again.Wherein, the synthetic employing 4-hydroxyl 6-iodine quinazoline of 4-chloro-6-iodine quinazoline is a raw material, and with excess chlorination sulfoxide or phosphorus oxychloride reaction, aftertreatment difficulty, environmental pollution is big.
Three, summary of the invention
Technical problem: this patent provides a kind of lapatinibditosylate to synthesize the new preparation process of key intermediate N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine.
Technical scheme: a kind of preparation technology of lapatinibditosylate synthetic intermediate, processing step is: with 5-iodo-2-aminobenzonitrile and DMF-DMA (N, the dinethylformamide dimethylacetal) mixes, the feed ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is 1: 1-5,90-100 ℃ of reflux 1-2h, 0.1MPa/70-80 a ℃ underpressure distillation 10-30min removes excessive DMF-DMA, add Glacial acetic acid, 3-chloro-4-(3-fluorobenzene methoxyl group) aniline, in 5-iodo-2-aminobenzonitrile quality, the charging capacity of described Glacial acetic acid is 1-40ml/g, 3-chloro-4-(3-fluorobenzene methoxyl group) aniline and 5-iodo-2-aminobenzonitrile molar ratio are 1: 0.6-3,90-100 ℃ of reflux 1h, be cooled to room temperature, pour in the frozen water suction filtration into, filter cake washs with frozen water, use methanol wash again, vacuum-drying obtains faint yellow solid N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine.
The molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is preferably 1: 2-3.
In 5-iodo-2-aminobenzonitrile quality, the charging capacity of Glacial acetic acid is 5-20ml/g.
3-chloro-4-(3-fluorobenzene methoxyl group) aniline and 5-iodo-2-aminobenzonitrile molar ratio are 1: 1-1.5.
Beneficial effect: this synthetic route avoids using sulfur oxychloride or phosphorus oxychloride, has reduced the pollution to environment; Yield is higher, and is simple to operate, is suitable for suitability for industrialized production.
Four, description of drawings
The preparation were established figure of Fig. 1 N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine.Wherein route 1 is the prior art synthetic route, and route 2 is the application's synthetic route.
Five, embodiment
The following examples can make those skilled in the art comprehensively understand the present invention, but do not limit the present invention in any way.
The preparation of embodiment 1 N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine (1)
5-iodo-2-aminobenzonitrile (18.4g, 75mmol), DMF-DMA (N, the dinethylformamide dimethylacetal, 40ml) join in the 100ml eggplant-shape bottle, 90-100 ℃ of reflux 1h removes excessive DMF-DMA under reduced pressure, add Glacial acetic acid (100ml), 3-chloro-4-(3-fluorobenzene methoxyl group) aniline (15g, 59.5mmol) reflux 1h, be cooled to room temperature, pour in the frozen water (500ml), suction filtration, filter cake washs with frozen water (about 500ml), methyl alcohol (1L) washing, vacuum-drying, obtain faint yellow solid 1 24.8g, yield 82.4%.
1H?NMR(DMSO-d6，300Hz)：5.26(s，2H)；7.18(m，1H)；7.34-7.26(m，3H)；7.47(m，1H)；7.56(d，J＝8.7Hz，1H)；7.75(d，J＝8.8Hz，1H)；8.03(s，1H)；8.11(d，J＝8.6Hz，1H)；8.61(s，1H)；8.95(s，1H)；9.84(s，1H)；
13C?NMR(DMSO-d6，300MHz)：162.2(d，J＝970Hz)，156.3，154.7，149.7，148.7，141.2，139.6(d，J＝30Hz)，133.0，131.3，130.5(d，J＝33Hz)，129.7，123.9，123.2(d，J＝10.8Hz)，122.1，121.1，116.8，114.6(d，J＝82.8Hz)，114.3，114.0(d，J＝87.3Hz)，91.3，69.4；LC-MS：506[M+H]
+。
The preparation of embodiment 2 N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine (1)
5-iodo-2-aminobenzonitrile and DMF-DMA are mixed, the molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is 1: 1-5,90-100 ℃ of reflux 1h, 0.1MPa/70-80 a ℃ underpressure distillation 30min removes excessive DMF-DMA, add Glacial acetic acid, 3-chloro-4-(3-fluorobenzene methoxyl group) aniline, in 5-iodo-2-aminobenzonitrile quality, the charging capacity of described Glacial acetic acid is 1-40ml/g, 3-chloro-4-(3-fluorobenzene methoxyl group) aniline and 5-iodo-2-aminobenzonitrile molar ratio are 1: 1-3,90-100 ℃ of reflux 1h, be cooled to room temperature, pour in the frozen water suction filtration into, filter cake washs with frozen water, use methanol wash again, vacuum-drying obtains faint yellow solid N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine.
The molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is preferably 1: 2-3.
In 5-iodo-2-aminobenzonitrile quality, the charging capacity of Glacial acetic acid is preferably 5-20ml/g.
3-chloro-4-(3-fluorobenzene methoxyl group) aniline and 5-iodo-2-aminobenzonitrile molar ratio are preferably 1: 1-1.5.
Claims (1)
1. the preparation technology of a lapatinibditosylate synthetic intermediate, it is characterized in that processing step is: 5-iodo-2-aminobenzonitrile and DMF-DMA are mixed, the molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is 1: 2-3,90-100 ℃ of reflux 1-2h, 0.1MPa/70-80 a ℃ underpressure distillation 10-30min removes excessive DMF-DMA, add Glacial acetic acid, 3-chloro-4-(3-fluorobenzene methoxyl group) aniline, in 5-iodo-2-aminobenzonitrile quality, the charging capacity of described Glacial acetic acid is 5-20mL/g, 3-chloro-4-(3-fluorobenzene methoxyl group) aniline and 5-iodo-2-aminobenzonitrile molar ratio are 1: 1-1.5,90-100 ℃ of reflux 1h, be cooled to room temperature, pour in the frozen water, suction filtration, filter cake washs with frozen water, uses methanol wash again, vacuum-drying obtains faint yellow solid N-(3-chloro-4-(3-fluorobenzene methoxyl group) phenyl)-6-iodine quinazoline-4-amine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100333278A CN101575319B (en) | 2009-06-18 | 2009-06-18 | Process for preparing lapatinib synthetic intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100333278A CN101575319B (en) | 2009-06-18 | 2009-06-18 | Process for preparing lapatinib synthetic intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101575319A CN101575319A (en) | 2009-11-11 |
| CN101575319B true CN101575319B (en) | 2011-07-27 |
Family
ID=41270409
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100333278A Expired - Fee Related CN101575319B (en) | 2009-06-18 | 2009-06-18 | Process for preparing lapatinib synthetic intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101575319B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101792416B (en) * | 2010-01-15 | 2011-10-05 | 南京医科大学 | Process for preparing bosutinib |
| CN102532109B (en) * | 2010-12-27 | 2015-05-13 | 浙江海正药业股份有限公司 | Synthetic method of lapatinib and salt of lapatinib |
| CN102321076B (en) * | 2011-07-07 | 2013-08-21 | 中国科学技术大学 | Preparation method of lapatinib intermediate and analogues thereof |
| CN102675297B (en) * | 2012-04-17 | 2014-10-15 | 人福医药集团股份公司 | Preparation method of Lapatinib |
| CN103483324B (en) * | 2012-06-12 | 2016-03-30 | 人福医药集团股份公司 | The new preparation process of lapatinibditosylate |
| CN103539702B (en) * | 2012-07-12 | 2016-03-30 | 陕西师范大学 | The novel preparation method of N '-aryl-N, N-dimethyl carbonamidine |
| CN103159747A (en) * | 2013-02-26 | 2013-06-19 | 常州鸿创高分子科技有限公司 | Synthetic method of lapatinib |
| CN110698417B (en) * | 2018-07-09 | 2020-11-20 | 新发药业有限公司 | Preparation method of 6-substituent furyl-4-substituted amino quinazoline derivative and key intermediate thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006079833A1 (en) * | 2005-01-31 | 2006-08-03 | Arrow Therapeutics Limited | Quinazoline derivatives as antiviral agents |
| WO2008056149A1 (en) * | 2006-11-09 | 2008-05-15 | Arrow Therapeutics Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
| CN101321740A (en) * | 2005-10-07 | 2008-12-10 | 阿罗治疗有限公司 | Chemical compounds |
