CN107641095A - A kind of synthetic method of the ketone of 7 methoxyl group iso-indoles 1 - Google Patents
A kind of synthetic method of the ketone of 7 methoxyl group iso-indoles 1 Download PDFInfo
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- CN107641095A CN107641095A CN201711133543.0A CN201711133543A CN107641095A CN 107641095 A CN107641095 A CN 107641095A CN 201711133543 A CN201711133543 A CN 201711133543A CN 107641095 A CN107641095 A CN 107641095A
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- indoles
- ketone
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- methoxyl group
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Abstract
The present invention relates to the synthetic method of the ketone of 7 methoxyl group iso-indoles 1.Mainly solves the technical problem that existing synthetic method utilizes the dangerous property of hydrogen reducing halides.The technical scheme is that：A kind of synthetic method of the ketone of 7 methoxyl group iso-indoles 1, comprises the following steps：The ketone of 4 bromine, 7 methoxyl group iso-indoles 1 is dissolved in NMP (N methyl pyrrolidones) solution, adds PdCl2, triethyl silicane stirring reaction is added dropwise, is poured into water and separates out solid, filter, be recrystallized to give the ketone of 7 methoxyl group iso-indoles 1.Product of the present invention is the key intermediate of HER2/EGFR kinase inhibitors.
Description
Technical field
The present invention relates to the synthetic method of 7- methoxyl group iso-indoles -1- ketone.
Background technology
7- methoxyl group iso-indoles -1- ketone is the key intermediate of HER2/EGFR kinase inhibitors, and in Medicine small molecule
Conventional structure fragment.The hydrogen that is synthesized by of the fragment of document report hydrogenates the bromo- 7- methoxyl groups iso-indoles -1- of 4- at present
Ketone dehalogenate is realized.Certain danger be present using hydrogen hydrogenation-dehalogenation element, there is special requirement to experimental facilities.
Applicant touches the restoring method of the silane of chlorination palladium chtalyst under study for action.This method has yield high, selects
The advantages that selecting property is good, strong applicability, and reaction condition is gentle.Silane is a kind of cheap, stable, safe industrial chemicals.This
Process safety is high, simple to operate, can be realized by common chemical industry equipment.Whether can be by the silane of chlorination palladium chtalyst
Restoring method is applied in the synthesis of 7- methoxyl group iso-indoles -1- ketone, dangerous existing for hydrogenation-dehalogenation to solve, due to being
Different compound synthesis method applications, this is the key point that the present invention innovates.
The content of the invention
Present invention mainly solves the danger using hydrogen reducing halides, a kind of particularity of equipment, there is provided new system
The method of standby 7- methoxyl group iso-indoles -1- ketone.
The technical scheme is that：A kind of synthetic method of 7- methoxyl groups iso-indoles -1- ketone, comprises the following steps：Will
The bromo- 7- methoxyl groups iso-indoles -1- ketone of 4- is dissolved in NMP (1-METHYLPYRROLIDONE) solution, adds PdCl2 , triethyl group silicon is added dropwise
Alkane stirring reaction, it is poured into water and separates out solid, filter, be recrystallized to give 7- methoxyl group iso-indoles -1- ketone.Reaction equation is as follows：
。
Research has been surprisingly found that NMP as reaction dissolvent, can react, preferably room temperature between -10 ~ 60 DEG C（20-30℃）
Reaction, triethyl silicane equivalents use PdCl between 8 ~ 20 eq.2As catalysts.
Beneficial effects of the present invention：By the use of NMP as reaction dissolvent, silane replaces hydrogen as reducing agent, PdCl2As
Catalysts, reaction yield is improved, improve the security of technique, reduced the requirement to equipment, reduce cost.
Embodiment
Embodiment 1, a (2.0 g, 8.3 mmol) is dissolved in 20 mL nmp solutions, adds PdCl2 (90 mg,
0.5 mmol), triethyl silicane is added dropwise（11.5 g, 99 mmol）.It is stirred at room temperature 1 hour.Question response finishes, and is added to the water,
Filtering, filter cake recrystallization, obtains the g of product 1.3, yield 96%.1HNMR (400 MHz, DMSO-d6): δ=8.19(1H,
s), 7.53-7.49(1H, m), 7.09-7.07(1H, d), 7.00-6.98(1H, d), 4.28(2H, s), 3.83
(3H, s). MS (M+1):164.
