CN109897002B - Preparation of 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate - Google Patents
Preparation of 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate Download PDFInfo
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Abstract
The application discloses a preparation method of 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-methyl magnesium sulfonate hexahydrate. The method comprises the step of reacting analgin serving as a raw material with magnesium salt in a reaction medium to obtain the 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-magnesium methylsulfonate hexahydrate. The method has simple process, and the prepared analgin magnesium has higher yield, high quality and stable process, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation 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-methylaminopyrazolin-5-one-N-methyl-sulfonic acid magnesium hexahydrate), can be used for emergency fever abatement in acute hyperpyrexia, and can be used for treating headache, migraine, myalgia, rheumatalgia, toothache, arthralgia and menstrual pain; 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 displacement of analgin with magnesium chloride, 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, resulting in inefficient replacement of sodium and magnesium ions. Thus, repeating the examples of this patent shows a low yield and poor quality of the resulting analgin magnesium.
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 and crystallizing. 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 with simple working procedure, higher total reaction yield and high product quality so as to overcome the defects and shortcomings of the prior art in the industrial large-scale production process of analgin magnesium.
Disclosure of Invention
According to one aspect of the present application, there is provided a method for preparing magnesium 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate hexahydrate.
The preparation method of the 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-methyl magnesium sulfonate hexahydrate comprises the step of reacting analgin serving as a raw material with magnesium salt in a reaction medium to obtain the 1-phenyl-2, 3-dimethyl-4-methylamino pyrazoline-5-ketone-N-methyl magnesium sulfonate hexahydrate.
According to some embodiments of the present invention, the mass ratio of the reaction medium to the analgin is (1-20): 1.
according to some embodiments of the present invention, the molar ratio of the analgin to the magnesium salt is (0.3-2.0): 1.
according to some embodiments of the present invention, the reaction temperature of the analgin as a raw material and the magnesium salt in the reaction medium is 10-40 ℃.
According to some embodiments of the invention, the magnesium salt is selected from the group consisting of magnesium oxide, magnesium carbonate, basic magnesium carbonate, and magnesium hydroxide.
According to some embodiments of the invention, wherein the reaction medium is selected from the group consisting of methanol, ethanol, and isopropanol.
According to some embodiments of the invention, the method further comprises a step of preparing analgin, which comprises: the analgin is prepared by acidifying analgin serving as a raw material.
According to some embodiments of the invention, wherein the acid used for acidification is selected from HCl, H3PO4、HNO3、H2SO4、CH3COOH and CF3One or more combinations of COOH.
According to some embodiments of the present invention, the molar ratio of analgin to the acid used for acidification is (1-1.2): 1.
according to some embodiments of the invention, the step of preparing analgin comprises: and adding acid into the mixed solution of the analgin and the organic solvent, and reacting to obtain the analgin.
According to some embodiments of the present invention, the organic solvent used for preparing analgin is selected from one or more of methanol, ethanol, isopropanol, butanol, acetone and butanone.
According to some embodiments of the present invention, wherein the organic solvent used for preparing analgin is selected from one or more of methanol, ethanol, and isopropanol.
According to some embodiments of the present invention, the organic solvent used for preparing analgin is selected from methanol and/or ethanol.
According to some embodiments of the present invention, the mass ratio of analgin to the organic solvent used for preparing analgin is 1: (1-20).
According to some embodiments of the invention, the acid is added dropwise to the mixed solution of analgin and the organic solvent.
According to some embodiments of the invention, the step of preparing analgin comprises: and adding acid into the mixed solution of the analgin and the organic solvent, and reacting at 0-40 ℃ to obtain the analgin.
According to some embodiments of the present invention, the step of preparing analgin comprises acidifying analgin as a raw material, and then concentrating and crystallizing to obtain analgin.
According to some embodiments of the invention, the method further comprises a step of preparing analgin, which comprises: mixing 4-methylamino antipyrine and aldehyde water solution, and reacting with SO in reaction solvent2And (3) reacting to prepare the analgin.
According to some embodiments of the invention, wherein the aldehyde is formaldehyde or paraformaldehyde.
According to some embodiments of the invention, wherein the molar ratio of 4-methylaminoantipyrine to aldehyde is 1: (1-2).
According to some specific embodiments of the present invention, the mass/mass concentration of the aldehyde in the aqueous solution of aldehyde is 10 to 50%.
