CN111662229B - Preparation process of chloroquine phosphate - Google Patents
Preparation process of chloroquine phosphate Download PDFInfo
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- CN111662229B CN111662229B CN202010652629.XA CN202010652629A CN111662229B CN 111662229 B CN111662229 B CN 111662229B CN 202010652629 A CN202010652629 A CN 202010652629A CN 111662229 B CN111662229 B CN 111662229B
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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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a preparation process of chloroquine phosphate. The preparation process of chloroquine phosphate comprises the following steps: (1) Using 4,7-quinclorac as initial raw material, carrying out condensation reaction with 2-amino-5-diethylamino pentane, and carrying out alkalization extraction to obtain chloroquine; (2) Salifying the chloroquine obtained in the step (1) and phosphoric acid to prepare chloroquine phosphate. The preparation process of chloroquine phosphate provided by the invention avoids the use of organic solvents such as benzene and other catalysts such as phenol in the preparation process, introduces the step of condensation crystallization and impurity removal, ensures that the product has high purity, has single impurity less than 0.1 percent, accords with the green chemical requirement and pharmacopoeia standard, is simple and convenient to operate, simplifies the working procedures, improves the production efficiency, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation process of chloroquine phosphate.
Background
Chloroquine Phosphate (Chloroquine Phosphate), chemical name N ', N' -diethyl-N4- (7-chloro-4-quinolyl) -1,4-pentanediamine diphosphate, is used for treating malaria such as Chloroquine-sensitive falciparum malaria and vivax malaria. Can also be used for treating extraintestinal amebiasis, and also has antirheumatic effect. According to research, the medicine can effectively inhibit the infection of the novel coronavirus 2019-nCoV at a cellular level.
In the previously disclosed preparation method of chloroquine phosphate, the raw materials used are 4,7-quinclorac solution, an equivalent amount of solvent and catalyst phenol, 2-amino-5-diethylaminopentane. The specific technological process includes the first eliminating benzene from 4,7-quinclorac solution at normal pressure, the subsequent decompression steaming to 120-125 deg.c, cooling to below 100 deg.c, adding phenol and reaction at 115-120 for 1 hr. Slowly adding the 2-amino-5-diethylamino pentane (the internal temperature is below 130), and after the addition is finished, heating to 135-138 ℃ for reaction for 12 hours. After the reaction is finished, cooling to 80 ℃, adding alkali liquor for alkalization, stirring uniformly, extracting with toluene, separating toluene, and extracting the water layer with toluene for 3-4 times. The toluene solutions were combined, washed with water to a pH of about =9, toluene was recovered at normal pressure, and 136 ℃/160mm fractions were collected by distillation under reduced pressure.
The process is relatively laggard, phenol is used as a solvent and a catalyst, the phenol pollution is relatively large, and the waste water which is changed into sodium phenolate after the post-treatment is one of the waste water which is relatively large in pollution and difficult to treat in industrial waste water and is one of the waste water which is mainly controlled by the state. Phenol is toxic and highly corrosive, is solid at normal temperature, can be produced and used only by being heated into liquid, is complex to operate and difficult to recover, and increases the difficulty of aftertreatment.
4,7-quinclorac benzene solution is used as raw material, and the distillation process operation of benzene also exists, so that the benzene has very high carcinogenicity and toxicity and is easy to obtain leukemia. Even if human body protection is used and the requirement for ventilation system is high, the benzene concentration in the factory cannot exceed 1ppm and the time cannot exceed 8 hours in the United states in 1987. Meanwhile, the problem of detecting the benzene residue in the finished product is also considered, and the problems of high process energy consumption, complex operation, low production efficiency, no friendliness to human bodies and environment and the like exist.
Disclosure of Invention
The invention mainly aims to provide a preparation process of chloroquine phosphate, which overcomes the defects in the prior art.
