CN111747890A - Preparation method of 4, 7-dichloroquinoline - Google Patents
Preparation method of 4, 7-dichloroquinoline Download PDFInfo
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- CN111747890A CN111747890A CN202010636897.2A CN202010636897A CN111747890A CN 111747890 A CN111747890 A CN 111747890A CN 202010636897 A CN202010636897 A CN 202010636897A CN 111747890 A CN111747890 A CN 111747890A
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- dichloroquinoline
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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
- C07D215/18—Halogen atoms or nitro radicals
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Abstract
The invention discloses a preparation method of 4, 7-dichloroquinoline, which takes 3-chloroaniline and ethoxy diethyl methylene malonate as raw materials and obtains the 4, 7-dichloroquinoline through the steps of condensation, cyclization, hydrolysis, decarboxylation and chlorination; the steps of condensation, cyclization and hydrolysis are as follows: putting 3-chloroaniline, diethyl ethoxymethylene malonate and paraffin oil into a reaction kettle, heating to 230-260 ℃ for reaction, cooling to 90-100 ℃ after the reaction is finished, adding toluene, caustic soda flakes and deionized water, keeping the temperature of 90-100 ℃ for reaction till the reaction is complete, layering, recovering an organic layer, and putting a water layer into the next reaction; the decarboxylation step is as follows: adding the water layer into an autoclave, performing decarboxylation reaction under the pressure of 6.0-6.5 kg and the temperature of 150-. Mild reaction condition, high yield and high quality.
Description
Technical Field
The invention relates to a preparation method of 4, 7-dichloroquinoline, belonging to the technical field of organic synthesis.
Background
Chloroquine is an antimalarial drug and is also a novel effective therapeutic drug for coronary pneumonia, and 4, 7-dichloroquinoline is an important intermediate for synthesizing the chloroquine. 4, 7-dichloroquinoline is not available in the market at present as the parent nucleus of chloroquine and hydroxychloroquine. The old process for producing the 4, 7-dichloroquinoline has high production cost, harsh conditions and long production period, and can not meet the market demand. It is significant to find the production process suitable for the current situation as soon as possible.
Patent documents CN201310680605 and CN1847226A respectively use 7-chloro 4-hydroxyquinoline 3-carboxylic acid ethyl ester and ethoxy methylene malonic acid diethyl ester as starting materials for synthesis, and the raw materials are expensive and not easy to obtain, which is not beneficial to industrial production.
CN104447534A and' research on Process of antimalarial 4, 7-dichloroquinoline (first phase of volume 4 of 2.2006, of Zhongnan pharmacy) disclose a preparation method of 4, 7-dichloroquinoline, which comprises the steps of taking m-chloroaniline and diethyl ethoxymethylidynemalonate as raw materials, performing condensation cyclization, decarboxylation and chlorination to obtain 4, 7-dichloroquinoline.
The specific reaction steps are as follows: (1) heating diethyl ethoxymethylidynemalonate to 110-130 ℃ in a dry container, adding m-chloroaniline for reaction for 1-3h, heating to 255-260 ℃, adding sodium hydroxide into the reaction liquid, then cooling the reaction liquid to room temperature after reaction for 1-2h, carrying out suction filtration, collecting filtrate, regulating the pH value to 2-3 by using hydrochloric acid, separating out a solid, carrying out suction filtration, and drying a filter cake to obtain a white solid product, namely 7-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester;
(2) in a drying container, adding the 7-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester prepared in the step (1) into liquid paraffin, heating to 255-260 ℃, reacting for 30-40min, cooling to 90-100 ℃, adding phosphorus oxychloride, refluxing and reacting for 1-2h, cooling the reaction solution to room temperature, washing with hydrochloric acid, performing suction filtration, and drying to obtain a light yellow solid product, namely 4, 7-dichloroquinoline. The reaction formula is as follows:
the reaction needs to be heated to 255-260 ℃ during cyclization and decarboxylation, and the reaction temperature is high, thus being not beneficial to industrial production.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide another preparation method of 4, 7-dichloroquinoline, which reduces the reaction temperature during decarboxylation, simplifies the treatment process, and has high yield and good product quality.