According to some embodiments of the invention, wherein the reaction solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol, acetone, and a mixture of one or more of butanone.
According to some embodiments of the invention, the mass ratio of 4-methylaminoantipyrine to the reaction solvent is 1: (1-20).
According to some embodiments of the invention, 4-methylaminoantipyrine is reacted with SO in a reaction solvent in the presence of formaldehyde2The reaction temperature is 30-80 ℃.
According to some embodiments of the invention, 4-methylaminoantipyrine is reacted with SO in a reaction solvent in the presence of an aldehyde2The reaction pressure is 10-100 psi.
According to some embodiments of the invention, whereinThe step of preparing analgin comprises reacting 4-methylaminoantipyrine with SO in the presence of an aldehyde in a reaction solvent2And reacting, concentrating and crystallizing to obtain the analgin.
According to some embodiments of the invention, the method further comprises the step of recrystallizing the analgin with an organic solvent after reacting the analgin with the magnesium salt to obtain 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulphonate magnesium hexahydrate.
According to some embodiments of the invention, the organic solvent used for recrystallization is selected from one or more of methanol, ethanol and isopropanol.
According to some embodiments of the present invention, the mass ratio of the magnesium 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate hexahydrate to the organic solvent used for recrystallization is 1: (1-20).
According to some embodiments of the invention, the recrystallization comprises dissolving the obtained crude 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate and an organic solvent under reflux conditions, filtering, cooling the filtrate for crystallization to obtain recrystallized 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate (preferably filtering after crystallization (preferably washing the filter cake with an organic solvent)) and drying.
According to some embodiments of the invention, the cooling crystallization is crystallization at 5 to 10 ℃.
According to some specific embodiments of the invention, the cooling crystallization is stirring crystallization at 5-10 ℃.
According to some embodiments of the present invention, the cooling crystallization is performed by stirring crystallization at a rotation speed of 100-350rpm at 5-10 ℃. Preferably stirred for 1h for crystallization.
According to some embodiments of the present invention, the cooling crystallization is to cool the filtrate naturally to 20-30 ℃ and then to 5-10 ℃ for crystallization.
According to some embodiments of the present invention, the cooling crystallization is performed by naturally cooling the filtrate to 20 to 30 ℃ under stirring, and then cooling to 5 to 10 ℃ for crystallization.
According to some embodiments of the present invention, the cooling crystallization is to cool the filtrate to 20-30 ℃ under stirring at a rotation speed of 100-200rpm, and then cool the filtrate to 5-10 ℃ for crystallization.
According to some embodiments of the invention, the recrystallization comprises refluxing 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate in the solvent used for recrystallization and rendering 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate substantially clear.
According to some embodiments of the present invention, the recrystallization includes dissolving 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate in a solvent used for recrystallization and filtering, then naturally cooling the filtrate to 20 to 30 ℃ while stirring at a rotation speed of 100 to 200rpm and stirring for 1 hour, then cooling the filtrate to 5 to 10 ℃ in an ice water bath while stirring at a rotation speed of 100 to 200rpm for crystallization, filtering, washing the filter cake with the recrystallization solvent, and drying to obtain analgin magnesium.
The process for preparing the analgin magnesium salt comprises the following steps: the first step is to prepare analgin, method 1 is to acidify analgin (ANJ-Na), and obtain analgin (ANJ-H) after drying, filtering, concentrating and crystallizing; the method 2 is that 4-methylamino antipyrine (MAA), formaldehyde solution (or paraformaldehyde) and SO2 completely react in a solvent, and analgin (ANJ-H) is obtained through concentration and crystallization. The second step is to prepare analgin magnesium salt, and analgin acid reacts with magnesium salt in a solvent to obtain a crude product of analgin magnesium. The third step is to recrystallize the crude analgin magnesium product in a solvent to obtain analgin magnesium (ANJ-Mg), which is characterized by comprising the following steps:
the method comprises the following steps:
the method 1 is to acidify analgin (ANJ-Na) in a solvent to prepare analgin (ANJ-H),the acid is selected from HCl and H3PO4、HNO3、H2SO4、CH3COOH and CF3COOH, preferably HCl; the solvent used is selected from methanol, ethanol, isopropanol, butanol, acetone, butanone or any combination thereof, preferably methanol; the weight ratio of the ANJ-Na to the used solvent is 1 (1-20); the reaction temperature is 0-40 ℃; the molar ratio of analgin to acid is 1.0 (1.0-1.2).
