CN108239027A - The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones - Google Patents
The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones Download PDFInfo
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- CN108239027A CN108239027A CN201710718875.9A CN201710718875A CN108239027A CN 108239027 A CN108239027 A CN 108239027A CN 201710718875 A CN201710718875 A CN 201710718875A CN 108239027 A CN108239027 A CN 108239027A
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- solution
- methyl
- quinolinones
- synthetic method
- pharmaceutical intermediate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the synthetic methods of 1 methyl of pharmaceutical intermediate, 2 quinolinone, which is characterized in that includes the following steps：2 methylquinolines are added in reaction vessel, 2 chlorobenzene phenol solutions control solution temperature, add in aqueous solution, and butane solution controls mixing speed, reaction；Then Klorvess Liquid, iridium dioxide powder are added in, increases temperature, the reaction was continued, reduces temperature, solution is layered, and oil reservoir is washed with sodium nitrate solution, diethylene glycol dimethyl ethereal solution washing, it is recrystallized in sulfolane solution, dehydrating agent dehydration obtains 1 methyl of finished product, 2 quinolinone.
Description
Technical field
The present invention relates to a kind of preparation methods of medicine intermediate, belong among organic synthesis field more particularly to drug
The synthetic method of body 1- methyl -2- quinolinones.
Background technology
1- methyl -2- quinolinones are mainly used for the synthesis of pharmaceutical intermediate, and existing synthetic method is mostly using quinoline, sulfuric acid
The raw materials such as dimethyl ester, sodium hydroxide solution, the potassium ferricyanide are as reactant, the dimethyl suflfate used due to this synthetic method
It is potential carcinogen and the mutagens that chromosome aberration can be caused, tool volatility, toxicity, corrosivity and environmental hazard can
It is larger to synthesis operator's health harm by skin, mucous membrane and gastrointestinal absorption；Sodium hydroxide solution has extremely strong corrosion
Property, solution or dust splash on skin, especially splash mucous membrane, can generate soft scab, and can penetrate into deep tissues, are stayed after burning
There is scar, splash in human eye, not only corneal damage, but also can damage eyes deep tissue, therefore can increase as synthesis material
Security risk；The scorching hot decomposition of the potassium ferricyanide or chance acid generate hypertoxic cyanide, also result in the increase of building-up process danger coefficient；Cause
This, above-mentioned factor can all lead to this synthetic method, and there are many shortcomings, it is necessary to propose a kind of new synthetic method.
Invention content
Technical problems based on background technology, the present invention propose the conjunction of pharmaceutical intermediate 1- methyl -2- quinolinones
Into method, include the following steps：
A:2- methylquinolines, 2- chlorobenzene phenol solutions are added in reaction vessel, control solution temperature is added in 20-26 DEG C
Aqueous solution, butane solution control mixing speed 210-230rpm, react 90-120min；
B:Then Klorvess Liquid, iridium dioxide powder are added in, raising temperature is to 30-35 DEG C, the reaction was continued 1-2h, reduction
For temperature to 5-9 DEG C, solution layering, oil reservoir washs 30-50min, diethylene glycol dimethyl ethereal solution washing 20- with sodium nitrate solution
40min is recrystallized in sulfolane solution, and dehydrating agent dehydration obtains finished product 1- methyl -2- quinolinones.
Preferably, 2- chlorophenols liquid quality fraction is 30-37%.
Preferably, butane liquid quality fraction is 10-16%.
Preferably, Klorvess Liquid mass fraction is 20-25%.
Preferably, sodium nitrate solution mass fraction is 5-11%.
Preferably, diethylene glycol dimethyl ethereal solution mass fraction is 70-78%.
Preferably, sulfolane solution mass fraction is 80-86%.