In order to achieve the purpose, the technical scheme of the invention is as follows: a preparation method of 4, 7-dichloroquinoline is characterized in that 3-chloroaniline and diethyl ethoxy methylene malonate are used as raw materials, and the 4, 7-dichloroquinoline is obtained through the steps of condensation, cyclization and hydrolysis, the step of decarboxylation and the step of chlorination in sequence;
wherein the steps of condensation, cyclization and hydrolysis are as follows: putting 3-chloroaniline, diethyl ethoxymethylene malonate and paraffin oil into a reaction kettle, heating to 230-260 ℃ for reaction, cooling to 90-100 ℃ after the reaction is finished, adding toluene, caustic soda flakes and deionized water, keeping the temperature of 90-100 ℃ for reaction till the reaction is complete, layering, recovering an organic layer, and putting a water layer into the next reaction;
the decarboxylation step is as follows: adding the water layer into an autoclave, performing decarboxylation reaction under the pressure of 6.0-6.5 kg and the temperature of 150-.
In the steps of condensation, cyclization and hydrolysis, the temperature is raised to 230-260 ℃, the reaction time is 3-5h, the hydrolysis reaction time is 2-3h, after the hydrolysis is finished, only a water layer and an organic layer are obtained by layering, other treatments are not needed, then the water layer is directly added into an autoclave for decarboxylation, the high-pressure reaction is adopted, the reaction time is 5-6h, the temperature is reduced, the energy consumption is reduced, the reaction condition is mild, and the operability is improved. The total yield from condensation to decarboxylation step can reach 96%.
The chlorination step comprises: the chlorination step comprises: adding toluene, phosphorus oxychloride and 4-hydroxy-7-chloroquinoline into a reaction container, reacting at 110 ℃, after the reaction is finished, evaporating the toluene and the unreacted phosphorus oxychloride under reduced pressure, adding water, neutralizing with liquid alkali to a pH value of 5-6, filtering, adding EDTA and activated carbon into the filtrate for decolorization, adjusting the pH value to 5-6 with acetic acid, filtering, adjusting the pH value to 7-8 with alkali, separating out a product, filtering, and drying to obtain the 4, 7-dichloroquinoline. The chlorination reaction time is 5-6h, toluene is added as a solvent during chlorination, the usage amount of phosphorus oxychloride is reduced, and the yield of the step can reach 77%.
In the scheme, the method comprises the following steps: the molar ratio of the 3-chloroaniline to the diethyl ethoxymethylidene malonate is 1-1.2: 1.
In the scheme, the method comprises the following steps: the mol ratio of the diethyl ethoxymethylene malonate to the flaky alkali is 1: 2-5.
In the scheme, the method comprises the following steps: in the steps of condensation, cyclization and hydrolysis, the mass concentration of the caustic soda flakes is 10-15%.
In the scheme, the method comprises the following steps: the molar ratio of the phosphorus oxychloride to the 4-hydroxy-7-chloroquinoline is 1.2-1.5: 1.
In the scheme, the method comprises the following steps: the base used to adjust the pH of the chlorination step is sodium carbonate or sodium bicarbonate.
Has the advantages that: the invention provides a method for synthesizing 4, 7-dichloroquinoline by taking m-chloroaniline and ethoxy diethyl methylene malonate as raw materials through reaction, which can be carried out under a high-pressure condition during decarboxylation by redesigning the reaction steps, reduces the temperature of the decarboxylation reaction, and finally obtains a product which is similar to white, wherein the total yield is over 73 percent, the yield is high, and the product quality is good.
Detailed Description
The invention is further illustrated below by reference to the reaction scheme and examples:
example 1
Synthesis of intermediate Z3
Putting 2.77mol of 3-chloroaniline, 2.77mol of diethyl ethoxymethylene malonate and 350ml of paraffin oil into a reaction kettle, heating to 230 ℃ for reaction for 5h, cooling to 90-100 ℃ after the reaction is finished, adding 300ml of toluene and 300ml of 10 mass percent flake caustic soda solution prepared from 5.54mol of flake caustic soda and 300ml of deionized water, maintaining the temperature of 90-100 ℃ for hydrolysis reaction for 3h until the reaction is complete, layering, recovering an organic layer, and putting a water layer into the next step for reaction.