Step two: analgin (ANJ-H) and magnesium salt react in a solvent to obtain crude analgin magnesium salt, wherein the required magnesium salt is selected from magnesium oxide, magnesium carbonate, basic magnesium carbonate or magnesium hydroxide, preferably magnesium oxide; the solvent used is selected from methanol, ethanol, isopropanol or any combination thereof, preferably isopropanol; the weight ratio of the ANJ-H to the used solvent is 1 (1-20); the reaction temperature is 10-40 ℃; the molar ratio of analgin to magnesium salt used is 0.3-2.0, preferably 0.45-0.55.
Step three: recrystallizing the crude analgin magnesium salt to obtain analgin magnesium (ANJ-Mg), wherein the solvent is selected from methanol, ethanol, isopropanol or any combination thereof, preferably isopropanol; the weight ratio of the analgin magnesium salt crude product to the used solvent is 1 (1-20).
The beneficial effects that this application can produce include:
the method has simple process, and the prepared analgin magnesium has high yield, high quality and stable process, and is suitable for industrial large-scale production.
Drawings
FIG. 1 is a UV spectrum of magnesium 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate hexahydrate prepared in example 23.
FIG. 2 is an infrared spectrum of magnesium 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate hexahydrate prepared in example 23.
FIG. 3 is an HPLC chromatogram of magnesium 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate hexahydrate prepared in example 23.
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.
Preparation of compound ANJ-H
Example 1 the compound AMJ-Na (35.1g,0.1mol) and 70ml of methanol were added to a 250ml reaction flask, stirred and dissolved at 20-30 ℃, 12.5g of 35% by mass HCl-methanol solution was slowly added dropwise, and after dropping, stirred at 20-30 ℃ for 1 h. Adding anhydrous magnesium sulfate, drying, standing for a while, and filtering. Concentrating the filtrate at 30 ℃ under reduced pressure until the total weight is 70g, cooling to 0-5 ℃ in an ice water bath, maintaining the temperature, crystallizing for 2H, performing suction filtration, washing a filter cake with a small amount of ice methanol, and performing vacuum drying to obtain 28.6g of analgin (ANJ-H), wherein the yield is 92.1%, the HPLC purity is 99.86%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 2 the compound AMJ-Na (35.1g,0.1mol) and 105ml ethanol were added to a 250ml reaction flask, stirred and dissolved at 20-30 ℃, 11.5g HCl-ethanol solution with 38% mass fraction was slowly added dropwise, and after dropping, stirred at 20-30 ℃ for 1h with heat preservation. Adding anhydrous magnesium sulfate, drying, standing for a while, and filtering. Concentrating the filtrate at 30 deg.C under reduced pressure to total weight of 70g, cooling to 0-5 deg.C in ice water bath, maintaining the temperature, crystallizing for 2 hr, vacuum filtering, washing the filter cake with small amount of glacial ethanol, vacuum drying to obtain 29.0g analgin (ANJ-H),the yield is 93.3 percent, the HPLC purity is 99.82 percent,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 3 the compound AMJ-Na (35.1g,0.1mol) and 175.5ml isopropanol were added to a 500ml reaction flask, stirred at 20-30 ℃ until clear, 21.9g of a 20% by mass HCl-isopropanol solution was slowly added dropwise, and after dropping, stirred at 20-30 ℃ for 1 h. Adding anhydrous magnesium sulfate, drying, standing for a period of time, and filtering. Concentrating the filtrate at 30 ℃ under reduced pressure until the total weight is 70g, cooling to 0-5 ℃ in an ice water bath, maintaining the temperature for crystallization for 2H, performing suction filtration, washing a filter cake with a small amount of ice isopropanol, and performing vacuum drying to obtain 26.5g of analgin (ANJ-H), wherein the yield is 85.3%, the HPLC purity is 99.95%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
table 1: effect of solvent type and amount on Analgic acid yield and quality in method 1
