CN114957114A - Synthetic method of 4-bromo-3-chloro-7-methoxyquinoline - Google Patents
Synthetic method of 4-bromo-3-chloro-7-methoxyquinoline Download PDFInfo
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- CN114957114A CN114957114A CN202110215273.8A CN202110215273A CN114957114A CN 114957114 A CN114957114 A CN 114957114A CN 202110215273 A CN202110215273 A CN 202110215273A CN 114957114 A CN114957114 A CN 114957114A
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- methoxyquinoline
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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
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Abstract
The invention discloses a synthesis method of 4-bromo-3-chloro-7-methoxyquinoline, which takes 4-hydroxy-7-methoxyquinoline, N-chlorosuccinimide (NCS), tribromooxyphosphorus as raw materials and obtains a target product, namely 4-bromo-3-chloro-7-methoxyquinoline through two-step reaction. The method has the advantages of environmental friendliness, readily available raw materials, wide sources, low cost, simple method and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of synthesis of drug intermediates, in particular to a synthesis method of 4-bromo-3-chloro-7-methoxyquinoline.
Background
4-bromo-3-chloro-7-methoxyquinoline is an important medical intermediate in medicinal chemistry, wherein 3-position chlorine atoms and 4-position bromine atoms are reaction sites with high activity, 4-position bromine atoms can perform amination, etherification, coupling, aldolization, cyanation and the like with fragments or intermediates, and 3-position chlorine atoms can also perform amination, etherification, coupling, aldolization, cyanation and the like. The 4-bromo-3-chloro-7-methoxyquinoline compound has important effects on research and development of new drugs and application thereof.
Therefore, the synthesis of some specific compounds from 4-bromo-3-chloro-7-methoxyquinoline and the screening of some drug molecules with good activity have attracted attention and become one of the hot spots in the pharmaceutical chemistry field.
4-bromo-3-chloro-7-methoxyquinoline the compound is a novel compound, and the structure and the synthetic method thereof are not reported in documents.
Disclosure of Invention
The invention aims to provide a synthetic method of 4-bromo-3-chloro-7-methoxyquinoline, which is environment-friendly, has easily available raw materials, wide sources, low cost and simple method, and is suitable for industrial production.
The purpose of the invention is realized as follows:
a synthetic method of 4-bromo-3-chloro-7-methoxyquinoline is characterized by comprising the following steps: the method comprises the following steps:
(1) adding 4-hydroxy-7-methoxyquinoline into the first solvent, stirring to dissolve, and adding N-chlorosuccinimide (NCS) into the first solvent, wherein: the mass ratio of the 4-hydroxy-7-methoxyquinoline to the first solvent is 1 (3-10), and the molar ratio of the 4-hydroxy-7-methoxyquinoline to the N-chlorosuccinimide (NCS) is 1: (1-3); reacting for 2-24 hours at 0-110 ℃, and performing suction filtration to obtain a 3-chloro-4-hydroxy-7-methoxyquinoline product;
(2) adding 3-chloro-4-hydroxy-7-methoxyquinoline into a second solvent at room temperature, stirring for dissolving, cooling to-15-10 ℃, and adding tribromooxyphosphorus into the second solvent, wherein: the mass ratio of the 3-chloro-4-hydroxy-7-methoxyquinoline to the second solvent is 1: (3-10), the molar ratio of the 3-chloro-4-hydroxy-7-methoxyquinoline to the tribromooxyphosphorus is 1: (1-5); reacting at-15-100 ℃ for 3-24 hours until brown solid is generated, filtering to obtain solid, pouring the solid into ice water for dissolving, adjusting the pH of the solution to be not less than 7 by using alkali, separating out the solid, filtering, and drying to obtain the finished product of the 4-bromo-3-chloro-7-methoxyquinoline.
Preferably, the first solvent in step (1) is one or two mixed solvents of glacial acetic acid, N-dimethylformamide, dimethyl sulfoxide and acetonitrile; the reaction temperature is 10-70 ℃ and the reaction time is 3-15 hours.