Entire building-up process can be used following net reaction to represent：
Compared to synthetic method disclosed in background technology, pharmaceutical intermediate 1- methyl -2- quinolinones provided by the invention
Synthetic method does not need to avoid sulphur as reactant using raw materials such as dimethyl suflfate, sodium hydroxide solution, the potassium ferricyanides
Dimethyl phthalate causes the harm of the risk and its toxicity of chromosome aberration to environment, so as to also avoid it to synthesizing operating personnel
Health hazard；It also avoids that there is extremely strong corrosive sodium hydroxide to do reactant simultaneously, reduces building-up process safety wind
Danger；It also avoids the scorching hot decomposition of the potassium ferricyanide or chance acid generates the risk of hypertoxic cyanide, the danger coefficient of building-up process is reduced；
Reaction intermediate link reduces very much, and the reaction time also shortens much, and reaction yield also improves, while the present invention provides one
The new synthetic route of kind is laid a good foundation further to promote reaction yield.
Description of the drawings
Fig. 1 is the infrared analysis spectrogram of finished product 1- methyl -2- quinolinones.
Specific embodiment
Embodiment 1：
The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones, includes the following steps：
A:3mol 2- methylquinolines are added in reaction vessel, 800ml mass fractions are 30% 2- chlorobenzene phenol solutions,
Solution temperature is controlled to 20 DEG C, adds in 6mol aqueous solutions, 1.2L mass fractions are 10% butane solution, control mixing speed
210rpm reacts 90min；
B:Then the Klorvess Liquid that 600ml mass fractions are 20%, 6mol iridium dioxide powder are added in, raising temperature is extremely
30 DEG C, the reaction was continued 1h, temperature is reduced to 5 DEG C, solution layering, oil reservoir is washed with the sodium nitrate solution that mass fraction is 5%
30min, the diethylene glycol dimethyl ethereal solution that mass fraction is 70% wash 20min, in the sulfolane solution that mass fraction is 80%
Middle recrystallization, dehydrating agent activated alumina dehydration, obtains finished product 1- methyl -2- quinolinone 464.598g, yield 97.4%.
Embodiment 2：
The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones, includes the following steps：
A:3mol 2- methylquinolines are added in reaction vessel, the 2- chlorophenols that 800ml mass fractions are 33.5% are molten
Liquid, control solution temperature add in 7.5mol aqueous solutions to 23 DEG C, and 1.2L mass fractions are 13% butane solution, and control is stirred
Speed 220rpm reacts 105min；
B:Then the Klorvess Liquid that 600ml mass fractions are 22.5%, 7mol iridium dioxide powder are added in, increases temperature
To 32.5 DEG C, the reaction was continued 1.5h reduces temperature to 7 DEG C, and solution layering, oil reservoir mass fraction is 8% sodium nitrate solution
40min is washed, the diethylene glycol dimethyl ethereal solution that mass fraction is 74% washs 30min, in the sulfolane that mass fraction is 83%
It is recrystallized in solution, the dehydration of dehydrating agent activated alumina obtains finished product 1- methyl -2- quinolinone 465.552g, yield 97.6%.
Embodiment 3：
The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones, includes the following steps：
A:3mol 2- methylquinolines are added in reaction vessel, 800ml mass fractions are 37% 2- chlorobenzene phenol solutions,
Solution temperature is controlled to 26 DEG C, adds in 9mol aqueous solutions, 1.2L mass fractions are 16% butane solution, control mixing speed
230rpm reacts 120min；
B:Then the Klorvess Liquid that 600ml mass fractions are 25%, 8mol iridium dioxide powder are added in, raising temperature is extremely
35 DEG C, the reaction was continued 2h, temperature is reduced to 9 DEG C, solution layering, oil reservoir is washed with the sodium nitrate solution that mass fraction is 11%
50min, the diethylene glycol dimethyl ethereal solution that mass fraction is 78% wash 40min, in the sulfolane solution that mass fraction is 86%
Middle recrystallization, dehydrating agent activated alumina dehydration, obtains finished product 1- methyl -2- quinolinone 467.937g, yield 98.1%.
Fig. 1 is the infrared analysis spectrogram of finished product 1- methyl -2- quinolinones.
Table 1 is infrared analysis data.