Example 4 the compound AMJ-Na (35.1g,0.1mol) and 70ml of methanol were added to a 250ml reaction flask, stirred to dissolve at 20-30 ℃, 22.5g of 50% by mass trifluoroacetic acid-methanol solution was slowly added dropwise, and after dropping, stirred at 20-30 ℃ for 1h with heat preservation. Adding anhydrous magnesium sulfate, drying, standing for a while, and filtering. Concentrating the filtrate under reduced pressure at 30 ℃ until the total weight is 70g, cooling to 0-5 ℃ in an ice water bath, maintaining the temperature, crystallizing for 2H, performing suction filtration, washing a filter cake with a small amount of ice methanol, performing vacuum drying to obtain 10.9g of analgin (ANJ-H), wherein the yield is 35.1%, the HPLC purity is 99.91%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 5 the compound AMJ-Na (35.1g,0.1mol) and 70ml of methanol were added to a 250ml reaction flask and dissolved with stirring at 20-30 deg.CAnd cleaning, slowly dropwise adding 19.6g of phosphoric acid-methanol solution with the mass fraction of 50%, and stirring for 1h at the temperature of 20-30 ℃ after dropwise adding. Adding anhydrous magnesium sulfate, drying, standing for a while, and filtering. Concentrating the filtrate at 30 ℃ under reduced pressure until the total weight is 70g, cooling to 0-5 ℃ in an ice water bath, maintaining the temperature, crystallizing for 2H, performing suction filtration, washing a filter cake with a small amount of glacial methanol, and performing vacuum drying to obtain 22.7g of analgin (ANJ-H), wherein the yield is 73.2%, the HPLC purity is 99.88%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 6 the compound AMJ-Na (35.1g,0.1mol) and 70ml of methanol were added to a 250ml reaction flask, stirred and dissolved at 20-30 ℃, 19.6g of a 50% by mass sulfuric acid-methanol solution was slowly added dropwise, and after completion of the addition, stirred at 20-30 ℃ for 1 hour with heat preservation. Adding anhydrous magnesium sulfate, drying, standing for a while, and filtering. Concentrating the filtrate at 30 ℃ under reduced pressure until the total weight is 70g, cooling to 0-5 ℃ in an ice water bath, maintaining the temperature, crystallizing for 2H, performing suction filtration, washing a filter cake with a small amount of ice methanol, and performing vacuum drying to obtain 14.2g of analgin (ANJ-H), wherein the yield is 45.8%, the HPLC purity is 99.94%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 7 the compound AMJ-Na (35.1g,0.1mol) and 70ml of methanol were added to a 250ml reaction flask, stirred and dissolved at 20-30 ℃, 10.4g of 35% by mass HCl-methanol solution was slowly added dropwise, and after dropping, stirred at 20-30 ℃ for 1 h. Adding anhydrous magnesium sulfate, drying, standing for a while, and filtering. Concentrating the filtrate under reduced pressure at 30 ℃ until the total weight is 70g, cooling to 0-5 ℃ in an ice water bath, maintaining the temperature, crystallizing for 2H, performing suction filtration, leaching the filter cake with a small amount of ice methanol, and performing vacuum drying to obtain 27.5g of analgin (ANJ-H), wherein the yield is 88.5%, the HPLC purity is 99.92%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
table 2: influence of the type of acid, its amount and the type of solvent on the yield and quality of analgin in Process 1
Example 8 the reaction was terminated by charging a compound MMA (21.7g,0.1mol) and 100ml of methanol in this order into a 250ml reaction flask, stirring and dissolving them to be clear, charging 10.0g of an aqueous formaldehyde solution having a mass fraction of 30% or a mixed solution of 3.0g of paraformaldehyde and 7.0g of purified water into the reaction flask, introducing sulfur dioxide into the reaction flask, and controlling the reaction temperature to 65 to 75 ℃ while keeping the MAA purity in the reaction system by HPLC monitoring substantially unchanged. Concentrating the reaction solution to 50g under reduced pressure, cooling 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 methanol, carrying out vacuum drying to obtain 25.8g of analgin, wherein the yield is 82.9%, the HPLC purity is 99.78%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 9A compound MMA (21.7g,0.1mol) and 100ml of methanol were sequentially charged into a 500ml hydrogenation vessel, 10.0g of a 30% by mass aqueous solution of formaldehyde or a mixture of 3.0g of paraformaldehyde and 7.0g of purified water was then added, sulfur dioxide was introduced into the hydrogenation vessel, the pressure inside the hydrogenation vessel was increased to 40 to 60psi, and the reaction was carried out at 60 to 80 ℃. If the pressure of the hydrogenation kettle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the hydrogenation kettle at 20-40 psi. Reacting until the pressure in the hydrogenation kettle is basically unchanged within 0.5-1 hour, cooling to room temperature, concentrating the reaction solution to 50g under reduced pressure, 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 methanol, and carrying out vacuum drying to obtain 29.1g of analgin, wherein the yield is 93.6%, and the HPLC purity is 99.74%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 10A compound MMA (21.7g,0.1mol) and 100ml of methanol were sequentially charged into a 500ml hydrogenation vessel, 10.0g of a 30% by mass aqueous solution of formaldehyde or a mixture of 3.0g of paraformaldehyde