Preferably, the first solvent in step (1) is glacial acetic acid.
Preferably, the second solvent in step (2) is one or two mixed solvents of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloromethane, trichloromethane, carbon tetrachloride and 1, 2-dichloroethane, the reaction temperature is-10-90 ℃ and the reaction time is 5-20 hours.
Preferably, the alkali in the step (2) is one of sodium hydroxide, potassium hydroxide, ammonia water, potassium carbonate and sodium carbonate.
Preferably, the alkali in the step (2) is sodium hydroxide or ammonia water.
The invention takes 4-hydroxy-7-methoxyquinoline, N-chlorosuccinimide (NCS), tribromooxyphosphorus and the like as raw materials, and obtains the target product of 4-bromo-3-chloro-7-methoxyquinoline through two-step reaction.
The molecular structural formula of the 4-bromo-3-chloro-7-methoxyquinoline is as follows:
the method has the advantages of environmental friendliness, readily available raw materials, wide sources, low cost, simple method and suitability for industrial production. The invention has important effect on the research and development of new anti-infection drugs and anti-tumor drugs.
Drawings
FIG. 1 is a hydrogen spectrum of 4-bromo-3-chloro-7-methoxyquinoline.
Detailed Description
The invention is further described with reference to the following examples and with reference to the accompanying drawings.
Unless otherwise specified, various starting materials of the present invention are commercially available or prepared according to conventional methods in the art.
The synthesis line of the 4-bromo-3-chloro-7-methoxyquinoline is as follows:
example 1:
a synthetic method of 4-bromo-3-chloro-7-methoxyquinoline comprises the following steps:
the first step is as follows: synthesis of 3-chloro-4-hydroxy-7-methoxyquinoline
Glacial acetic acid (150g) and 4-hydroxy-7-methoxyquinoline (50.0 g,0.29 mol) are added into a reaction bottle in sequence, stirred and dissolved, then N-chlorosuccinimide (NCS) (38.74 g,0.29 mol) is added, reaction is carried out for 5 hours at 50 ℃, yellow solid is generated, and 39.52g of 3-chloro-4-hydroxy-7-methoxyquinoline product is obtained after suction filtration and drying;
the second step is that: synthesis of 4-bromo-3-chloro-7-methoxyquinoline
Adding N, N-dimethylformamide (150g) and 3-chloro-4-hydroxy-7-methoxyquinoline (50g, 0.24mol) into a reaction bottle at room temperature, stirring for dissolving, cooling to-15 ℃, adding tribromooxyphosphorus (68.81 g,0.24 mol), heating after adding, reacting at 0 ℃ for 30 minutes, reacting at 20 ℃ for 10 hours, generating brown solid, performing suction filtration to obtain solid, pouring the solid into ice water for dissolving, adjusting the pH value of the solution to be not less than 7 by using sodium hydroxide, separating out the solid, performing suction filtration, washing with water, and drying to obtain 38.48g of a finished product of the 4-bromo-3-chloro-7-methoxyquinoline.
Example 2:
a method for synthesizing 4-bromo-3-chloro-7-methoxyquinoline comprises the following steps:
the first step is as follows: synthesis of 3-chloro-4-hydroxy-7-methoxyquinoline
Adding glacial acetic acid (250g) and 4-hydroxy-7-methoxyquinoline (50g, 0.29 mol) into a reaction bottle in sequence, stirring for dissolving, adding N-chlorosuccinimide (NCS) (77.45 g,0.44 mol), stirring for dissolving, reacting at 110 ℃ for 24 hours to generate yellow solid, performing suction filtration, and drying to obtain 49.85g of 3-chloro-4-hydroxy-7-methoxyquinoline;
the second step: synthesis of 4-bromo-3-chloro-7-methoxyquinoline
At room temperature, adding chloroform (200g), N, N-dimethylformamide (5g) and 3-chloro-4-hydroxy-7-methoxyquinoline (50g, 0.24mol) into a reaction bottle in sequence, stirring for dissolving, cooling to 0 ℃, adding tribromooxyphosphorus (137.61 g,0.48 mol), heating after adding, reacting at 10 ℃ for 30 minutes, reacting at 100 ℃ for 8 hours, generating brown solid, performing suction filtration to obtain solid, pouring the solid into ice water for dissolving, adjusting the pH of the solution to be not less than 7 by using ammonia water, separating out the solid, performing suction filtration, washing with water, and drying to obtain 55.60g of a finished product of 4-bromo-3-chloro-7-methoxyquinoline.
