CN110172038B - Process for preparing analgin magnesium by one-pot method - Google Patents
Process for preparing analgin magnesium by one-pot method Download PDFInfo
- Publication number
- CN110172038B CN110172038B CN201810600186.2A CN201810600186A CN110172038B CN 110172038 B CN110172038 B CN 110172038B CN 201810600186 A CN201810600186 A CN 201810600186A CN 110172038 B CN110172038 B CN 110172038B
- Authority
- CN
- China
- Prior art keywords
- magnesium
- reaction
- analgin
- reaction medium
- methylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
- C07D231/48—Oxygen atom in position 3 or 5 and nitrogen atom in position 4 with hydrocarbon radicals attached to said nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a process for preparing analgin magnesium by a one-pot method, which comprises the steps of preparing 4-methylamino antipyrine, formaldehyde and magnesium saltOr oxides thereof, with SO 2 Gas reaction is carried out to obtain a 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-methyl magnesium sulfonate crude product, and the crude product is further refined through recrystallization to obtain 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-methyl magnesium sulfonate hexahydrate. The method has the advantages of simple process steps, cheap and easily-obtained raw materials, high yield of the synthesized analgin magnesium finished product, good quality and stable process, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and a refining method of 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-methyl magnesium sulfonate hexahydrate.
Background
Analgin magnesium (1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-one-N-methyl magnesium sulfonate hexahydrate) can be used for emergency fever abatement in acute hyperpyrexia, and can also be used for treating headache, migraine, myalgia, rheumatalgia, toothache, arthralgia, menstrual pain, etc.; can also be used as veterinary drug for treating myalgia, rheumatism, febrile diseases, hernia pain, etc., and has the following structure formula:
through comprehensive literature research, we found that there are two main methods for preparing analgin magnesium:
the method comprises the following steps: patent CN99120402.6 reports the synthesis of analgin magnesium by metal ion exchange of analgin with magnesium chloride and magnesium sulfate in methanol, ethanol or isopropanol. The main problem of this method is that sodium and magnesium ions are very similar in their properties under these conditions and are difficult to completely displace; magnesium sulfate is almost insoluble in methanol, ethanol or isopropanol, so that sodium ions and magnesium ions cannot be effectively replaced, and accordingly, conversion effect of analgin magnesium is poor, yield is low, and quality is poor.
The second method comprises the following steps: zikolov, P in the literature (Farmatsiya (Sofia, bulgana), 1976,20 (6), 11-17) reports the preparation of analgin magnesium by passing analgin over a cation exchange resin to remove sodium ions, then exchanging it with magnesium ions and finally concentrating the crystals. The method has the main problems that the ion exchange resin is expensive, and analgin magnesium is unstable in an aqueous solution, so that the product quality is unstable and the production cost is high.
Aiming at the problems, the invention aims to design a preparation process of analgin magnesium, which has the advantages of one-pot process, cheap and easily available raw materials, high total reaction yield and high product quality, so as to overcome the defects and shortcomings of the prior art.
Disclosure of Invention
According to one aspect of the application, a process for preparing analgin magnesium by a one-pot method (hereinafter also referred to as a preparation method) is provided.
Specifically, the process for preparing analgin by the one-pot method provided by the invention takes 4-methylamino antipyrine (hereinafter also referred to as MAA), formaldehyde and magnesium salt as raw materials, and SO 2 The gas reacts to obtain the product.
According to some embodiments of the invention, the magnesium salt or oxide thereof is selected from the group consisting of magnesium oxide, magnesium carbonate, basic magnesium carbonate, and a combination of one or more of magnesium hydroxide, preferably magnesium oxide.
According to some embodiments of the invention, the above reaction process (preparation of crude product) is carried out in a reaction medium selected from the group consisting of one or more combinations of methanol, ethanol, and isopropanol; isopropyl alcohol is preferred.