and 7.0g of purified water was then added, sulfur dioxide was introduced into the hydrogenation vessel, the pressure inside the hydrogenation vessel was increased to 40 to 60psi, and the reaction was carried out at 60 to 80 ℃. If the pressure of the hydrogenation kettle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the hydrogenation kettle at 40-60 psi. Reacting until the pressure in the hydrogenation kettle is basically unchanged within 0.5-1 hour, cooling to room temperature, concentrating the reaction solution to 50g under reduced pressure, 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 methanol, and carrying out vacuum drying to obtain 29.7g of analgin, wherein the yield is 95.6%, and the HPLC purity is 99.71%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
EXAMPLE 11 the reaction was completed by charging MMA (21.7g,0.1mol) compound and 100ml ethanol in this order into a 250ml reaction flask, stirring and dissolving them to be clear, charging 10.0g of 30% by mass aqueous formaldehyde solution or a mixture of 3.0g of paraformaldehyde and 7.0g of purified water into the reaction flask, charging sulfur dioxide into the reaction flask, reacting at 65 to 75 ℃ and monitoring the MAA purity in the reaction system by HPLC to be substantially unchanged. Concentrating the reaction solution to 50g under reduced pressure, cooling 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 glacial ethanol, carrying out vacuum drying to obtain 27.3g of analgin, wherein the yield is 87.8%, the HPLC purity is 99.57%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 12A compound MMA (21.7g,0.1mol) and 100ml of ethanol were sequentially added to a 500ml hydrogenation vessel, 10.0g of a 30% by mass aqueous solution of formaldehyde or a mixture of 3.0g of paraformaldehyde and 7.0g of purified water was added thereto, sulfur dioxide was introduced into the hydrogenation vessel, the pressure inside the hydrogenation vessel was increased to 40 to 60psi, and the reaction was carried out at 60 to 80 ℃. If the pressure of the hydrogenation kettle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the hydrogenation kettle at 20-40 psi. Inverse directionUntil the pressure inside the hydrogenation kettle is basically unchanged within 0.5-1 hour, cooling to room temperature, concentrating the reaction solution to 50g under reduced pressure, 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, carrying out vacuum drying to obtain 29.7g of analgin, wherein the yield is 95.4%, and the HPLC purity is 99.58%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 13A compound MMA (21.7g,0.1mol) and 100ml of ethanol were sequentially added to a 500ml hydrogenation vessel, 10.0g of a 30% by mass aqueous solution of formaldehyde or a mixture of 3.0g of paraformaldehyde and 7.0g of purified water was added thereto, sulfur dioxide was introduced into the hydrogenation vessel, the pressure inside the hydrogenation vessel was increased to 40 to 60psi, and the reaction was carried out at 60 to 80 ℃. If the pressure of the hydrogenation kettle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the hydrogenation kettle at 40-60 psi. Reacting until the pressure in the hydrogenation kettle is basically unchanged within 0.5-1 hour, cooling to room temperature, concentrating the reaction solution to 50g under reduced pressure, 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 30.6g of analgin, wherein the yield is 98.5%, and the HPLC purity is 99.65%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
example 14A compound MMA (21.7g,0.1mol) and 100ml of butanol were sequentially added to a 500ml hydrogenation vessel, 10.0g of a 30% by mass aqueous solution of formaldehyde or a mixture of 3.0g of paraformaldehyde and 7.0g of purified water was added thereto, sulfur dioxide was introduced into the hydrogenation vessel, the pressure inside the hydrogenation vessel was increased to 40 to 60psi, and the reaction was carried out at 60 to 80 ℃. If the pressure of the hydrogenation kettle is reduced, continuously introducing sulfur dioxide, and maintaining the internal pressure of the hydrogenation kettle at 40-60 psi. Reacting until the pressure in the hydrogenation kettle is basically unchanged within 0.5-1 hour, cooling to room temperature, concentrating the reaction solution to 50g under reduced pressure, 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 butanol, carrying out vacuum drying to obtain 29.0g of analgin, wherein the yield is 93.3%, and the HPLC purity is 98.73%,1H-NMR(6d-DMSO)：11.00ppm(br，1H)；7.35～7.52ppm(m，5H)；4.87ppm(s，2H)；3.11ppm(s，3H)；3.04ppm(s，3H)；2.19ppm(s，3H)。
table 3: influence of solvent type and reaction pressure on yield and quality of analgin in method 2