1 infrared analysis data of table
It described in above example, is merely preferred embodiments of the present invention, but protection scope of the present invention not office
Be limited to this, any one skilled in the art in the technical scope disclosed by the present invention, the technique according to the invention
Scheme and its inventive concept are subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (8)
1. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones, which is characterized in that include the following steps：
A:2- methylquinolines, 2- chlorobenzene phenol solutions are added in reaction vessel, control solution temperature adds in water-soluble to 20-26 DEG C
Liquid, butane solution control mixing speed 210-230rpm, react 90-120min；
B:Then Klorvess Liquid, iridium dioxide powder are added in, raising temperature is to 30-35 DEG C, the reaction was continued 1-2h, reduction temperature
To 5-9 DEG C, solution layering, oil reservoir washs 30-50min, diethylene glycol dimethyl ethereal solution washing 20-40min with sodium nitrate solution,
It is recrystallized in sulfolane solution, dehydrating agent dehydration obtains finished product 1- methyl -2- quinolinones.
2. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones according to claim 1, which is characterized in that described
2- chlorophenols liquid quality fraction is 30-37%.
3. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones according to claim 1, which is characterized in that described
Butane liquid quality fraction is 10-16%.
4. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones according to claim 1, which is characterized in that described
Klorvess Liquid mass fraction is 20-25%.
5. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones according to claim 1, which is characterized in that described
Sodium nitrate solution mass fraction is 5-11%.
6. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones according to claim 1, which is characterized in that described
Diethylene glycol dimethyl ethereal solution mass fraction is 70-78%.
7. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones according to claim 1, which is characterized in that described
Sulfolane solution mass fraction is 80-86%.
8. the synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones according to claim 1, which is characterized in that including such as
Lower step：
A:3mol 2- methylquinolines are added in reaction vessel, 800ml mass fractions are 37% 2- chlorobenzene phenol solutions, are controlled
Solution temperature adds in 9mol aqueous solutions to 26 DEG C, and 1.2L mass fractions are 16% butane solution, control mixing speed
230rpm reacts 120min；
B:Then the Klorvess Liquid that 600ml mass fractions are 25%, 8mol iridium dioxide powder, raising temperature to 35 are added in
DEG C, the reaction was continued 2h reduces temperature to 9 DEG C, and solution layering, oil reservoir is washed with the sodium nitrate solution that mass fraction is 11%
50min, the diethylene glycol dimethyl ethereal solution that mass fraction is 78% wash 40min, in the sulfolane solution that mass fraction is 86%
Middle recrystallization, dehydrating agent activated alumina dehydration, obtains finished product 1- methyl -2- quinolinones.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710718875.9A CN108239027A (en) | 2017-08-21 | 2017-08-21 | The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones |
| GBGB1714445.2A GB201714445D0 (en) | 2017-08-21 | 2017-09-08 | Drug intermediates 1-methyl-2-quinolinone synthesis method |
| AU2018101123A AU2018101123A4 (en) | 2017-08-21 | 2018-08-11 | Drug intermediates 1-methyl-2-quinolinone synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710718875.9A CN108239027A (en) | 2017-08-21 | 2017-08-21 | The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones |
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| Publication Number | Publication Date |
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| CN108239027A true CN108239027A (en) | 2018-07-03 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710718875.9A Pending CN108239027A (en) | 2017-08-21 | 2017-08-21 | The synthetic method of pharmaceutical intermediate 1- methyl -2- quinolinones |
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| Country | Link |
|---|---|
| CN (1) | CN108239027A (en) |
| AU (1) | AU2018101123A4 (en) |
| GB (1) | GB201714445D0 (en) |
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2017
- 2017-08-21 CN CN201710718875.9A patent/CN108239027A/en active Pending
- 2017-09-08 GB GBGB1714445.2A patent/GB201714445D0/en not_active Ceased
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2018
- 2018-08-11 AU AU2018101123A patent/AU2018101123A4/en not_active Ceased
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| Publication number | Publication date |
|---|---|
| AU2018101123A4 (en) | 2018-09-06 |
| GB201714445D0 (en) | 2017-10-25 |
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Application publication date: 20180703 |