In order to achieve the above object, the embodiment of the present invention adopts a technical solution comprising:
the embodiment of the invention provides a preparation process of chloroquine phosphate, which comprises the following steps:
(1) 4,7-dichloroquinoline as initial material is condensated with 2-amino-5-diethylamino pentane and alkalized and extracted
(2) Salifying the chloroquine obtained in the step (1) and phosphoric acid to prepare chloroquine phosphate, wherein the chemical reaction formula is as follows:
further, the step (1) includes: mixing 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane, stirring, heating for condensation, alkalifying for extraction, washing with water, concentrating under reduced pressure, and crystallizing to obtain chloroquine.
Furthermore, the molar ratio of 4,7-dichloroquinoline to 2-amino-5-diethylaminopentane is 1:1-1.5.
Further, the extraction solvent for the extraction is dichloromethane.
Further, the step (2) includes: salifying the chloroquine obtained in the step (1) and phosphoric acid in an ethanol solvent, and then refining the chloroquine phosphate by purified water and ethanol.
Compared with the prior art, the invention has the following beneficial effects:
the preparation process of chloroquine phosphate avoids the use of organic solvents such as benzene and other catalysts such as phenol in the preparation process, introduces the step of condensation crystallization and impurity removal, ensures that the product has high purity, has single impurity less than 0.1 percent, accords with the green chemical requirement and pharmacopoeia standard, has simple and convenient operation, simplifies the working procedures, improves the production efficiency, and is suitable for industrial production.
Detailed Description
The invention will be more fully understood by the following detailed description, which should be read in conjunction with the accompanying chemical reaction formulae. Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed embodiment.
In view of the defects of the prior art, the inventor of the present invention has made long-term research and great practice to provide the technical scheme of the present invention, which mainly aims at overcoming the defects of the existing chloroquine phosphate preparation method, avoiding the use of organic solvents such as benzene and other catalysts such as phenol, and selecting appropriate raw materials, and meeting the requirements of green chemistry. The technical solution, its implementation and principles will be further explained as follows.
One aspect of the embodiments of the present invention provides a preparation process of chloroquine phosphate, which includes the following steps:
(1) 4,7-dichloroquinoline as initial material is condensated with 2-amino-5-diethylamino pentane and alkalized and extracted
(2) Salifying the chloroquine obtained in the step (1) and phosphoric acid to prepare chloroquine phosphate, wherein the chemical reaction formula is as follows:
in some preferred versions of the embodiments of the present invention, the step (1) includes: mixing 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane, stirring, heating for condensation, alkalifying for extraction, washing with water, concentrating under reduced pressure, and crystallizing to obtain chloroquine.
In some preferred embodiments, the mole ratio of 4,7-dichloroquinoline to 2-amino-5-diethylaminopentane is 1:1 to 1.5.
In some preferred embodiments, the extraction solvent for the extraction is dichloromethane.
In some preferred embodiments, the reaction temperature of the stirring temperature-rising condensation is 135-140 ℃, and the reaction time is based on the central control detection endpoint.
In some preferred embodiments, the crystallization solvent for reduced pressure concentration is isopropyl ether, and the crystallization temperature is-5 ℃ to 0 ℃.
In some preferable aspects of the embodiments of the present invention, the step (2) includes: salifying the chloroquine obtained in the step (1) and phosphoric acid in an ethanol solvent, and then refining the chloroquine phosphate by purified water and ethanol.
In some preferred embodiments, the step (2) comprises: and (2) adding the chloroquine obtained in the step (1) and phosphoric acid into an ethanol solvent, stirring and heating, cooling, carrying out suction filtration, and washing to obtain a chloroquine phosphate crude product.
In some preferred embodiments, the step (2) further comprises: and adding the chloroquine phosphate crude product into purified water, stirring, heating, filtering, adding ethanol, refluxing, heating, cooling, performing suction filtration, and washing to obtain the chloroquine phosphate.
In some more specific preferred embodiments of the present invention, a process for preparing chloroquine phosphate comprises the following steps:
(1) 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane are directly mixed and reacted under the conditions of no solvent and no catalyst.
(2) And (3) judging the reaction end point by adopting an HPLC (high performance liquid chromatography) central control technology, namely sampling and detecting by HPLC after the reaction time is 24 hours after the heat preservation reaction, stopping the heat preservation reaction and carrying out the next operation, wherein the raw material is less than or equal to 1.0 percent.