According to some embodiments of the invention, SO is introduced directly into the system formed by said feedstock 2 Carrying out one-pot reaction on the gas; preferably, 4-methylamino antipyrine, formaldehyde and magnesium salt are dispersed in a reaction medium, and SO is introduced into the dispersion system 2 The aeration pressure is controlled to be 5-150 psi (preferably the aeration is carried out so that the reaction pressure is 10-100 psi). Under the aeration pressure, the aeration speed and the aeration quantity can be controlled, and the reaction progress degree can be controlled.
According to some embodiments of the invention, SO is introduced directly into the system formed by the feedstock 2 The gas adopts a gas blowing method or a gas sealing method.
According to some embodiments of the invention, wherein the molar ratio of MAA to magnesium salt or oxide thereof (preferably magnesium oxide) is (0.8 to 1.2): 1;
and/or:
the mass ratio of the reaction medium to the MAA is (1-20): 1, preferably 4:1.
in the process of the invention, formaldehyde can be provided in the form of solution or solid formaldehyde, and can be used as a polymerization agent to enable MAA and SO to be added into a reaction system 2 Combining magnesium oxide into analgin magnesium; the dosage of the magnesium oxide: MAA is preferably 1 to 1.4.
According to some embodiments of the invention, the reaction is terminated when the reaction system of the reaction has a pH of 3 to 5.
According to some embodiments of the present invention, the determination of the reaction end point can be based on the method of detecting the pH value of the reaction system at 3-5 and/or the reaction solution sampling and HPLC (MAA ≤ 0.5%).
According to some embodiments of the invention, wherein the reaction temperature is between 0 and 80 ℃.
As a preferable embodiment of the present invention, the process further comprises a step of recrystallizing the crude magnesium 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate (hereinafter, it may also be referred to as crude analgin magnesium or crude ANJ-Mg) obtained after the reaction is completed;
preferably, the recrystallization is: adding the reaction medium aqueous solution into the 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-methyl magnesium sulfonate crude product, adding active carbon, heating, carrying out hot melt filtration, and then carrying out crystallization on the filtrate.
According to some embodiments of the present invention, the amount of activated carbon is 0.2% -10% of the amount of crude analgin magnesium.
According to some embodiments of the present invention, the aqueous solution of the reaction medium used in the recrystallization process is an aqueous solution of an organic solvent prepared by mixing one or more of methanol, ethanol, isopropanol, butanol, acetone, and butanone with purified water that has been boiled; preferably an aqueous isopropanol solution, more preferably the mass ratio of the two is (1-20): 1, the isopropanol aqueous solution is selected as the reaction medium aqueous solution, which is beneficial to more complete recrystallization and improves the reaction yield.
Preferably, in the process of the present invention, the reaction medium is selected in accordance with the "reaction medium" in the aqueous reaction medium solution used for recrystallization.
According to some embodiments of the present invention, the temperature is increased by stirring after adding activated carbon, and the temperature is maintained by refluxing the system at 60-85 ℃.
According to some embodiments of the invention, wherein the crystallization temperature is between 0 ℃ and 25 ℃.
According to some embodiments of the invention, the organic solvent used for preparing the crude ANJ-Mg is selected from one or more of methanol, ethanol, isopropanol, butanol, acetone, and butanone.
According to some embodiments of the invention, wherein the step of refining (which may also be expressed as a refining step) comprises: adding activated carbon into the mixed solution of the crude analgin magnesium product and the reaction medium aqueous solution, refluxing and decoloring at 60-85 ℃, carrying out suction filtration while hot, cooling and crystallizing (preferably cooling to 0-5 ℃ for heat preservation), and obtaining the high-quality analgin magnesium product.
According to some embodiments of the invention, wherein the refining of the filter cake may be by vacuum drying, forced air drying and cyclone drying.