| Kind of solvent | Pressure/psi | Yield of | HPLC(purity) |
| Methanol | / | 82.9％ | 99.78％ |
| Ethanol | / | 87.8％ | 99.57％ |
| Isopropanol (I-propanol) | / | 80.5％ | 99.65％ |
| Methanol | 20～40 | 93.6％ | 99.74％ |
| Ethanol | 20～40 | 95.4％ | 99.58％ |
| Isopropyl alcohol | 20～40 | 96.5％ | 99.55％ |
| Methanol | 40～60 | 95.6％ | 99.71％ |
| Ethanol | 40～60 | 98.5％ | 99.65％ |
| Isopropanol (I-propanol) | 40～60 | 93.6％ | 99.67％ |
| Butanol | 40～60 | 93.3％ | 98.73％ |
| Acetone (II) | 40～60 | 85.2％ | 98.26％ |
| Butanone | 40～60 | 95.9％ | 97.97％ |
The pressure "/" in Table 3 indicates that sulfur dioxide was fed into the reaction flask during the reaction, and the pressure in the reaction flask was maintained at substantially atmospheric pressure during the reaction (as in example 8).
Preparation of crude dipyrone magnesium salt
Example 15A compound ANJ-H (31.1g,0.1mol) and 60ml of methanol were added to a reaction flask, 2.0g of magnesium oxide was added in portions, the temperature of the reaction system was controlled to 20 to 30 ℃, and the reaction was carried out for 3 hours with heat preservation. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of methanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 24.5g of crude analgin magnesium salt, wherein the yield is 65.1%, the HPLC purity is 99.96%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 16A compound ANJ-H (31.1g,0.1mol) and 60ml ethanol were added to a reaction flask, 2.0g of magnesium oxide was added in portions, the temperature of the reaction system was controlled to 20 to 30 ℃, and the reaction was carried out for 3 hours with heat preservation. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of ethanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 33.7g of crude analgin magnesium salt, wherein the yield is 89.5%, the HPLC purity is 99.93%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 17 the compound ANJ-H (31.1g,0.1mol) and 60ml of isopropanol were added to a reaction flask, and 2.0g of magnesium oxide was added in portions, while controlling the temperature of the reaction system at 20 to 30 ℃ and reacting for 3 hours while maintaining the temperature. Then cooling to 5-10 ℃ in ice water bath, and preserving heatStirring for 1h, then performing suction filtration, leaching a filter cake with a small amount of isopropanol, performing vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 33.9g of crude analgin magnesium salt, wherein the yield is 90.1%, the HPLC purity is 99.85%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 18A compound ANJ-H (31.1g,0.1mol) and 60ml of methanol were added to a reaction flask, 2.92g of magnesium hydroxide was added in portions, the temperature of the reaction system was controlled to 20 to 30 ℃, and the reaction was carried out for 3 hours with heat preservation. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of methanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 16.3g of crude analgin magnesium salt, wherein the yield is 43.3%, the HPLC purity is 99.96%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 19 adding a compound ANJ-H (31.1g,0.1mol) and 60ml methanol into a reaction flask, adding 4.2g magnesium carbonate in batches, controlling the temperature of the reaction system to be 20-30 ℃, keeping the temperature for reaction for 3H, then cooling to 5-10 ℃ in an ice water bath, keeping the temperature and stirring for 1H, then carrying out suction filtration, leaching a filter cake with a small amount of methanol, and carrying out vacuum drying on the filter cake at 20-30 ℃ for 3H to obtain 25.1g analgin-magnesium salt, wherein the yield is 66.7%, the HPLC purity is 99.95%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 20A compound ANJ-H (31.1g,0.1mol) and 60ml methanol were added to a reaction flask, 4.86g basic magnesium carbonate was added in portions, the temperature of the reaction system was controlled to 20-30 ℃, and the reaction was maintained for 3 hours. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of methanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 31.0g of crude analgin magnesium salt, wherein the yield is 82.3%, the HPLC purity is 99.93%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
table 4: influence of magnesium salt species and solvent species on yield and quality of analgin magnesium
Preparation of compound ANJ-Mg