(3) After the condensation alkalization is finished, the used extraction solvent is dichloromethane; the extracted dichloromethane is at the lower layer, which is convenient for operation and improves the process efficiency.
(4) After the dichloromethane solution is decompressed and concentrated to be dry, isopropyl ether solution is added for crystallization, namely, the crystallization solvent of the chloroquine crude product is isopropyl ether, and the crystallization temperature is-5 ℃ to 0 ℃.
According to the preparation process of chloroquine phosphate provided by the embodiment of the invention, the use of organic solvents such as benzene and other catalysts such as phenol is avoided in the preparation process, and the condensation crystallization impurity removal step is introduced, so that the product purity is high, the single impurity is less than 0.1%, the product meets the green chemical requirements and pharmacopoeia standards, the operation is simple and convenient, the working procedures are simplified, the production efficiency is improved, and the preparation process is suitable for industrial production.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further explained with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention, and that experimental conditions and set parameters therein are not to be considered as limitations of the basic embodiments of the invention. And the scope of the present invention is not limited to the following examples. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
4,7-dichloroquinoline 30g and 24g 2-amino-5-diethylamino pentane are added into a three-mouth round-bottom flask, stirred and heated, and then the mixture is kept at 135-140 ℃ for reaction for more than 24 hours, and the HPLC detection judges the reaction end point. Cooling to about 100 deg.C, adding 75g of 6-percent NaOH solution, measuring pH value to about 11-12, further cooling to about 40 deg.C, adding 90g of dichloromethane, stirring, standing for layering, collecting organic layer, extracting water layer with 54g of dichloromethane for 2 times, mixing organic layers, and washing with 120g of water for 3 times. And evaporating the organic layer to dryness in a water bath at 65 ℃ under reduced pressure, adding 200g of isopropyl ether, stirring and crystallizing for 3 hours at-5-0 ℃, and performing suction filtration to obtain a yellowish-brown solid with the wet weight of 43.5g. Blowing and drying at 50 ℃ to obtain 35.0g of dry product with the yield of 72.34%.
Salifying: adding 35.0g of chloroquine crude product into 105g of 80% ethanol, stirring and heating to 60 ℃, dropwise adding 25.0g of phosphoric acid, keeping the temperature at 60-65 ℃ for 2-3 h after dropwise adding is finished, separating out yellowish solid, cooling to 25-30 ℃, carrying out suction filtration, washing with a proper amount of 95% ethanol to obtain white-like solid, wherein the wet weight is 108g.
Refining: adding 108g of chloroquine phosphate crude product into 162g of water, stirring, heating to about 80 ℃ for complete dissolution, adding 3.0g of needle carbon, preserving heat at 80-85 ℃ for 1h, filtering, evaporating filtrate in 70 ℃ water bath under reduced pressure to remove 120g of water, adding 162g of 95% ethanol, refluxing and preserving heat for 2h to separate out a white solid, cooling to 25-30 ℃, carrying out suction filtration, and washing with a proper amount of 95% ethanol to obtain the white solid, wherein the wet weight is 54g. Drying at 80 deg.C to constant weight to obtain dry product 48.9g. The yield is 62.6 percent, the purity is 99.67 percent, the maximum single impurity content is 0.16 percent (the standard is less than or equal to 0.5 percent), and the melting point is 196-198 ℃.
Example 2
Condensation: 4,7-dichloroquinoline 50g and 2-amino-5-diethylamino pentane 50g are added into a three-mouth round-bottom flask, stirred and heated, and then the mixture is kept at the temperature of 135-140 ℃ for reaction for more than 24 hours, and the HPLC detection judges the reaction end point. Cooling to about 100 deg.C, adding 125g of 6% NaOH solution, measuring pH to about 11-12, further cooling to about 40 deg.C, adding 150g of dichloromethane, stirring, standing for layering, collecting organic layer, extracting water layer with 90g of dichloromethane for 2 times, mixing organic layers, and washing with 200g of water for 3 times. And evaporating the organic layer to dryness in a 65 ℃ water bath under reduced pressure, adding 200g of isopropyl ether, stirring and crystallizing for 3 hours at the temperature of 0-5 ℃, and performing suction filtration to obtain 73g of a solid yellowish brown in wet weight. Blowing and drying at 50 ℃ to obtain 58.5g of a dry product with the yield of 72.44 percent.