The process for preparing the analgin magnesium salt comprises the following steps: the first step is to prepare crude analgin magnesium by mixing MAA, magnesium salt or its oxideIntroducing SO into a reaction medium (preferably isopropanol) dispersion system of formaldehyde 2 Reacting, filtering and drying to obtain crude analgin magnesium product; the second step is to prepare the finished product of analgin magnesium, and the method comprises the following steps: adding the dried crude product into a reaction medium aqueous solution (preferably an isopropanol aqueous solution), adding activated carbon, carrying out thermal dissolution, carrying out suction filtration after heat preservation, recrystallizing the filtrate, carrying out suction filtration and drying to obtain a finished product.
Specifically, the method comprises the following steps:
the method comprises the following steps: dispersing 4-methylamino antipyrine (MAA), magnesium salt or its oxide and formaldehyde solution (or paraformaldehyde) in a reaction medium according to a certain proportion, and introducing SO 2 Reacting the gas, and determining a reaction end point by measuring the pH value of the later reaction to obtain a crude product of analgin;
the reaction medium is selected from methanol, ethanol, isopropanol, butanol, acetone, butanone or any combination thereof, preferably isopropanol;
the magnesium salt or the oxide thereof is selected from magnesium oxide, magnesium carbonate, basic magnesium carbonate or magnesium hydroxide, preferably magnesium oxide;
the weight ratio of MAA to the reaction medium is 1; the molar ratio of MAA to formaldehyde solution is 1:1.0 to 2.0; the reaction temperature is 0-80 ℃, preferably 40 ℃, and the reaction pressure is 10-100psi, preferably 30psi;
step two: dispersing the crude analgin product in a reaction medium water solution, adding activated carbon, and heating for dissolving and decoloring. Filtering while hot, crystallizing the mother liquor (preferably cooling naturally under stirring (120-360 r/min)), filtering and drying to obtain a finished product of analgin magnesium;
the reaction medium aqueous solution preferably adopts isopropanol aqueous solution, wherein the molar ratio of isopropanol to water is 1: (0.1-4); the mass addition amount of the activated carbon is 0.2-10 percent; the heating temperature is 60-85 ℃, preferably 82 ℃.
The beneficial effect that this application can produce includes:
the method has the advantages of simple process, high yield of prepared analgin magnesium, high detection purity and stable process.
Drawings
FIG. 1 is a UV spectrum of a finished product of analgin magnesium;
FIG. 2 is a high performance liquid chromatography spectrum of a finished product of analgin magnesium;
FIG. 3 is an infrared detection spectrum of a finished product of analgin magnesium.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
Unless otherwise specified, the raw materials and catalysts in the examples of the present application were all purchased commercially.
1. Preparation of crude ANJ-Mg product
Example 1
Adding a compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgO (40.3g, 1mol) formaldehyde solution (110 g, mass fraction of 36%) and 550ml methanol into a 1L reaction bottle, stirring at 20-30 ℃ to disperse the system, and slowly introducing SO 2 Gas, the reaction temperature is 30-80 ℃, and the end point of the reaction is judged by PH test paper in the later period of aeration. And stirring for 1h at the temperature of 20-50 ℃. And (3) cooling the reaction system to 0-25 ℃, carrying out heat preservation and crystallization for 2h, carrying out suction filtration, washing a filter cake with a small amount of glacial isopropanol, and carrying out forced air drying to obtain 350.2g of analgin magnesium (ANJ-Mg) with the yield of 93%.
Example 2
Adding MMA (217.3g, 1mol), mgO (40.3g, 1mol), formaldehyde solution (110 g, mass fraction 36%) and 550ml of isopropanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, controlling the reaction temperature to be 30-80 ℃, and judging that the reaction is finished when the purity of MAA in the reaction system is less than or equal to 0.5% by HPLC monitoring. And cooling the reaction liquid to 0-5 ℃ in an ice water bath, carrying out heat preservation and crystallization for 2h, carrying out suction filtration, leaching a filter cake with a small amount of ice isopropanol, and carrying out air blast drying to obtain 354.0g of analgin magnesium with the yield of 94%.