Example 3:
a method for synthesizing 4-bromo-3-chloro-7-methoxyquinoline comprises the following steps:
the first step is as follows: synthesis of 3-chloro-4-hydroxy-7-methoxyquinoline
Glacial acetic acid (350 g), N, N-dimethylformamide (10g) and 4-hydroxy-7-methoxyquinoline (50g, 0.29 mol) are sequentially added into a reaction bottle and stirred to be dissolved, then N-chlorosuccinimide (NCS) (50.7 g,0.58 mol) is added and stirred to be dissolved, reaction is carried out for 20 hours at the temperature of 0 ℃, yellow solid is generated, and the mixture is filtered, filtered and dried to obtain 55.93g of 3-chloro-4-hydroxy-7-methoxyquinoline product;
the second step is that: synthesis of 4-bromo-3-chloro-7-methoxyquinoline
Dichloromethane (400 g), N, N-dimethylformamide (5g) and 3-chloro-4-hydroxy-7-methoxyquinoline (50g, 0.24mol) are sequentially added into a reaction bottle at room temperature, stirred and dissolved, cooled to 2 ℃, tribromooxyphosphorus oxide (172.01 g,0.6 mol) is added, after the addition, the temperature is raised again, the mixture reacts at 5 ℃ for 30 minutes, the reaction lasts for 3 hours at 70 ℃, brown solid is generated, the solid is obtained by suction filtration, then poured into ice water to be dissolved, the solution is adjusted to pH not less than 7 by sodium carbonate, the solid is separated out, the suction filtration, the water washing and the drying are carried out, and 58.86g of a finished product of the 4-bromo-3-chloro-7-methoxyquinoline is obtained.
Example 4:
a method for synthesizing 4-bromo-3-chloro-7-methoxyquinoline comprises the following steps:
the first step is as follows: synthesis of 3-chloro-4-hydroxy-7-methoxyquinoline
Adding acetonitrile (250g) and 4-hydroxy-7-methoxyquinoline (50.0 g,0.29 mol) into a reaction bottle in sequence, stirring for dissolving, adding N-chlorosuccinimide (NCS) (38.74 g,0.29 mol), stirring for dissolving, reacting at 70 ℃ for 7 hours to generate yellow solid, performing suction filtration, and drying to obtain 46.78g of 3-chloro-4-hydroxy-7-methoxyquinoline;
the second step is that: synthesis of 4-bromo-3-chloro-7-methoxyquinoline
Adding carbon tetrachloride (250g) and 3-chloro-4-hydroxy-7-methoxyquinoline (50g, 0.24mol) into a reaction bottle at room temperature in sequence, stirring for dissolving, cooling to-10 ℃, adding tribromooxyphosphorus (172.01 g,0.6 mol), heating after adding, reacting at 3 ℃ for 30 minutes, reacting at 30 ℃ for 12 hours, generating brown solid, performing suction filtration to obtain solid, pouring the solid into ice water for dissolving, adjusting the pH of the solution to be not less than 7 by using potassium hydroxide, separating out the solid, performing suction filtration, washing with water, and drying to obtain 58.86g of a finished product of the 4-bromo-3-chloro-7-methoxyquinoline.