Salifying: adding 58.5g of chloroquine crude product into 175g of 80% ethanol, stirring and heating to 60 ℃, dropwise adding 41.5g of phosphoric acid, keeping the temperature at 60-65 ℃ for 2-3 h after dropwise adding is finished, separating out yellowish solid, cooling to 25-30 ℃, carrying out suction filtration, washing with a proper amount of 95% ethanol to obtain white-like solid, wherein the wet weight is 180g.
Refining: adding 180g of chloroquine phosphate crude product into 270g of water, stirring, heating to about 80 ℃ for complete dissolution, adding 5g of needle carbon, preserving heat at 80-85 ℃ for 1h, filtering, evaporating filtrate in 70 ℃ water bath under reduced pressure to remove 195g of water, adding 270g of 95% ethanol, refluxing and preserving heat for 2h to separate out white solid, cooling to 25-30 ℃, carrying out suction filtration, washing with a proper amount of 95% ethanol to obtain the white solid, wherein the wet weight is 90g. Drying at 80 deg.C to constant weight to obtain dry product 81.5g. The yield is 62.58 percent, the purity is 99.58 percent, the maximum single impurity content is 0.20 percent (the standard is less than or equal to 0.5 percent), and the melting point is 197 to 198.5 ℃.
Example 3
Condensation: 4,7-dichloroquinoline 50g and 2-amino-5-diethylamino pentane 60g are added into a three-mouth round-bottom flask, stirred and heated, and then the mixture is kept at the temperature of 135-140 ℃ for reaction for more than 24 hours, and the HPLC detection judges the reaction end point. Cooling to about 100 deg.C, adding 125g of 6% NaOH solution, measuring pH to about 11-12, cooling to about 40 deg.C, adding 150g of dichloromethane, stirring, standing for layering, collecting organic layer, extracting water layer with 90g of dichloromethane for 2 times, mixing organic layers, and washing with 200g of water for 3 times. And evaporating the organic layer to dryness in a water bath at 65 ℃ under reduced pressure, adding 200g of isopropyl ether, stirring and crystallizing for 3 hours at-5-0 ℃, and performing suction filtration to obtain 80g of a yellowish solid with wet weight. Blowing and drying at 50 ℃ to obtain 64.5g of dry product with the yield of 79.88%.
Salifying: adding 64.5g of chloroquine crude product into 175g of 80% ethanol, stirring and heating to 60 ℃, dropwise adding 45.5g of phosphoric acid, keeping the temperature at 60-65 ℃ for 2-3 h after dropwise adding is finished, separating out yellowish solid, cooling to 25-30 ℃, carrying out suction filtration, washing with a proper amount of 95% ethanol to obtain white-like solid, wherein the wet weight is 195g.
Refining: adding 195g of chloroquine phosphate crude product into 290g of water, stirring, heating to about 80 ℃ for complete dissolution, adding 5g of needle carbon, preserving heat at 80-85 ℃ for 1h, filtering, evaporating filtrate in 70 ℃ water bath under reduced pressure to remove 215g of water, adding 290g of 95% ethanol, refluxing and preserving heat for 2h to separate out white solid, cooling to 25-30 ℃, carrying out suction filtration, washing with a proper amount of 95% ethanol to obtain the white solid, wherein the wet weight is 98g. Drying at 80 ℃ to constant weight to obtain 85g of dry product. The yield is 65.26%, the purity is 99.67%, the maximum single impurity is 0.17% (standard is less than or equal to 0.5%), and the melting point is 196-198 ℃.