Example 3
Adding a compound MMA (217.3g, 1mol), mgO (40.3g, 1mol), a formaldehyde solution (110 g, 36 mass percent) and 550ml of ethanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, pressurizing until the internal pressure of the reaction bottle is 40-60 psi, and heating to 40-80 ℃ for reaction. If the pressure of the reaction bottle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the reaction bottle at 20-50 psi. And (3) reacting until the pressure inside the reaction bottle is basically unchanged within 0.5-1 hour, cooling to room temperature, cooling the reaction solution to 0-5 ℃ in an ice water bath, carrying out heat preservation and crystallization for 2 hours, carrying out suction filtration, leaching a filter cake with a small amount of glacial ethanol, and carrying out forced air drying to obtain 338.9g of analgin magnesium with the yield of 90%.
Table 1: influence of solvent type and dosage on yield of crude product of analgin magnesium
Example 4
Adding a compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgO (40.3g, 1mol) formaldehyde solution (110 g, mass fraction 36%) and 550ml methanol into a 1L reaction bottle, stirring at 20-30 ℃ to disperse the system, and slowly introducing SO 2 Gas, the reaction temperature is 30-80 ℃, and the end point of the reaction is judged by PH test paper in the later period of aeration. And stirring for 1h at the temperature of 20-50 ℃. And (3) cooling the reaction system to 0-25 ℃, carrying out heat preservation and crystallization for 2h, carrying out suction filtration, washing a filter cake with a small amount of glacial isopropanol, and carrying out forced air drying to obtain 302g of analgin magnesium (ANJ-Mg), wherein the yield is 80.2%.
Example 5
The compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mg (OH) 2 (58.3 g, 1mol) Formaldehyde solution (110 g, mass fraction 36%) and 550ml isopropyl alcohol were added to a 1L reaction flask, stirred at 20-30 ℃ to disperse the system, and SO was slowly added 2 Gas, the reaction temperature is 30-80 ℃, and the end point of the reaction is judged by PH test paper in the later period of aeration.And stirring for 1h at the temperature of 20-50 ℃. And (3) cooling the reaction system to 0-25 ℃, maintaining the temperature, crystallizing for 2 hours, then performing suction filtration, washing a filter cake with a small amount of ice isopropanol, and performing forced air drying to obtain 320.1g of analgin magnesium (ANJ-Mg), wherein the yield is 85%.
Example 6
The compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgCO 3 (84g, 1mol) Formaldehyde solution (110 g, mass fraction 36%) and 550ml ethanol were added to a 1L reaction flask, stirred at 20-30 ℃ to disperse the system, and SO was slowly introduced 2 Gas, the reaction temperature is 30-80 ℃, and the end point of the reaction is judged by PH test paper in the later period of aeration. And stirring for 1h at the temperature of 20-50 ℃. And cooling the reaction system to 0-25 ℃, carrying out heat preservation and crystallization for 2h, carrying out suction filtration, washing a filter cake with a small amount of glacial isopropanol, and carrying out forced air drying to obtain 328.4g of analgin magnesium (ANJ-Mg), wherein the yield is 87.2%.
Example 7
The compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), 4MgCO 3 ·Mg(OH) 2 ·5H 2 Adding O (97.2 g,0.2 mol) formaldehyde solution (110 g, mass fraction 36%) and 550ml isopropanol into a 1L reaction bottle, stirring at 20-30 ℃ to disperse the system, and slowly introducing SO 2 Gas, the reaction temperature is 30-80 ℃, and the end point of the reaction is judged by PH test paper in the later period of aeration. And stirring for 1h at the temperature of 20-50 ℃. And (3) cooling the reaction system to 0-25 ℃, maintaining the temperature, crystallizing for 2 hours, then performing suction filtration, washing a filter cake with a small amount of ice isopropanol, and performing forced air drying to obtain 328.4g of analgin magnesium (ANJ-Mg), wherein the yield is 87.2%.