Example 5:
a method for synthesizing 4-bromo-3-chloro-7-methoxyquinoline comprises the following steps:
the first step is as follows: synthesis of 3-chloro-4-hydroxy-7-methoxyquinoline
Adding tetrahydrofuran (300 g), N, N-dimethylformamide (5g) and 4-hydroxy-7-methoxyquinoline (50.0 g and 0.29 mol) into a reaction bottle in sequence, stirring and dissolving, adding N-chlorosuccinimide (NCS) (38.74 g and 0.68 mol), stirring and dissolving, reacting for 2 hours at 33 ℃ until yellow solid is generated, filtering, and drying to obtain 50.43g of a 3-chloro-4-hydroxy-7-methoxyquinoline product;
the second step is that: synthesis of 4-bromo-3-chloro-7-methoxyquinoline
Acetonitrile (500g) and 3-chloro-4-hydroxy-7-methoxyquinoline (50g, 0.24mol) are sequentially added into a reaction bottle at room temperature, stirred and dissolved, the temperature is reduced to-2 ℃, tribromooxyphosphorus (172.01 g,0.6 mol) is added, the temperature is raised after the addition, the reaction is carried out for 30 minutes at 5 ℃, the reaction is carried out for 15 hours at 55 ℃, brown solid is generated, suction filtration is carried out to obtain solid, the solid is poured into ice water for dissolution, the solution is adjusted to the PH value being not less than 7 by using potassium carbonate, the solid is separated out, suction filtration, water washing and drying are carried out to obtain 58.86g of a finished product of the 4-bromo-3-chloro-7-methoxyquinoline.
Example 6:
a method for synthesizing 4-bromo-3-chloro-7-methoxyquinoline comprises the following steps:
the first step is as follows: synthesis of 3-chloro-4-hydroxy-7-methoxyquinoline
Adding dimethyl sulfoxide (500g) and 4-hydroxy-7-methoxyquinoline (50.0 g,0.29 mol) into a reaction bottle in sequence, stirring for dissolving, adding N-chlorosuccinimide (NCS) (38.74 g,0.87 mol), stirring for dissolving, reacting at 90 ℃ for 12 hours to generate yellow solid, performing suction filtration, and drying to obtain 58.56g of 3-chloro-4-hydroxy-7-methoxyquinoline product;
the second step is that: synthesis of 4-bromo-3-chloro-7-methoxyquinoline
Adding 1, 2-dichloroethane (250g), N, N-dimethylformamide (5g) and 3-chloro-4-hydroxy-7-methoxyquinoline (50g, 0.24mol) into a reaction bottle at room temperature in sequence, stirring for dissolving, cooling to-7 ℃, adding tribromooxyphosphorus (172.01 g,0.48 mol), heating after adding, reacting at 9 ℃ for 30 minutes, reacting at 70 ℃ for 24 hours, generating brown solid, performing suction filtration to obtain solid, pouring the solid into ice water for dissolving, adjusting the pH of the solution to be not less than 7 by using ammonia water, separating out the solid, performing suction filtration, washing with water, and drying to obtain 64.21g of a finished product of 4-bromo-3-chloro-7-methoxyquinoline.
The above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the concept and the protection scope of the present invention, and a person skilled in the art of the present invention may modify or equivalently replace the technical solutions of the present invention, add the auxiliary components, select the specific modes, etc. without departing from the spirit and scope of the technical solutions, and all of them should be covered in the claims of the present invention.