-
2009
- 2009-06-18 CN CN2009100333278A patent/CN101575319B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006079833A1 (en) * | 2005-01-31 | 2006-08-03 | Arrow Therapeutics Limited | Quinazoline derivatives as antiviral agents |
| CN101321740A (en) * | 2005-10-07 | 2008-12-10 | 阿罗治疗有限公司 | Chemical compounds |
| WO2008056149A1 (en) * | 2006-11-09 | 2008-05-15 | Arrow Therapeutics Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
Non-Patent Citations (2)
| Title |
|---|
| Tsou,HR.等.6-Substituted-4-（3-bromophenylamino） quinazolines as putative irreversible inhibitorsof epidermal growth factor receptor （EGFR） and humanepidermal growth factor receptor （HER-2） tyrosine kinases with enhanced antitumour activity.《Journal of Medicinal Chemistry》.2001,第44卷(第17期),全文. * |
| 王武伟等.N-(3-氯-4-(3-氟苯甲氧基)苯基)-6-碘喹唑啉-4-胺盐酸盐的合成.《化工中间体》.2008,(第11期),全文. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101575319A (en) | 2009-11-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101575319B (en) | Process for preparing lapatinib synthetic intermediate | |
| CN102558056B (en) | Celecoxib and preparing method thereof | |
| CN106928184B (en) | A kind of Ai Le replaces the preparation method of Buddhist nun | |
| CN103936678B (en) | The chloro-2-cyano group of a kind of 4--N, the synthetic method of N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide | |
| CN106117482A (en) | A kind of modified high-thin arch dam naphthalene water reducer and preparation method thereof | |
| CN103626699A (en) | Industrial preparation method of 4,7-dichloroquinoline | |
| CN102532116A (en) | Synthesis method of anti-tumor targeted therapeutic drug tivozanib | |
| CN104910067A (en) | Regorafenib synthesis method by one kettle way | |
| CN105037236B (en) | Rui Boxini intermediates and preparation method thereof | |
| CN102304116A (en) | Fluorescein compound and preparation method thereof | |
| CN103626697B (en) | A kind of preparation method of the cyanopyridine of 2 chlorine, 4 trifluoromethyl 3 | |
| CN104710320A (en) | Method for preparing pregabalin | |
| CN108997209B (en) | Preparation method of regorafenib | |
| CN104326975A (en) | Preparation method of high-purity milrinone | |
| CN103058936B (en) | The preparation method of 4-[(the chloro-2-pyrimidyl of 4-) is amino] cyanophenyl | |
| CN109694354A (en) | The synthetic method of the chloro- 2- methylthiopyrimidine -5- Ethyl formate of 4- | |
| CN103304491A (en) | Preparation method of gefitinib | |
| CN105085485B (en) | A kind of preparation method of HKI-272 | |
| CN104418845B (en) | Prepare the method and intermediate of Lapatinib | |
| CN105801559B (en) | The preparation method of 4- methyl -3- [[4- (3- pyridyl group) -2- pyrimidine radicals] amino] ethyl benzoate | |
| CN102603316A (en) | Low-heat-conduction silicon mullite brick and preparation method thereof | |
| CN103288707B (en) | A kind of preparation method of 3-benzene sulfydryl indole derivative | |
| CN110577496A (en) | Preparation method of uracil | |
| CN104230717B (en) | One prepares the method for 2,2 '-two (trifluoromethyl)-4,4 '-dinitro diphenyl ether | |
| CN105085496A (en) | Method for preparing Lapatinib and intermediate |
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 | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110727 Termination date: 20120618 |