Table 2: influence of magnesium salt species and solvent species on yield of analgin magnesium
Example 8
Compound MAA (217.3g, 1mol), mgCO 3 (84g,1mol)Adding a formaldehyde solution (110 g, the mass fraction is 36%) and 550ml of ethanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, controlling the reaction temperature to be 60-85 ℃, and judging that the reaction is finished when the purity of MAA in a reaction system is less than or equal to 0.5% by HPLC monitoring. And stirring for 1h at the temperature of 20-50 ℃. And (3) cooling the reaction system to 0-25 ℃, maintaining the temperature, crystallizing for 2 hours, then performing suction filtration, washing a filter cake with a small amount of glacial ethanol, and performing forced air drying to obtain 328.4g of crude analgin magnesium (ANJ-Mg) with the yield of 87.2%.
Example 9
The compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgCO 3 (84g, 1mol) formaldehyde solution (110 g, mass fraction 36%) and 550ml ethanol were added to a 1L reaction flask, sulfur dioxide was introduced into the reaction flask, the pressure inside the reaction flask was increased to 20 to 50psi, and the mixture was heated to 60 to 80 ℃ for reaction. If the pressure of the reaction bottle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the reaction bottle at 20-50 psi. And (3) reacting until the pressure in the reaction bottle is basically unchanged within 0.5-1 hour, cooling to room temperature, cooling the reaction solution to 0-5 ℃ in an ice water bath, keeping the temperature for crystallization for 2 hours, performing suction filtration, leaching a filter cake with a small amount of glacial ethanol, and performing forced air drying to obtain 338.9g of crude analgin magnesium with the yield of 90%.
Example 10
Adding a compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgO (40.3g, 1mol) formaldehyde solution (110 g, mass fraction of 36%) and 550ml methanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, pressurizing until the internal pressure of the reaction bottle is 20-50 psi, and heating to 60-80 ℃ for reaction. If the pressure of the reaction bottle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the reaction bottle at 20-50 psi. And (3) reacting until the pressure inside the reaction bottle is basically unchanged within 0.5-1 hour, stirring and cooling to room temperature, cooling to 0-5 ℃ in an ice water bath, preserving heat and crystallizing for 2 hours, performing suction filtration, leaching a filter cake with a small amount of glacial methanol, and performing vacuum drying to obtain 331.4g of crude analgin magnesium with the yield of 88%.
Example 11
Adding a compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgO (40.3g, 1mol) formaldehyde solution (110 g, mass fraction of 36%) and 550ml ethanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, and judging that the reaction is finished when the purity of the MAA in the reaction system is less than or equal to 0.5% by HPLC (high performance liquid chromatography) monitoring at the reaction temperature of 65-75 ℃. Stirring and cooling to room temperature, cooling to 0-5 ℃ in ice water bath, keeping the temperature and crystallizing for 2h, carrying out suction filtration, leaching a filter cake with a small amount of glacial ethanol, and carrying out vacuum drying to obtain 330.6g of crude analgin magnesium with the yield of 87.8%.
Example 12
Adding a compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgO (40.3g, 1mol) formaldehyde solution (110 g, mass fraction of 36%) and 550ml ethanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, pressurizing until the internal pressure of the reaction bottle is 20-50 psi, and heating to 60-80 ℃ for reaction. If the pressure of the reaction bottle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the reaction bottle at 20-50 psi. And (3) reacting until the pressure inside the reaction bottle is basically unchanged within 0.5-1 hour, stirring and cooling to room temperature, cooling to 0-5 ℃ in an ice water bath, carrying out heat preservation and crystallization for 2 hours, carrying out suction filtration, leaching a filter cake with a small amount of glacial ethanol, and carrying out vacuum drying to obtain 351.7g of crude analgin magnesium, wherein the yield is 93.4%, and the HPLC purity is 99.58%.