Preparation of intermediate Z4: adding the water layer into an autoclave, performing decarboxylation reaction for 5 hours under the pressure of 6.0-6.5 kg and the temperature of 150-.
Example 2
Synthesis of intermediate Z3
3.3mol of 3-chloroaniline, 2.77mol of diethyl ethoxymethylene malonate and 350ml of paraffin oil are put into a reaction kettle, the temperature is increased to 260 ℃ for reaction for 3 hours, the temperature is reduced to 90-100 ℃ after the reaction is finished, 15% caustic soda flakes solution and 300ml of deionized water which are prepared from 300ml of toluene and 13.8mol of caustic soda flakes and have mass concentration are added, the 90-100 ℃ is kept for hydrolysis reaction for 2 hours until the reaction is complete, the layers are separated, the organic layer is recovered, and the water layer is put into the next reaction.
Preparation of intermediate Z4: adding the water layer into an autoclave, performing decarboxylation reaction for 5 hours under the pressure of 6.0-6.5 kg and the temperature of 150-.
Example 3
Synthesis of intermediate Z3
3.0mol of 3-chloroaniline, 2.77mol of diethyl ethoxymethylene malonate and 350ml of paraffin oil are put into a reaction kettle, the temperature is increased to 250 ℃ for reaction for 5h, the temperature is reduced to 90-100 ℃ after the reaction is finished, 300ml of toluene and 300ml of 10 mass percent flake caustic soda solution prepared from 6mol of flake caustic soda and 300ml of deionized water are added, the 90-100 ℃ is kept for hydrolysis reaction for 3h until the reaction is complete, the layers are separated, the organic layer is recovered, and the water layer is put into the next reaction.
Preparation of intermediate Z4: adding the water layer into an autoclave, performing decarboxylation reaction for 6 hours under the pressure of 6.0-6.5 kg and the temperature of 150-.
Example 4
Synthesis of Z5
100ml of toluene, 3.2mol of phosphorus oxychloride and 2.67mol of 4-hydroxy-7-chloroquinoline are added into a reaction container, after the reaction is finished at 110 ℃ for 5 hours, the toluene and the unreacted phosphorus oxychloride are evaporated under reduced pressure after the reaction is finished, 200ml of water are added, liquid alkali (30% of sodium hydroxide) is used for neutralizing until the pH value is 5-6, EDTA and active carbon are added into filtered filtrate for stirring and decoloring, the pH value is adjusted to be 5-6 by acetic acid, the filtrate is filtered, the pH value is adjusted to 7-8 by alkali (sodium carbonate or sodium bicarbonate), a product is separated out, filtered and dried to obtain 2.06mol of white-like 4, 7-dichloroquinoline, and the yield is 77%.
Example 5
Synthesis of Z5
100ml of toluene, 4.0mol of phosphorus oxychloride and 2.67mol of 4-hydroxy-7-chloroquinoline are added into a reaction vessel and reacted for 5 hours at the temperature of 100 ℃ and 110 ℃, after the reaction is finished, the toluene and the unreacted phosphorus oxychloride are evaporated under reduced pressure, 250ml of water are added, liquid alkali (30% of sodium hydroxide) is used for neutralizing until the pH value is 5-6, EDTA and active carbon are added into a filtered solution after filtration, stirring and decoloring are carried out, the pH value is adjusted to 5-6 by acetic acid, filtration is carried out, the pH value is adjusted to 7-8 by alkali (sodium carbonate or sodium bicarbonate), a product is separated out, filtration and drying are carried out to obtain 2.02mol of white-like 4, 7-dichloroquinoline, and the yield is 75.6%.