Example 21 adding 25g of crude analgin magnesium salt and 50g of methanol into a reaction bottle, heating, refluxing for reaction for 30min, filtering while hot, and naturally cooling the filtrate to 20-30 ℃ while stirring. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of methanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 19.2g of analgin, wherein the yield is 76.6%, the HPLC purity is 99.96%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 22 adding 25g of crude analgin magnesium salt and 75g of methanol into a reaction bottle, heating, refluxing for reaction for 30min, filtering while hot, and naturally cooling the filtrate to 20-30 ℃ while stirring. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of methanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 16.1g of analgin, wherein the yield is 64.2%, the HPLC purity is 99.95%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 23 adding 25g of crude analgin magnesium salt and 50g of ethanol into a reaction bottle, heating, refluxing for reaction for 30min, filtering while hot, and naturally cooling the filtrate to 20-30 ℃ while stirring. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of ethanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 20.9g of analgin, wherein the yield is 83.4%, the HPLC purity is 99.94%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 24 adding 25g of crude analgin magnesium salt and 125g of ethanol into a reaction bottle, heating, refluxing for reaction for 30min, filtering while hot, and naturally cooling the filtrate to 20-30 ℃ while stirring. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of ethanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 16.6g of analgin, wherein the yield is 66.5%, the HPLC purity is 99.96%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 25g of crude analgin magnesium salt and 50g of isopropanol are added into a reaction bottle, the mixture is heated up and refluxed for reaction for 30min, then the hot mixture is filtered, and the filtrate is naturally cooled to 20-30 ℃ under stirring. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of isopropanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 23.9g of analgin, wherein the yield is 95.5%, the HPLC purity is 99.95%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 26 adding 25g of crude analgin magnesium salt and 125g of isopropanol into a reaction bottle, heating, refluxing for reaction for 30min, filtering while hot, and naturally cooling the filtrate to 20-30 ℃ while stirring. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of isopropanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 18.0g of analgin, wherein the yield is 72.1%, the HPLC purity is 99.96%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
example 27 adding 25g of crude analgin magnesium salt and 250g of isopropanol into a reaction bottle, heating, refluxing for reaction for 30min, filtering while hot, and naturally cooling the filtrate to 20-30 ℃ while stirring. Then cooling to 5-10 ℃ in an ice water bath, preserving heat, stirring for 1h, then carrying out suction filtration, leaching a filter cake with a small amount of isopropanol, carrying out vacuum drying on the filter cake at 20-30 ℃ for 3h to obtain 13.9g of analgin, wherein the yield is 55.5%, the HPLC purity is 99.96%,1H-NMR(6d-DMSO)：7.35～7.52ppm(m，10H)；4.87ppm(s，4H)；3.73ppm(s，12H)；3.11ppm(s，6H)；3.04ppm(s，6H)；2.19ppm(s，6H)。
table 5: influence of solvent type and solvent dosage on refining yield and quality of analgin magnesium
The parameters and results of the tests for the products of examples 21-27 are shown in the following table
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 (33)
1. A preparation method of 1-phenyl-2, 3-dimethyl-4-methylaminopyrazoline-5-one-N-magnesium methylsulfonate hexahydrate is characterized by comprising the steps of taking analgin as a raw material, and reacting the analgin with magnesium salt in a reaction medium to obtain the 1-phenyl-2, 3-dimethyl-4-methylaminopyrazoline-5-one-N-magnesium methylsulfonate hexahydrate;
the reaction medium is selected from the group consisting of methanol, ethanol and isopropanol.
2. The preparation method according to claim 1, wherein the mass ratio of the reaction medium to the analgin is (1-20): 1.
3. the preparation method according to claim 1, wherein the molar ratio of the analgin to the magnesium salt is (0.3-2.0): 1.
4. the method according to claim 1, wherein the reaction temperature is 10 to 40 ℃.
5. The method of claim 1, wherein the magnesium salt is selected from the group consisting of magnesium oxide, magnesium carbonate, basic magnesium carbonate, and magnesium hydroxide.
6. The method of claim 1, further comprising a step of preparing analgin comprising: the analgin is prepared by acidifying analgin serving as a raw material.
7. The method of claim 6, wherein the acid used for acidification is selected from HCl and H3PO4、HNO3、H2SO4、CH3COOH and CF3One or more combinations of COOH.
8. The preparation method according to claim 6, wherein the molar ratio of analgin to the acid used for acidification is (1.0-1.2): 1.