Example 13
Adding a compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgO (40.3g, 1mol) formaldehyde solution (110 g, mass fraction of 36%) and 550ml ethanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, pressurizing until the internal pressure of the reaction bottle is 20-50 psi, and heating to 60-80 ℃ for reaction. If the pressure of the reaction bottle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the reaction bottle at 20-50 psi. And (3) reacting until the pressure inside the reaction bottle is basically unchanged within 0.5-1 hour, stirring and cooling to room temperature, cooling to 0-5 ℃ in an ice water bath, preserving heat and crystallizing for 2 hours, performing suction filtration, leaching a filter cake with a small amount of glacial ethanol, and performing vacuum drying to obtain 388.9g of crude analgin magnesium product with the yield of 90.0%.
Example 14
Adding a compound 4-Methylaminoantipyrine (MAA) (217.3g, 1mol), mgO (40.3g, 1mol) formaldehyde solution (110 g, mass fraction of 36%) and 550ml butanol into a 1L reaction bottle, introducing sulfur dioxide into the reaction bottle, pressurizing until the internal pressure of the reaction bottle is 20-50 psi, and heating to 60-80 ℃ for reaction. If the pressure of the reaction bottle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the reaction bottle at 20-50 psi. And (3) reacting until the pressure inside the reaction bottle is basically unchanged within 0.5-1 hour, stirring and cooling to room temperature, cooling to 0-5 ℃ in an ice water bath, preserving heat and crystallizing for 2 hours, performing suction filtration, leaching a filter cake with a small amount of butanol, and performing vacuum drying to obtain 316.3g of analgin with the yield of 84.0%.
Table 3: influence of solvent type and reaction pressure on crude analgin magnesium product yield
2. Recrystallization of crude product
Example 15
Adding crude analgin magnesium (217.3 g, prepared in example 1) and 500ml of methanol aqueous solution (10) into a reaction bottle, adding activated carbon, stirring, heating, refluxing and keeping the temperature of the system at 60-85 ℃, and keeping the temperature for reaction for 0.5h. Filtering while hot, placing the filtrate in a 50-60 deg.C water bath kettle, stirring, crystallizing, naturally cooling, and placing the reaction bottle in a 0-5 deg.C water bath kettle for 2 hr when the system is cooled to room temperature; and (3) carrying out suction filtration, and drying a filter cake in a forced air drying oven to obtain 265.5g of a finished product of the analgin magnesium, wherein the yield is 70.5%, the HPLC purity is 99.90%, and a UV spectrum, a high performance liquid chromatography spectrum and an infrared detection spectrum are respectively shown in a figure 1-a figure 3.
Example 16
Adding crude analgin magnesium (217.3 g, prepared in example 2) and 500ml ethanol aqueous solution (4). Filtering while hot, placing the filtrate in a 50-60 deg.C water bath kettle, stirring, crystallizing, naturally cooling, and placing the reaction bottle in a 0-5 deg.C water bath kettle for 2 hr when the system is cooled to room temperature; and (4) carrying out suction filtration, and drying a filter cake in a forced air drying oven to obtain 152.5g of a finished product of the analgin magnesium, wherein the yield is 40.5%, and the HPLC purity is 99.88%.
Example 17
Adding crude analgin magnesium (217.3 g, prepared in example 3) and 500ml isopropanol aqueous solution (6). Filtering while hot, placing the filtrate in a 50-60 deg.C water bath kettle, stirring, crystallizing, naturally cooling, and placing the reaction bottle in a 0-5 deg.C water bath kettle for 2 hr when the system is cooled to room temperature; and (4) performing suction filtration, and drying a filter cake in a blast drying oven to obtain 282.4g of a finished product of analgin magnesium, wherein the yield is 75.0%, and the HPLC purity is 99.92%.