Claims (7)
1. A method for synthesizing 4-bromo-3-chloro-7-methoxyquinoline is characterized by comprising the following steps: the method comprises the following steps:
(1) adding 4-hydroxy-7-methoxyquinoline into a first solvent, stirring for dissolving, and adding N-chlorosuccinimide into the first solvent, wherein: the mass ratio of the 4-hydroxy-7-methoxyquinoline to the first solvent is 1 (3-10), and the molar ratio of the 4-hydroxy-7-methoxyquinoline to the N-chlorosuccinimide is 1: (1-3); reacting for 2-24 hours at 0-110 ℃, and performing suction filtration to obtain a 3-chloro-4-hydroxy-7-methoxyquinoline product;
(2) adding 3-chloro-4-hydroxy-7-methoxyquinoline into a second solvent at room temperature, stirring for dissolving, cooling to-15-10 ℃, and adding tribromooxyphosphorus into the second solvent, wherein: the mass ratio of the 3-chloro-4-hydroxy-7-methoxyquinoline to the second solvent is 1: (3-10), the molar ratio of the 3-chloro-4-hydroxy-7-methoxyquinoline to the tribromooxyphosphorus is 1: (1-5); reacting at-15-100 ℃ for 3-24 hours until brown solid is generated, filtering to obtain solid, pouring the solid into ice water for dissolving, adjusting the pH of the solution to be not less than 7 by using alkali, separating out the solid, filtering, and drying to obtain the finished product of the 4-bromo-3-chloro-7-methoxyquinoline.
2. The method of synthesizing 4-bromo-3-chloro-7-methoxyquinoline according to claim 1, wherein: in the step (1), the first solvent is one or two of glacial acetic acid, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, the reaction temperature is 10-70 ℃, and the reaction time is 3-15 hours.
3. The method for synthesizing 4-bromo-3-chloro-7-methoxyquinoline according to claim 1, wherein the method comprises the following steps: in the step (1), the first solvent is glacial acetic acid.
4. The method of synthesizing 4-bromo-3-chloro-7-methoxyquinoline according to claim 1, wherein: in the step (2), the second solvent is one or two mixed solvents of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloromethane, trichloromethane, carbon tetrachloride and 1, 2-dichloroethane.
5. The method of synthesizing 4-bromo-3-chloro-7-methoxyquinoline according to claim 4, wherein: in the step (2), the second solvent is one or two mixed solvents of N, N-dimethylformamide, dichloromethane, trichloromethane, carbon tetrachloride or 1, 2-dichloroethane, the reaction temperature is-10-90 ℃, and the reaction time is 5-20 hours.
6. The method of synthesizing 4-bromo-3-chloro-7-methoxyquinoline according to claim 1, wherein: in the step (2), the alkali is one of sodium hydroxide, potassium hydroxide, ammonia water, potassium carbonate and sodium carbonate.
7. The method of synthesizing 4-bromo-3-chloro-7-methoxyquinoline according to claim 6, wherein: and (3) in the step (2), the alkali is sodium hydroxide or ammonia water.
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| US20050159411A1 (en) * | 2002-01-29 | 2005-07-21 | Daines Robert A. | Aminopiperidine derivatives |
| US20060041123A1 (en) * | 2002-12-18 | 2006-02-23 | Axten Jeffrey M | Antibacterial agents |
| US20120142727A1 (en) * | 2009-08-06 | 2012-06-07 | Isao Kinoyama | Nitrogenous-ring acylguanidine derivative |
| CN106632093A (en) * | 2016-11-23 | 2017-05-10 | 山东友帮生化科技有限公司 | Preparation method of 2-bromine-5,6-diphenyl pyrazine |
| US20200017516A1 (en) * | 2018-07-12 | 2020-01-16 | Eli Lilly And Company | Selective estrogen receptor degraders |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050159411A1 (en) * | 2002-01-29 | 2005-07-21 | Daines Robert A. | Aminopiperidine derivatives |
| US20060041123A1 (en) * | 2002-12-18 | 2006-02-23 | Axten Jeffrey M | Antibacterial agents |
| US20120142727A1 (en) * | 2009-08-06 | 2012-06-07 | Isao Kinoyama | Nitrogenous-ring acylguanidine derivative |
| CN106632093A (en) * | 2016-11-23 | 2017-05-10 | 山东友帮生化科技有限公司 | Preparation method of 2-bromine-5,6-diphenyl pyrazine |
| US20200017516A1 (en) * | 2018-07-12 | 2020-01-16 | Eli Lilly And Company | Selective estrogen receptor degraders |
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