Comparative example 1
Condensation: 4,7-dichloroquinoline 60g and 2-amino-5-diethylamino pentane 43.5g are added into a three-mouth round-bottom flask, stirred and heated, and then the mixture is kept at the temperature of 135-140 ℃ for reaction for more than 32 hours, and the HPLC detection judges the reaction end point. Cooling to about 100 deg.C, adding 125g of 6% NaOH solution, measuring pH to about 11-12, cooling to about 40 deg.C, adding 150g of dichloromethane, stirring, standing for layering, collecting organic layer, extracting water layer with 90g of dichloromethane for 2 times, mixing organic layers, and washing with 200g of water for 3 times. And evaporating the organic layer to dryness in a water bath at 65 ℃ under reduced pressure, adding 200g of isopropyl ether, stirring and crystallizing for 3 hours at-5-0 ℃, and performing suction filtration to obtain a yellowish-brown solid with the wet weight of 75g. Blowing and drying at 50 ℃ to obtain 59.5g of a dry product with the yield of 73.68 percent.
Salifying: adding 59.5g of chloroquine crude product into 178.5g of 80 percent ethanol, stirring and heating to 60 ℃, dropwise adding 42g of phosphoric acid, keeping the temperature at 60-65 ℃ for 2-3 h after the dropwise adding is finished, separating out yellowish solid, cooling to 25-30 ℃, performing suction filtration, washing with a proper amount of 95 percent ethanol to obtain a white-like solid with the wet weight of 182g.
Refining: adding 182g of chloroquine phosphate crude product into 273g of water, stirring, heating to about 80 ℃ for complete dissolution, adding 5g of needle carbon, preserving heat at 80-85 ℃ for 1h, filtering, evaporating filtrate in 70 ℃ water bath under reduced pressure to remove 200g of water, adding 273g of 95% ethanol, refluxing and preserving heat for 2h to separate out white solid, cooling to 25-30 ℃, carrying out suction filtration, washing with a proper amount of 95% ethanol to obtain the white solid, wherein the wet weight is 88.5g. Drying at 80 deg.C to constant weight to obtain dry product 72.5g. The yield is 55.67%, the purity is 99.32%, the maximum single impurity is 0.43% (standard is less than or equal to 0.5%), and the melting point is 196.5-197.5 ℃.
Comparative example 2
Condensation: 4,7-dichloroquinoline 50g and 2-amino-5-diethylaminopentane 64g are added into a three-neck round-bottom flask, stirred, heated, kept at 135-140 ℃ for reaction for more than 24 hours, and subjected to HPLC detection to judge the reaction end point. Cooling to about 100 deg.C, adding 125g of 6% NaOH solution, measuring pH to about 11-12, further cooling to about 40 deg.C, adding 150g of dichloromethane, stirring, standing for layering, collecting organic layer, extracting water layer with 90g of dichloromethane for 2 times, mixing organic layers, and washing with 200g of water for 3 times. And evaporating the organic layer to dryness in a water bath at 65 ℃ under reduced pressure, adding 200g of isopropyl ether, stirring and crystallizing for 3 hours at-5-0 ℃, and performing suction filtration to obtain 83g of a solid yellowish brown wet weight. Blowing and drying at 50 ℃ to obtain 65.3g of a dry product with the yield of 80.87 percent.
Salifying: adding 65.3g of chloroquine crude product into 196g of 80% ethanol, stirring and heating to 60 ℃, dropwise adding 46g of phosphoric acid, keeping the temperature at 60-65 ℃ for 2-3 h after the dropwise adding is finished, separating out yellowish solid, cooling to 25-30 ℃, performing suction filtration, washing with a proper amount of 95% ethanol to obtain a white-like solid, wherein the wet weight of the white-like solid is 208g.
Refining: adding 208g of chloroquine phosphate crude product into 312g of water, stirring, heating to about 80 ℃ for complete dissolution, adding 5g of needle carbon, preserving heat at 80-85 ℃ for 1h, filtering, evaporating filtrate in 70 ℃ water bath under reduced pressure to remove 232g of water, adding 312g of 95% ethanol, refluxing and preserving heat for 2h to separate out white solid, cooling to 25-30 ℃, carrying out suction filtration, washing with a proper amount of 95% ethanol to obtain the white solid, wherein the wet weight is 106g. Drying at 80 deg.C to constant weight to obtain 86.1g dry product. The yield is 66.11 percent, the purity is 99.41 percent, the maximum single impurity content is 0.39 percent (the standard is less than or equal to 0.5 percent), and the melting point is 195.5 to 197 ℃.