。
Embodiment 2, reaction temperature room temperature, triethyl silicane equivalents are 8, and yield 83%, remaining is the same as embodiment 1.
Embodiment 3, reaction temperature room temperature, triethyl silicane equivalents are 20, and yield 95%, remaining is the same as embodiment 1.
Embodiment 4, -10-0 DEG C of reaction temperature, triethyl silicane equivalents are 12, and yield 92%, remaining is the same as embodiment 1.
Embodiment 5,50-60 DEG C of reaction temperature, triethyl silicane equivalents are 12, and yield 95%, remaining is the same as embodiment 1.
Comparative example 1, reaction temperature room temperature, triethyl silicane equivalents are 17, solvent 2-Me-THF, remaining same embodiment
1, yield 0%.
Comparative example 2, reaction temperature room temperature, triethyl silicane equivalents are 17, solvent DCM, and remaining is received with embodiment 1
Rate is 0%.
Claims (4)
1. a kind of synthetic method of 7- methoxyl groups iso-indoles -1- ketone, it is characterized in that：Comprise the following steps：By the bromo- 7- methoxyl groups of 4-
Iso-indoles -1- ketone is dissolved in 1-METHYLPYRROLIDONE solution, adds PdCl2 , triethyl silicane stirring reaction is added dropwise, pours into water
In, filtering, 7- methoxyl group iso-indoles -1- ketone is recrystallized to give, reaction equation is as follows：
。
2. a kind of synthetic method of 7- methoxyl groups iso-indoles -1- ketone according to claim 1, it is characterized in that：Reaction temperature
For -10 ~ 60 DEG C.
3. a kind of synthetic method of 7- methoxyl groups iso-indoles -1- ketone according to claim 2, it is characterized in that：Reaction temperature
For room temperature.
4. a kind of synthetic method of 7- methoxyl groups iso-indoles -1- ketone according to claim 1, it is characterized in that：Triethyl group silicon
Alkane equivalents is 8 ~ 20 eq..
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201711133543.0A CN107641095A (en) | 2017-11-16 | 2017-11-16 | A kind of synthetic method of the ketone of 7 methoxyl group iso-indoles 1 |
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| CN201711133543.0A CN107641095A (en) | 2017-11-16 | 2017-11-16 | A kind of synthetic method of the ketone of 7 methoxyl group iso-indoles 1 |
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| CN107641095A true CN107641095A (en) | 2018-01-30 |
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| CN201711133543.0A Pending CN107641095A (en) | 2017-11-16 | 2017-11-16 | A kind of synthetic method of the ketone of 7 methoxyl group iso-indoles 1 |
Country Status (1)
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801958A (en) * | 2007-07-19 | 2010-08-11 | 先灵公司 | Heterocyclic amide as protein kinase inhibitors |
-
2017
- 2017-11-16 CN CN201711133543.0A patent/CN107641095A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801958A (en) * | 2007-07-19 | 2010-08-11 | 先灵公司 | Heterocyclic amide as protein kinase inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| JAN BREITENFELD，等: "Synthesis, Reactivity, and Catalytic Application of a Nickel Pincer Hydride Complex", 《ORGANOMETALLICS》 * |
| NASSER IRANPOOR，等: "Diphenylphosphinite ionic liquid (IL-OPPh2): A solvent and ligand for palladium-catalyzed silylation and dehalogenation reaction of aryl halides with triethylsilane", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》 * |
| 薛福玲，等: "脱卤反应研究进展", 《有机化学》 * |
| 邓云盼，等: "金属配合物催化氢解脱卤研究", 《化学进展》 * |
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Effective date of registration: 20190108 Address after: 213127 No. 589 Yulong North Road, Xinbei District, Changzhou City, Jiangsu Province Applicant after: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Address before: 213034 Baizhang Old Street, Chunjiang Town, Xinbei District, Changzhou City, Jiangsu Province Applicant before: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Applicant before: Changzhou whole new drug research and Development Co., Ltd. |
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Application publication date: 20180130 |