The present invention is not limited to the above-described embodiments, and those skilled in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (7)
1. A preparation method of 4, 7-dichloroquinoline is characterized in that 3-chloroaniline and diethyl ethoxy methylene malonate are used as raw materials, and the 4, 7-dichloroquinoline is obtained through the steps of condensation, cyclization and hydrolysis, the step of decarboxylation and the step of chlorination in sequence;
wherein the steps of condensation, cyclization and hydrolysis are as follows: putting 3-chloroaniline, diethyl ethoxymethylene malonate and paraffin oil into a reaction kettle, heating to 230-260 ℃ for reaction, cooling to 90-100 ℃ after the reaction is finished, adding toluene, caustic soda flakes and deionized water, keeping the temperature of 90-100 ℃ for reaction till the reaction is complete, layering, recovering an organic layer, and putting a water layer into the next reaction;
the decarboxylation step is as follows: adding the water layer into an autoclave, performing decarboxylation reaction under the pressure of 6.0-6.5 kg and the temperature of 150-.
2. The process for the preparation of 4, 7-dichloroquinoline according to claim 1, wherein the chlorination step is: adding toluene, phosphorus oxychloride and 4-hydroxy-7-chloroquinoline into a reaction container, reacting at 110 ℃, after the reaction is finished, evaporating the toluene and the unreacted phosphorus oxychloride under reduced pressure, adding water, neutralizing with liquid alkali to a pH value of 5-6, filtering, adding EDTA and activated carbon into the filtrate for decolorization, adjusting the pH value to 5-6 with acetic acid, filtering, adjusting the pH value to 7-8 with alkali, separating out a product, filtering, and drying to obtain the 4, 7-dichloroquinoline.
3. The process for preparing 4, 7-dichloroquinoline according to claim 1, wherein: the molar ratio of the 3-chloroaniline to the diethyl ethoxymethylidene malonate is 1-1.2: 1.
4. The method for preparing 4, 7-dichloroquinoline according to claim 3, wherein: the mol ratio of the diethyl ethoxymethylene malonate to the flaky alkali is 1: 2-5.
5. The process for the preparation of 4, 7-dichloroquinoline according to any one of claims 1 to 4, wherein: in the steps of condensation, cyclization and hydrolysis, the mass concentration of the caustic soda flakes is 10-15%.
6. The method for preparing 4, 7-dichloroquinoline according to claim 5, wherein: the molar ratio of the phosphorus oxychloride to the 4-hydroxy-7-chloroquinoline is 1.2-1.5: 1.
7. The method for preparing 4, 7-dichloroquinoline according to claim 6, wherein: the base used to adjust the pH of the chlorination step is sodium carbonate or sodium bicarbonate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1062905A (en) * | 1991-01-01 | 1992-07-22 | 唐良平 | 4-hydroxyl-7-chloro-quinolinic acid synthetic method |
| CN103626699A (en) * | 2013-12-13 | 2014-03-12 | 武汉武药制药有限公司 | Industrial preparation method of 4,7-dichloroquinoline |
| CN104447534A (en) * | 2014-12-04 | 2015-03-25 | 厦门大学 | 6-[(7-chloroquinoline-4-oxyl) phenolic ether]-2-naphthamide derivative as well as preparation method and application thereof |
-
2020
- 2020-07-03 CN CN202010636897.2A patent/CN111747890A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1062905A (en) * | 1991-01-01 | 1992-07-22 | 唐良平 | 4-hydroxyl-7-chloro-quinolinic acid synthetic method |
| CN103626699A (en) * | 2013-12-13 | 2014-03-12 | 武汉武药制药有限公司 | Industrial preparation method of 4,7-dichloroquinoline |
| CN104447534A (en) * | 2014-12-04 | 2015-03-25 | 厦门大学 | 6-[(7-chloroquinoline-4-oxyl) phenolic ether]-2-naphthamide derivative as well as preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| NITIN G.RATHOD等: "Identification of impurities related to amodiaquine hydrochloride by using some analytical techniuqes", 《WORLD JOURNAL OF PHARMACEUTICAL RESEARCH》 * |
| 曾令国等: "抗疟药中间体4，7-二氯喹啉的工艺研究", 《中南药学》 * |
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