By comparing comparative examples 1-2 with examples 1-3, it can be seen that when the molar ratio of 4,7-dichloroquinoline to 2-amino-5-diethylaminopentane is less than 1:1, both the yield and purity are lower than 4,7-dichloroquinoline to 2-amino-5-diethylaminopentane at a molar ratio of 1:1 to 1.5; when the molar ratio of 4,7-dichloroquinoline to 2-amino-5-diethylaminopentane is greater than 1.5, the yield is higher than that of 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane and is 1:1-1.5, but the purity is lower than that of 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane and is 1:1-1.5, so that the yield and purity are optimal when the molar ratio of 4,7-dichloroquinoline to 2-amino-5-diethylaminopentane is 1:1-1.5.
The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.
The use of headings and chapters in this disclosure is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.
Throughout this specification, where a composition is described as having, containing, or comprising specific components or where a process is described as having, containing, or comprising specific process steps, it is contemplated that the composition of the present teachings also consist essentially of, or consist of, the recited components, and the process of the present teachings also consist essentially of, or consist of, the recited process steps.
Unless specifically stated otherwise, use of the terms "comprising", "including", "having" or "having" is generally to be understood as open-ended and not limiting.
It should be understood that the order of steps or the order in which particular actions are performed is not critical, so long as the teachings of the invention remain operable. Further, two or more steps or actions may be performed simultaneously.
In addition, the inventors of the present invention have also made experiments with other materials, process operations, and process conditions described in the present specification with reference to the above examples, and have obtained preferable results.
While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.
Claims (4)
1. The preparation process of chloroquine phosphate is characterized by comprising the following steps of:
(1) 4,7-dichloroJava is used as a starting material, and is subjected to condensation reaction with 2-amino-5-diethylaminopentane, and alkalization extraction to prepare the chloroJava, wherein the chemical reaction formula is as follows:
the method specifically comprises the following steps: mixing 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane, heating and condensing under stirring, adding 6 percent NaOH solution at about 100 ℃, measuring the pH value to 11-12, cooling to about 40 ℃, adding dichloromethane, stirring, standing, layering, collecting an organic layer, extracting a water layer with dichloromethane, combining the organic layers, washing with water, evaporating the organic layer to dryness, adding isopropyl ether, stirring at-5-0 ℃ for crystallization, and performing suction filtration and drying to obtain chloroquine;
the reaction temperature of the stirring, heating and condensation is 135-140 ℃, and the reaction time is based on the central control detection end point;
the solvent used for crystallization is isopropyl ether, and the crystallization temperature is-5 ℃ to 0 ℃;
(2) Salifying the chloroquine obtained in the step (1) and phosphoric acid to prepare chloroquine phosphate, wherein the chemical reaction formula is as follows:
the molar ratio of 4,7-dichloroquinoline to 2-amino-5-diethylaminopentane is 1:1-1.5.
2. The process for preparing chloroquine phosphate according to claim 1, wherein said step (2) comprises: salifying the chloroquine obtained in the step (1) and phosphoric acid in an ethanol solvent, and then refining the chloroquine phosphate by purified water and ethanol.
3. The process for preparing chloroquine phosphate according to claim 2, wherein said step (2) comprises: and (2) adding the chloroquine obtained in the step (1) and phosphoric acid into an ethanol solvent, stirring and heating, cooling, carrying out suction filtration, and washing to obtain a chloroquine phosphate crude product.
4. The process for preparing chloroquine phosphate according to claim 2, wherein said step (2) further comprises: and adding the chloroquine phosphate crude product into purified water, stirring and heating, filtering, adding ethanol, refluxing and heating, cooling, performing suction filtration, and washing to obtain the chloroquine phosphate.
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| WO2017079260A1 (en) * | 2015-11-02 | 2017-05-11 | University Of Rochester | Phosphonate-chloroquine conjugates and methods using same |
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| CN110283121A (en) * | 2019-08-06 | 2019-09-27 | 华东理工大学 | The synthetic method of hydroxychloroquine |
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