CN103551144A - Bimetallic composite catalyst for preparing afloqualone and method for preparing afloqualone - Google Patents
Bimetallic composite catalyst for preparing afloqualone and method for preparing afloqualone Download PDFInfo
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- CN103551144A CN103551144A CN201310601391.8A CN201310601391A CN103551144A CN 103551144 A CN103551144 A CN 103551144A CN 201310601391 A CN201310601391 A CN 201310601391A CN 103551144 A CN103551144 A CN 103551144A
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Abstract
The invention relates to the field of organic synthesis and discloses a bimetallic composite catalyst for preparing afloqualone. The bimetallic composite catalyst comprises a bimetallic catalyst and a carrier, wherein the bimetallic catalyst is a ruthenium-palladium catalyst or a palladium-platinum catalyst or a palladium-ruthenium catalyst; the carrier is activated carbon or alumina or zeolite. The bimetallic composite catalyst is adopted in the process of preparing the afloqualone, catalytic hydrogenation is performed at low pressure, and the yield and reaction selectivity are effectively improved. The invention also relates to a method for preparing the afloqualone. The method comprises the following steps: with 6-nitro-2-(fluoromethyl)-3-(2-methylphenyl)-4-(3H)-1,3-phthalazinone as a substrate and the bimetallic composite catalyst for preparing the afloqualone as a catalyst, reducing, filtering, regulating a pH value and recrystallizing to prepare the afloqualone. The preparation method is high in chemical selectivity and accords with a green chemistry idea, and the prepared product is high in purity and has wide application prospects.
Description
Technical field
The present invention relates to organic synthesis field, relate in particular to a kind of double-metal composite catalyst of preparing afloqualone, also relate to the preparation method of afloqualone.
Background technology
Afloqualone is a kind of muscle relaxant, and drug effect is in the upper maincenter of spinal cord position more widely, and then alleviates the hyperfunction state of muscular tone.Afloqualone is the relaxant that an opposite, musculi colli spasm have good efficacy, through the clinical practices of two more than ten years, and obtain good medical effect, as be applied to following symptom: the spastic paralysis that cerebrovascular disorder, cerebral paralysis, spasmodic spinal paralysis, spinal cord vascular disorder, ossified posterior longitudinal ligament, multiple sclerosis, ALS, SCD's disease, wound sequelae (spinal cord injury, head injury), postoperative sequelae (comprising brain, tumor of spinal cord) and other myelencephalon illness cause.
Because contain a plurality of positions that are easily hydrogenated in afloqualone structure, so this step of hydrogenating reduction can produce other a large amount of reduzates in former research, as: these three kinds of accessory substances of A, B and C.
Summary of the invention
The present invention is directed in the preparation process of existing middle fluorine quinoline, the shortcoming that product purity is low and chemo-selective is poor, discloses a kind of double-metal composite catalyst of preparing afloqualone, also discloses the preparation method of afloqualone; In preparation process, chemo-selective is strong, easy to prepare, and condition is simple, safe and reliable, is applicable to suitability for industrialized production.
In order to solve the problems of the technologies described above, the present invention is solved by following technical proposals.
A double-metal composite catalyst of preparing afloqualone, comprises bimetallic catalyst and carrier, and the quality of bimetallic catalyst is 1～8% of carrier quality; Bimetallic catalyst is ruthenium palladium catalyst or palladium platinum catalyst or platinum ruthenium catalyst; Carrier is activated carbon or aluminium oxide or zeolite.
As preferably, bimetallic catalyst is ruthenium palladium catalyst, and the mass ratio of metal Ru, Metal Palladium is 1:5～20.After ruthenium palladium catalyst loads on carrier, obtain ruthenium palladium composite catalyst.In ruthenium palladium composite catalyst, the mass ratio of metal Ru, Metal Palladium is 1:5～20 o'clock, and in afloqualone preparation process, catalytic effect is comparatively desirable, and by-product yields is lower.As preferably, the mass ratio of metal Ru, Metal Palladium is 1:5～10.When the mass ratio of metal Ru, Metal Palladium is 1:5～10, in afloqualone preparation process, catalytic effect is even more ideal, and by-product yields is lower.