Table 4: influence of magnesium salt species and solvent species on yield and quality of analgin magnesium
The method has simple process, the prepared analgin magnesium has high yield, high quality and stable process, and the detection parameters of the products in the examples 15-17 all accord with the following detection results (a UV spectrum, a high performance liquid chromatography spectrum and an infrared detection spectrum are respectively shown in figures 1-3):
although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
Claims (9)
1. The process for preparing analgin magnesium by one-pot method is characterized in that 4-methylamino antipyrine, formaldehyde, magnesium salt, magnesium hydroxide or magnesium oxide are used as raw materials and are mixed with SO 2 Gas reaction is carried out; the magnesium salt is selected from magnesium carbonate or basic magnesium carbonate;
firstly dispersing 4-methylamino antipyrine, formaldehyde, magnesium salt, magnesium hydroxide or magnesium oxide in a reaction medium, and then introducing SO into a dispersion system 2 Controlling the ventilation pressure of the gas to be 5-150 psi;
the reaction medium is selected from methanol, ethanol or isopropanol;
the molar ratio of the 4-methylamino antipyrine to the magnesium salt, the magnesium hydroxide or the magnesium oxide is (0.8-1.2): 1;
the mass ratio of the 4-methylamino antipyrine to the reaction medium is 1: (1-20).
2. The process according to claim 1, wherein the magnesium salt, magnesium hydroxide or magnesium oxide is selected from magnesium oxide.
3. The process of claim 1, wherein the reaction medium is selected from isopropanol.
4. The process according to any one of claims 1 to 3, wherein the reaction is terminated when the reaction system of the reaction has a pH of 3 to 5.
5. The process according to claim 4, further comprising the step of recrystallizing the crude magnesium 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate obtained after the completion of the reaction.
6. The process of claim 5, wherein the recrystallization is: adding a reaction medium aqueous solution into the 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-magnesium methylsulfonate crude product, adding active carbon, heating, carrying out hot-melt filtration, and recrystallizing the filtrate.
7. The process of claim 6 wherein said aqueous reaction medium solution is prepared from the reaction medium and purified water that has been boiled to remove oxygen.
8. The process according to claim 6 or 7, wherein the filtration is carried out while the solution is hot, the filtrate is subjected to gradient cooling, stirring and crystallization, the temperature of the system is controlled to be 0-5 ℃ after the temperature is reduced from 50 ℃ to room temperature, and the temperature is kept for 2 hours under stirring.
9. The process according to claim 6, characterized in that said recrystallization step comprises: dissolving the 1-phenyl-2, 3-dimethyl-4-methylaminopyrazoline-5-one-N-magnesium methylsulfonate crude product and the reaction medium aqueous solution under the reflux condition, decoloring by active carbon, filtering, cooling filtrate, stirring and crystallizing, cooling to 0-5 ℃, preserving heat, and filtering to obtain recrystallized 1-phenyl-2, 3-dimethyl-4-methylaminopyrazoline-5-one-N-magnesium methylsulfonate hexahydrate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810600186.2A CN110172038B (en) | 2018-06-12 | 2018-06-12 | Process for preparing analgin magnesium by one-pot method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810600186.2A CN110172038B (en) | 2018-06-12 | 2018-06-12 | Process for preparing analgin magnesium by one-pot method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110172038A CN110172038A (en) | 2019-08-27 |
| CN110172038B true CN110172038B (en) | 2022-10-18 |
Family