9. the method of claim 6, wherein the step of preparing analgin comprises: and adding acid into the mixed solution of the analgin and the organic solvent, and reacting to obtain the analgin.
10. The method according to claim 9, wherein the organic solvent is selected from a mixture of one or more of methanol, ethanol, isopropanol, butanol, acetone, and methyl ethyl ketone.
11. The preparation method according to claim 9, wherein the mass ratio of analgin to the organic solvent is 1: (1-20).
12. The method according to claim 9, wherein the acid is added dropwise.
13. The method according to claim 9, wherein the reaction temperature is 0 to 40 ℃.
14. The method according to claim 6, wherein the step of preparing analgin comprises acidification of analgin as a raw material, followed by concentration and crystallization to obtain analgin.
15. The method of claim 1, further comprising a step of preparing analgin comprising: mixing 4-methylamino antipyrine and aldehyde water solution, and reacting with SO in reaction solvent2And (3) reacting to prepare the analgin.
16. The method according to claim 15, wherein the aldehyde is selected from the group consisting of formaldehyde and paraformaldehyde.
17. The method of claim 15, wherein the molar ratio of 4-methylaminoantipyrine to aldehyde is 1: (1-2).
18. The method of claim 15, wherein the reaction solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol, acetone, and methyl ethyl ketone.
19. The method according to claim 15, wherein the mass ratio of 4-methylaminoantipyrine to the reaction solvent is 1: (1-20).
20. The method of claim 15, wherein reacting with SO2The reaction temperature is 30-80 ℃.
21. The method of claim 15, wherein reacting with SO2The reaction pressure is 10-100 psi.
22. The method of claim 15, wherein said step of preparing analgin comprises reacting 4-methylaminoantipyrine with SO in a reaction solvent in the presence of an aldehyde2The analgin is prepared by reaction, concentration and crystallization.
23. The method of claim 1, further comprising the step of recrystallizing the crude salt of analgin with an organic solvent after reacting the analgin with a magnesium salt to obtain the crude 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonate magnesium hexahydrate.
24. The method of claim 23, wherein the organic solvent is selected from the group consisting of methanol, ethanol, and isopropanol.
25. The method according to claim 23, wherein the mass ratio of 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methyl magnesium sulfonate hexahydrate to organic solvent is 1: (1-20).
26. The method according to claim 23, wherein the recrystallization comprises dissolving the crude 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonic acid magnesium hexahydrate and an organic solvent under reflux conditions, filtering, cooling the filtrate, and crystallizing to obtain recrystallized 1-phenyl-2, 3-dimethyl-4-methylaminopyrazolin-5-one-N-methylsulfonic acid magnesium hexahydrate.
27. The method according to claim 26, wherein the temperature of the crystallization is 5 to 10 ℃.
28. The method according to claim 26, wherein the crystallization is carried out under stirring at 5 to 10 ℃.
29. The method according to claim 28, wherein the stirring is performed at a rotation speed of 100 to 350 rpm.
30. The method of claim 28, wherein the stirring time is 1 hour.
31. The preparation method of claim 26, wherein the filtrate is naturally cooled to 20-30 ℃ and then cooled to 5-10 ℃ for crystallization.
32. The method according to claim 31, wherein the natural cooling is performed by stirring at a rotation speed of 100 to 200 rpm.
33. The method of claim 26, wherein the cake is rinsed with an organic solvent and dried after the crystallization.
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| DE617237C (en) * | 1934-01-14 | 1935-08-15 | I G Farbenindustrie Akt Ges | Process for the preparation of ªÏ-methylsulfonic acids of primary or secondary pyrazolone amines |
| 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 |
| CN102584707A (en) * | 2012-01-18 | 2012-07-18 | 河北冀衡（集团）药业有限公司 | Production method of analgin bulk drug |
| 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 |
| CN106279030A (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 the molten method of wine to obtain produces COS dipyrone |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE617237C (en) * | 1934-01-14 | 1935-08-15 | I G Farbenindustrie Akt Ges | Process for the preparation of ªÏ-methylsulfonic acids of primary or secondary pyrazolone amines |
| 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 |
| CN102584707A (en) * | 2012-01-18 | 2012-07-18 | 河北冀衡（集团）药业有限公司 | Production method of analgin bulk drug |
| 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 |
| CN106279030A (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 the molten method of wine to obtain produces COS dipyrone |
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