As preferably, bimetallic catalyst is platinum palladium catalyst; The mass ratio of metal platinum, Metal Palladium is 1:20～40.After platinum palladium catalyst loads on carrier, obtain platinum palladium composite catalyst.In platinum palladium composite catalyst, the mass ratio of metal platinum, Metal Palladium is 1:20～40 o'clock, and in afloqualone preparation process, catalytic effect is comparatively desirable, and by-product yields is lower.As preferably, the mass ratio of metal platinum, Metal Palladium is 1:20～30.When the mass ratio of metal platinum, Metal Palladium is 1:20～30, in afloqualone preparation process, catalytic effect is even more ideal, and by-product yields is lower.
As preferably, bimetallic catalyst is platinum ruthenium catalyst; The mass ratio of metal platinum, metal Ru is 1:1～10.After platinum ruthenium catalyst loads on carrier, obtain platinum ruthenium composite catalyst.In platinum ruthenium composite catalyst, the mass ratio of metal platinum, metal Ru is 1:1～10 o'clock, and in afloqualone preparation process, catalytic effect is comparatively desirable, and by-product yields is lower.As preferably, the mass ratio of metal platinum, metal Ru is 1:1～5.The mass ratio of metal platinum, metal Ru is 1:1～5 o'clock, and in afloqualone preparation process, catalytic effect is even more ideal, and by-product yields is lower.
It is upper that bimetallic catalyst is carried on carrier (activated carbon or aluminium oxide or zeolite), makes double-metal composite catalyst.The quality of bimetallic catalyst be carrier quality 1～8% time, catalytic effect is comparatively desirable, and the productive rate of the accessory substance of producing is lower.As preferably, the quality of bimetallic catalyst is 5～8% of carrier quality.The quality of bimetallic catalyst be carrier quality 5～8% time, catalytic effect is even more ideal, and the productive rate of the accessory substance of producing is lower.
The preparation method of afloqualone, its reaction equation is:
The preparation method of afloqualone, prepares in the process of afloqualone, using the above-mentioned catalyst of preparing afloqualone as double-metal composite catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, catalytic hydrogenation solvent and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02～0.4MPa, temperature is 0～70 ℃ of reaction, react after 2～20 hours, filter to obtain bimetallic catalyst and filtrate.
B. with ethanol, wash bimetallic catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).Reusable 1～15 non-inactivation of ruthenium palladium composite catalyst, platinum palladium composite catalyst and platinum ruthenium composite catalyst, is preferably used 8～13 times.
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2～11.0, at 20～25 ℃, stir 2 hours, filter to obtain afloqualone crude product.
D. add afloqualone crude product, every gram of afloqualone (6-amino-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone) in crude product, add the recrystallization solvent of 5～15ml, 0～40 ℃ of crystallization 3～8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:5～20.
In steps A, every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the volume that adds catalytic hydrogenation solvent in 3-phthalazone is 8～20ml; In steps A, catalytic hydrogenation solvent be acid content be 0.1～0.4N containing sour alcoholic solution or acid content, be 0.1～0.4N containing sour alcohol-ester mixed solution.
As preferably, containing sour alcoholic solution, comprise acid solution and alcoholic solution (I), acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (I) be in methyl alcohol, ethanol, isopropyl alcohol, butanols, isobutanol, the tert-butyl alcohol, amylalcohol one or both.Alcoholic solution (I) is the aqueous alcohol solutions that anhydrous alcohol solution or mass percent are 70～95%.
As preferably, containing sour alcohol-ester mixed solution, comprise acid solution, alcoholic solution (II) and ester solution (I); Acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (II) be in methyl alcohol, ethanol, isopropyl alcohol, butanols, isobutanol, the tert-butyl alcohol, amylalcohol one or both.Ester solution (I) is ethyl acetate or propyl acetate or butyl acetate or Ethyl formate or propyl formate or butyl formate.As preferably, contain in sour-ol-ester mixed solution, alcoholic solution (II) and ester solution (I) mix with arbitrary proportion.
In steps A, in the pressure limit of hydrogen in 0.02～0.4MPa, can make reaction have higher conversion ratio and selective, hypertonia can improve danger, and reduces the selective of reaction.
In steps A, the catalytic hydrogenation reaction time can follow the tracks of according to liquid chromatogram, and when raw material reaction is complete, reaction finishes, and is generally 2～20 hours, preferably 10～20 hours.
In step D, in every gram of afloqualone crude product, add the recrystallization solvent of 5～10ml.
In step D, recrystallization temperature is preferably 25～40 ℃; The recrystallization time is preferably 3～5h.
In step D, recrystallization solvent comprises alcoholic solution (III), ester solution (II) and water; The alcoholic solution that alcoholic solution (III) is C1～C4, the ester solution that ester solution (II) is C1～C6; The volume ratio of alcoholic solution (III), ester solution (II) and water is 1:0.2～1:0.2～1.
As preferably, in recrystallization solvent, alcoholic solution (III) be in methyl alcohol, ethanol, isopropyl alcohol, propyl alcohol one or more; Ester solution (II) is ethyl acetate or propyl acetate or butyl acetate or Ethyl formate or propyl formate or butyl formate.During recrystallization solvent, alcoholic solution (III) is selected one or more in methyl alcohol, ethanol, isopropyl alcohol, propyl alcohol; Ester solution (II) select ethyl acetate, propyl acetate, butyl acetate, Ethyl formate or, in propyl formate, butyl formate any one; And the volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.2～1:0.2～1, is preferably 1:0.5～1:0.2～0.5 o'clock, the productive rate of afloqualone recrystallization is the highest, purity is also the highest.
Compared with prior art, beneficial effect of the present invention is:
(1) the present invention has adopted double-metal composite catalyst, in low pressure, carries out catalytic hydrogenation, effectively raises yield, and productive rate can reach more than 90%, the highlyest can reach 96.9%.
(2) the present invention has adopted double-metal composite catalyst, in low pressure, carries out catalytic hydrogenation, effectively suppresses the generation of hydrogenated by-product A, B and C, has greatly improved the selective of reaction.
(3) preparation method of afloqualone of the present invention, simple to operate, environmental protection, economy, efficient, nontoxic, meet " Green Chemistry " theory, has wide prospects for commercial application.
(4) the invention provides the simple process for purification of a kind of afloqualone, improved the purity of product, reduced the content of impurity, meet the requirement of GB.
The specific embodiment
Embodiment 1
A double-metal composite catalyst of preparing afloqualone, comprises ruthenium palladium catalyst and activated carbon, and wherein, the mass ratio of metal Ru, Metal Palladium is 1:5, and the quality of ruthenium palladium catalyst is 1% of activated carbon quality.
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 31.3 grams of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, acid content 0.1N containing sour alcoholic solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02MPa, temperature is 0 ℃ of reaction, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 2 hours used times, filters to obtain ruthenium palladium catalyst and filtrate.
B. with ethanol washing ruthenium palladium catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).Reusable 8 times of ruthenium palladium composite catalyst, and non-inactivation.
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2, at 20 ℃, stir 2 hours, filter to obtain afloqualone crude product.Afloqualone yield is 92.1%, and liquid phase purity is 98.7%, and the productive rate of accessory substance A is 0.15%, and the productive rate of accessory substance B is 0.11%, and the productive rate of accessory substance C is 0.10%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 5ml, 0 ℃ of crystallization 3 hours, filter and obtain afloqualone.The afloqualone of take before recrystallization is benchmark, and afloqualone yield is 95.0%, and liquid phase purity is 99.6%, and the productive rate of accessory substance A is 0.10%, and the productive rate of accessory substance B is 0.07%, and the productive rate of accessory substance C is 0.11%.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:5.
In steps A, containing sour alcoholic solution, comprise sulfuric acid and absolute methanol.Wherein, every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcoholic solution is 8ml.
In step D, in recrystallization solvent, alcoholic solution (III) is methyl alcohol; Ester solution (II) is ethyl acetate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.2:0.2.
In high efficiency liquid phase detection method, liquid phase post specification is as follows: internal diameter is 4.6mm, and length is 15cm, and in liquid phase post, filler is octadecylsilane (ODS).Mobile phase layoutprocedure is as follows: 7.2 grams of sodium hydrogen phosphate dodecahydrates are dissolved in 1000 ml waters, with phosphoric acid,diluted, are adjusted to pH to 5.5, gets and in 600 milliliters of these solution, adds 400 milliliters of acetonitriles.In addition, column temperature is controlled at 40 ℃ of constant temperature; Detect wavelength and select 254nm; Flow rate of mobile phase is controlled at 1.0ml/min.
Embodiment 2
A double-metal composite catalyst of preparing afloqualone, comprises ruthenium palladium catalyst and activated carbon, and wherein, the mass ratio of metal Ru, Metal Palladium is 1:10; The quality of ruthenium palladium catalyst is 5% of activated carbon quality.
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, acid content are 0.1N0.3N containing sour alcohol-ester mixed solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02MPa, temperature is 5 ℃ of reactions, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 10 hours used times, filters to obtain ruthenium palladium catalyst and filtrate.
B. with ethanol washing ruthenium palladium catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).Reusable 15 non-inactivations of ruthenium palladium composite catalyst.
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.5, at 20 ℃, stir 2 hours, filter to obtain afloqualone crude product; The yield of afloqualone is 96.9%, and liquid phase purity is 99.8%, and accessory substance A productive rate is 0.09%, and accessory substance B productive rate is 0.09%, and accessory substance C productive rate is 0.09%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 10ml, 25 ℃ of crystallizations 5 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:10.
In steps A, containing sour alcohol-ester mixed solution, comprise sulfuric acid, amylalcohol and ethyl acetate; Wherein, amylalcohol and ethyl acetate mix with arbitrary proportion.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcohol-ester mixed solution is 10ml.
In step D, in recrystallization solvent, alcoholic solution (III) is propyl alcohol; Ester solution (II) is Ethyl formate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.5:0.5.
Embodiment 3
A double-metal composite catalyst of preparing afloqualone, comprises ruthenium palladium catalyst and aluminium oxide, and the mass ratio of metal Ru, Metal Palladium is 1:20; The quality of ruthenium palladium catalyst is 7% of quality of alumina; .
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, acid content are 0.3N containing sour alcohol-ester mixed solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.4MPa, temperature is 70 ℃ of reactions, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 20 hours used times, filters to obtain ruthenium palladium catalyst and filtrate.
B. with ethanol washing ruthenium palladium catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2～11.0, at 20～25 ℃, stir 2 hours, filter to obtain afloqualone crude product.The yield of afloqualone is 95.1%, and liquid phase purity is 98.1%, and accessory substance A productive rate is 0.17%, and accessory substance B productive rate is 0.10%, and accessory substance C productive rate is 0.09%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 10ml, 39 ℃ of crystallizations 7 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:10.
In steps A, containing sour alcohol-ester mixed solution, comprise glacial acetic acid, alcoholic solution (II) and propyl formate; Wherein, alcoholic solution (II) is isobutanol and the tert-butyl alcohol.Isobutanol, the tert-butyl alcohol and propyl formate mix with arbitrary proportion.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcohol-ester mixed solution is 12ml.
In step D, in recrystallization solvent, alcoholic solution (III) is ethanol, isopropyl alcohol and propyl alcohol; Ester solution (II) is propyl formate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.2:0.2.
Embodiment 4
A double-metal composite catalyst of preparing afloqualone, comprises palladium platinum catalyst and aluminium oxide, and wherein, the mass ratio of metal platinum, Metal Palladium is 1:40; The quality of platinum catalyst is 8% of quality of alumina.
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 31.2 grams of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, acid content 0.4N containing sour alcoholic solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.4MPa, temperature is 70 ℃ of reactions, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 20 hours used times, filters to obtain palladium platinum catalyst and filtrate.
B. with ethanol washing palladium platinum catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).Reusable 13 non-inactivations of palladium platinum composite catalyst.
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 11.0, at 25 ℃, stir 2 hours, filter to obtain afloqualone crude product; Yield: 91.9%, liquid phase purity 99.2%, A:0.15%, B:0.11%, C:0.10%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 15ml, 40 ℃ of crystallizations 8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:20.
In steps A, containing sour alcoholic solution, comprise hydrochloric acid and contain water quality to be that mass percent is 70% hydrous ethanol solution.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcoholic solution is 20ml.
In step D, in recrystallization solvent, alcoholic solution (III) is ethanol; Ester solution (II) is propyl acetate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:1:1.
Embodiment 5
A double-metal composite catalyst of preparing afloqualone, comprises palladium platinum catalyst and aluminium oxide, and wherein, the mass ratio of metal platinum, Metal Palladium is 1:30; The quality of palladium platinum catalyst is 5% of quality of alumina.
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, acid content are 0.4N containing sour alcohol-ester mixed solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.2MPa, temperature is 50 ℃ of reactions, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 2 hours used times, filters to obtain palladium platinum catalyst and filtrate.
B. with ethanol washing palladium platinum catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 11.0, at 25 ℃, stir 2 hours, filter to obtain afloqualone crude product.Afloqualone yield is 91.9%, and liquid phase purity is 99.2%, and the productive rate of accessory substance A is 0.15%, and the productive rate of accessory substance B is 0.11%, and the productive rate of accessory substance C is 0.10%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 15ml, 40 ℃ of crystallizations 3～8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:20.
In steps A, containing sour alcohol-ester mixed solution, comprise hydrochloric acid, alcoholic solution (II) and butyl formate; Alcoholic solution (II) is isopropyl alcohol and butanols.Wherein, isopropyl alcohol, butanols and butyl formate mix with arbitrary proportion.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcohol-ester mixed solution is 20ml.
In step D, in recrystallization solvent, alcoholic solution (III) is that ethanol, isopropyl alcohol and propyl alcohol mix with arbitrary proportion; Ester solution (II) is butyl formate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.2～1:0.2～1.
Embodiment 6
A double-metal composite catalyst of preparing afloqualone, comprises palladium platinum catalyst and activated carbon, and wherein, the mass ratio of metal platinum, Metal Palladium is 1:40; The quality of palladium platinum catalyst is 5% of activated carbon quality; .
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, 0.3N containing sour alcohol-ester mixed solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.4MPa, temperature is 70 ℃ of reactions, react after 20 hours, filter to obtain palladium platinum catalyst and filtrate.
B. with ethanol washing palladium platinum catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2, at 20 ℃, stir 2 hours, filter to obtain afloqualone crude product.Afloqualone yield is 96.9%, and liquid phase purity is 99.8%, and the productive rate of accessory substance A is 0.09%, and the productive rate of accessory substance B is 0.09%, and the productive rate of accessory substance C is 0.09%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 5ml, 0 ℃ of crystallization 3 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:5.
In steps A, containing sour alcohol-ester mixed solution, comprise sulfuric acid, alcoholic solution (II) and butyl formate; Alcoholic solution (II) is methyl alcohol and ethanol.Wherein, methyl alcohol, ethanol and butyl formate mix with arbitrary proportion.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcohol-ester mixed solution is 8ml.
In step D, in recrystallization solvent, alcoholic solution (III) is methyl alcohol; Ester solution (II) is ethyl acetate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.2～1:0.2～1.
Embodiment 7
A double-metal composite catalyst of preparing afloqualone, comprises platinum ruthenium catalyst and zeolite, and wherein, the mass ratio of metal platinum, metal Ru is 1:1; The quality of platinum ruthenium catalyst is 1～8% of zeolite quality; .
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 31.3 grams of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, 0.3N containing sour alcoholic solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.1MPa, temperature is 60 ℃ of reactions, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 10 hours used times, filters to obtain platinum ruthenium catalyst and filtrate.
B. with ethanol washing platinum ruthenium catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).Reusable 5 non-inactivations of platinum ruthenium composite catalyst.
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.5, at 23 ℃, stir 2 hours, filter to obtain afloqualone crude product; The yield of afloqualone is 90.53%, and liquid phase purity is 97.8%, and accessory substance A productive rate is 0.13%, and accessory substance B productive rate is 0.12%, and accessory substance C productive rate is 0.12%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 10ml, 0～40 ℃ of crystallization 3～8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:5～20.
In steps A, comprise sulfuric acid and alcoholic solution (I) containing sour alcoholic solution, alcoholic solution (I) be with arbitrarily than isopropyl alcohol and the butanols of mixing.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcoholic solution is 10ml.
In step D, in recrystallization solvent, alcoholic solution (III) is isopropyl alcohol and propyl alcohol; Ester solution (II) is butyl acetate or Ethyl formate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.5:0.2.
Embodiment 8
A double-metal composite catalyst of preparing afloqualone, comprises palladium ruthenium catalyst and zeolite, and wherein, the mass ratio of metal platinum, metal Ru is 1:20; The quality of bimetallic catalyst is 8% of carrier quality.
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, 0.4N containing sour alcohol-ester mixed solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02MPa, temperature is 5 ℃ of reactions, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 2 hours used times, filters to obtain palladium ruthenium catalyst and filtrate.
B. with ethanol washing palladium ruthenium catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2～11.0, at 20～25 ℃, stir 2 hours, filter to obtain afloqualone crude product.The yield of afloqualone is 96.1%, and liquid phase purity is 99.2%, and accessory substance A productive rate is 0.19%, and accessory substance B productive rate is 0.08%, and accessory substance C productive rate is 0.10%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 5～15ml, 0～40 ℃ of crystallization 3～8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:5.
In steps A, containing sour alcohol-ester mixed solution, comprise sulfuric acid, alcoholic solution (II) and butyl acetate; Alcoholic solution (II) is methyl alcohol and ethanol.Wherein, methyl alcohol, ethanol and butyl acetate mix with arbitrary proportion.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcohol-ester mixed solution is 8ml.
In step D, in recrystallization solvent, alcoholic solution (III) is ethanol; Ester solution (II) is ethyl acetate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.2～1:0.2～1.
Embodiment 9
A double-metal composite catalyst of preparing afloqualone, comprises palladium ruthenium catalyst and zeolite, and wherein, the mass ratio of metal platinum, metal Ru is 1:5; The quality of bimetallic catalyst is 5% of carrier quality.
The preparation method of afloqualone, prepares in the process of afloqualone, using the catalyst of preparing above afloqualone as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, acid content are 0.3N containing sour alcoholic solution and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02MPa, temperature is 70 ℃ of reactions, by liquid chromatogram, follow the tracks of reaction, when raw material reaction is complete, reaction finishes, and altogether 10 hours used times, filters to obtain palladium ruthenium catalyst and filtrate.
B. with ethanol washing palladium ruthenium catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 11.0, at 20 ℃, stir 2 hours, filter to obtain afloqualone crude product.The yield of afloqualone is 96.9%, and liquid phase purity is 99.8%, and accessory substance A productive rate is 0.11%, and accessory substance B productive rate is 0.13%, and accessory substance C productive rate is 0.15%.
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 10ml, 35 ℃ of crystallizations 4 hours, filter and obtain afloqualone.The afloqualone of take before recrystallization is benchmark, and the yield of afloqualone is 96.0%, and liquid phase purity is 99.5%, and accessory substance A productive rate is 0.09%, and accessory substance B productive rate is 0.09%, and accessory substance C productive rate is 0.11%.
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:10.
In steps A, comprise glacial acetic acid and alcoholic solution (I) containing sour alcoholic solution, alcoholic solution (I) be with arbitrarily than the tert-butyl alcohol and the amylalcohol of mixing.Every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, in 3-phthalazone, adding the volume containing sour alcoholic solution is 15ml.
In step D, in recrystallization solvent, in recrystallization solvent, alcoholic solution (III) is isopropyl alcohol; Ester solution (II) is butyl formate.The volume ratio of alcoholic solution (II), ester solution (II) and water is 1:0.2:0.2.
In a word, the foregoing is only preferred embodiment of the present invention, all equalizations of doing according to the present patent application the scope of the claims change and modify, and all should belong to the covering scope of patent of the present invention.
Claims (9)
1. a double-metal composite catalyst of preparing afloqualone, is characterized in that: comprise bimetallic catalyst and carrier, the quality of bimetallic catalyst is 1～8% of carrier quality;
Bimetallic catalyst is ruthenium palladium catalyst or palladium platinum catalyst or platinum ruthenium catalyst;
Carrier is activated carbon or aluminium oxide or zeolite.
2. a kind of double-metal composite catalyst of preparing afloqualone according to claim 1, is characterized in that: the quality of bimetallic catalyst is 5～8% of carrier quality.
3. a kind of double-metal composite catalyst of preparing afloqualone according to claim 1, is characterized in that: bimetallic catalyst is ruthenium palladium catalyst, and the mass ratio of metal Ru, Metal Palladium is 1:5～20.
4. a kind of double-metal composite catalyst of preparing afloqualone according to claim 1, is characterized in that: bimetallic catalyst is platinum palladium catalyst; The mass ratio of metal platinum, Metal Palladium is 1:20～40.
5. a kind of double-metal composite catalyst of preparing afloqualone according to claim 1, is characterized in that: bimetallic catalyst is platinum ruthenium catalyst; The mass ratio of metal platinum, metal Ru is 1:1～10.
6. the preparation method of afloqualone, is characterized in that: prepares in the process of afloqualone, using the catalyst of preparing afloqualone described in claim 3 or 4 or 5 as double-metal composite catalyst, comprises the following steps,
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone, catalytic hydrogenation solvent and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02～0.4MPa, temperature is 0～70 ℃ of reaction, react after 2～20 hours, filter to obtain bimetallic catalyst and filtrate;
B. with ethanol, wash bimetallic catalyst, temperature lower than the condition of 40 ℃ under, decompression obtains solution (I);
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2～11.0, at 20～25 ℃, stir 2 hours, filter to obtain afloqualone crude product;
D. add afloqualone crude product, in every gram of afloqualone crude product, add the recrystallization solvent of 5～15ml, 0～40 ℃ of crystallization 3～8 hours, filter and obtain afloqualone;
Wherein, in steps A, the quality of double-metal composite catalyst and 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the mass ratio of 3-phthalazone is 1:5～20;
In steps A, every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the volume that adds catalytic hydrogenation solvent in 3-phthalazone is 8～20ml;
In steps A, catalytic hydrogenation solvent be acid content be 0.1～0.4N containing sour alcoholic solution or acid content, be 0.1～0.4N containing sour alcohol-ester mixed solution;
In step D, recrystallization solvent comprises alcoholic solution (III), ester solution (II) and water; The alcoholic solution that alcoholic solution (III) is C1～C4, the ester solution that ester solution (II) is C1～C6; The volume ratio of alcoholic solution (III), ester solution (II) and water is 1:0.2～1:0.2～1.
7. the preparation method of afloqualone according to claim 6, is characterized in that: containing sour alcoholic solution, comprise acid solution and alcoholic solution (I), acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (I) be in methyl alcohol, ethanol, isopropyl alcohol, butanols, isobutanol, the tert-butyl alcohol, amylalcohol one or both.
8. the preparation method of afloqualone according to claim 6, is characterized in that: containing sour alcohol-ester mixed solution, comprise acid solution, alcoholic solution (II) and ester solution (I); Acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (II) be in methyl alcohol, ethanol, isopropyl alcohol, butanols, isobutanol, the tert-butyl alcohol, amylalcohol one or both; Ester solution (I) is ethyl acetate or propyl acetate or butyl acetate or Ethyl formate or propyl formate or butyl formate.
9. the preparation method of afloqualone according to claim 6, is characterized in that: alcoholic solution (III) in methyl alcohol, ethanol, isopropyl alcohol, propyl alcohol one or more; Ester solution (II) is ethyl acetate or propyl acetate or butyl acetate or Ethyl formate or propyl formate or butyl formate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106397338A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High yield preparation method of afloqualone |
| CN106496145A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of preparation method of afloqualone |
| CN106496144A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of synthesis technique of afloqualone |
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| CN106397338A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High yield preparation method of afloqualone |
| CN106496145A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of preparation method of afloqualone |
| CN106496144A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of synthesis technique of afloqualone |
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