ID=67689239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810600186.2A Active CN110172038B (en) | 2018-06-12 | 2018-06-12 | Process for preparing analgin magnesium by one-pot method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110172038B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU991716A1 (en) * | 1981-05-06 | 1987-12-30 | Институт физико-органической химии и углехимии АН УССР | 8-(n-methoxyphenyl)-1,3-dimethylimidazo-4/4',5'-c/-imidazo /1,2-a/ pyridine-2-on possessing analgetic and antiinflammatory activity |
| CN1297889A (en) * | 1999-12-01 | 2001-06-06 | 山东新华制药股份有限公司 | Preparation of magnesium [(1,5-dimethyl-2-phenyl-3-oxy-2,3-dioxy-1H-pyrazol-4-yl)methylamino] methane sulfonate hexahydrate |
| CN102399191A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药制药有限公司 | Method for synthesizing analgin |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN102659680A (en) * | 2012-03-31 | 2012-09-12 | 武汉武药制药有限公司 | Method for palladium-carbon catalytic hydrogenation synthesis of analgin |
| CN106279031A (en) * | 2016-08-08 | 2017-01-04 | 河北冀衡（集团）药业有限公司 | The method that the MAA crystallization using water soluble method to obtain produces COS dipyrone |
-
2018
- 2018-06-12 CN CN201810600186.2A patent/CN110172038B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU991716A1 (en) * | 1981-05-06 | 1987-12-30 | Институт физико-органической химии и углехимии АН УССР | 8-(n-methoxyphenyl)-1,3-dimethylimidazo-4/4',5'-c/-imidazo /1,2-a/ pyridine-2-on possessing analgetic and antiinflammatory activity |
| CN1297889A (en) * | 1999-12-01 | 2001-06-06 | 山东新华制药股份有限公司 | Preparation of magnesium [(1,5-dimethyl-2-phenyl-3-oxy-2,3-dioxy-1H-pyrazol-4-yl)methylamino] methane sulfonate hexahydrate |
| CN102399191A (en) * | 2011-12-21 | 2012-04-04 | 武汉武药制药有限公司 | Method for synthesizing analgin |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN102659680A (en) * | 2012-03-31 | 2012-09-12 | 武汉武药制药有限公司 | Method for palladium-carbon catalytic hydrogenation synthesis of analgin |
| CN106279031A (en) * | 2016-08-08 | 2017-01-04 | 河北冀衡（集团）药业有限公司 | The method that the MAA crystallization using water soluble method to obtain produces COS dipyrone |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110172038A (en) | 2019-08-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| WO2016107289A1 (en) | Method for preparing sofosbuvir crystal form-6 | |
| WO2017096772A1 (en) | Method for preparing anti-heart-failure medicine lcz696 | |
| CN108623567A (en) | Ao Si replaces the preparation method of Buddhist nun | |
| CN109553550B (en) | Method for synthesizing dihydrooat alkaloid | |
| CN113461580B (en) | N-acetyl-L-cysteine synthesis method | |
| CN106810534A (en) | Chinese mugwort Fluconazole crystal formation and preparation method thereof | |
| CN110172038B (en) | Process for preparing analgin magnesium by one-pot method | |
| CN113045447A (en) | 2-amino malonamide and synthetic method thereof | |
| CN112028896A (en) | Novel crystal form of acatinib and preparation method thereof | |
| CN102153461A (en) | Method for preparing glycollic acid with ethylene glycol | |
| CN107501260A (en) | A kind of inhibitor venetoclax of Bcl 2 and intermediate preparation method | |
| CN101270124B (en) | Novel method for purifying and preparing high-purity fluorandiol and fluorandiol salt | |
| CN114163419A (en) | Preparation method of lansoprazole | |
| CN110698381A (en) | Method for synthesizing N- (benzyloxycarbonyl) succinimide by one-pot two-phase method | |
| CN109897002B (en) | Preparation of 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate | |
| CN114195761B (en) | Preparation method of high-purity sitafloxacin hydrate 3/2 | |
| CN109485608B (en) | Industrial production method of 4, 6-dichloro-5-fluoro-2-aminopyrimidine | |
| CN111499533B (en) | Method for preparing acetamino dimethyl phthalate | |
| CN114702410B (en) | Preparation method of guanidinoacetic acid | |
| CN111499530B (en) | Method for preparing amino methyl phthalate by one step | |
| CN113214321B (en) | Preparation method of minodronate E crystal form | |
| CN103044427B (en) | Refining and purification method of medical-grade adenine | |
| CN112457254B (en) | Crystal form of clomipramine hydrochloride and preparation method | |
| CN111825614B (en) | Preparation method of gliquidone intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |