CN103551144B - 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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- CN103551144B CN103551144B CN201310601391.8A CN201310601391A CN103551144B CN 103551144 B CN103551144 B CN 103551144B CN 201310601391 A CN201310601391 A CN 201310601391A CN 103551144 B CN103551144 B CN 103551144B
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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, particularly relate to a kind of double-metal composite catalyst preparing afloqualone, also relate to the preparation method of afloqualone.
Background technology
Afloqualone is a kind of muscle relaxant, and drug effect in the upper maincenter of spinal cord position more widely, and then alleviates the hyperfunction state of muscle tone.The relaxant that afloqualone is an opposite, musculi colli spasm has good efficacy, through the clinical practice of two more than ten years, and obtain good medical effect, as being 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 containing multiple position be 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 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.
Prepare a double-metal composite catalyst for afloqualone, 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.
As preferably, bimetallic catalyst is ruthenium palladium catalyst, and the mass ratio of metal Ru, Metal Palladium is 1:5 ~ 20.Ruthenium palladium catalyst loads to after on carrier, obtains ruthenium palladium composite catalyst.In ruthenium palladium composite catalyst, when the mass ratio of metal Ru, Metal Palladium is 1:5 ~ 20, in afloqualone preparation process, catalytic effect is ideal, 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.Platinum palladium catalyst loads to after on carrier, obtains platinum palladium composite catalyst.In platinum palladium composite catalyst, when the mass ratio of metal platinum, Metal Palladium is 1:20 ~ 40, in afloqualone preparation process, catalytic effect is ideal, 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.Platinum ruthenium catalyst loads to after on carrier, obtains platinum ruthenium composite catalyst.In platinum ruthenium composite catalyst, when the mass ratio of metal platinum, metal Ru is 1:1 ~ 10, in afloqualone preparation process, catalytic effect is ideal, and by-product yields is lower.As preferably, the mass ratio of metal platinum, metal Ru is 1:1 ~ 5.When the mass ratio of metal platinum, metal Ru is 1:1 ~ 5, in afloqualone preparation process, catalytic effect is even more ideal, and by-product yields is lower.
Bimetallic catalyst is carried on carrier (activated carbon or aluminium oxide or zeolite), i.e. obtained double-metal composite catalyst.When the quality of bimetallic catalyst is 1 ~ 8% of carrier quality, catalytic effect is ideal, and the productive rate of the accessory substance produced is lower.As preferably, the quality of bimetallic catalyst is 5 ~ 8% of carrier quality.When the quality of bimetallic catalyst is 5 ~ 8% of carrier quality, catalytic effect is even more ideal, and the productive rate of the accessory substance produced 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 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 DEG C of reaction, react after 2 ~ 20 hours, filter to obtain bimetallic catalyst and filtrate.
B. wash bimetallic catalyst with ethanol, under the condition of temperature lower than 40 DEG C, decompression obtains solution (I).Reusable 1 ~ 15 non-inactivation of ruthenium palladium composite catalyst, platinum palladium composite catalyst and platinum ruthenium composite catalyst, preferably uses 8 ~ 13 times.
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2 ~ 11.0, stir 2 hours at 20 ~ 25 DEG C, filter to obtain afloqualone crude product.
D. afloqualone crude product is added, every gram of afloqualone (6-amino-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone) add the recrystallization solvent of 5 ~ 15ml in crude product, 0 ~ 40 DEG C of crystallization 3 ~ 8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:5 ~ 20.
In steps A, the volume adding catalytic hydrogenation solvent in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone is 8 ~ 20ml; In steps A, the alcoholic solution containing acid of catalytic hydrogenation solvent to be acid content be 0.1 ~ 0.4N or acid content are the alcohol-ester mixed solution containing acid of 0.1 ~ 0.4N.
As preferably, the alcoholic solution containing acid comprises acid solution and alcoholic solution (I), and acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (I) is methyl alcohol, in ethanol, isopropyl alcohol, butanols, isobutanol, the tert-butyl alcohol, amylalcohol one or both.Alcoholic solution (I) for anhydrous alcohol solution or mass percent be the aqueous alcohol solutions of 70 ~ 95%.
As preferably, comprise acid solution, alcoholic solution (II) and ester solution (I) containing sour alcohol-ester mixed solution; Acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (II) is methyl alcohol, in 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, containing in sour-ol-ester mixed solution, alcoholic solution (II) and ester solution (I) mix with arbitrary proportion.
In steps A, hydrogen is in the pressure limit of 0.02 ~ 0.4MPa, and reaction can be made to have higher conversion ratio and selective, and 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 terminates, 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 DEG C; 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) is methyl alcohol, in 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) select in methyl alcohol, ethanol, isopropyl alcohol, propyl alcohol one or more; 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, when being preferably 1:0.5 ~ 1:0.2 ~ 0.5, 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) present invention employs double-metal composite catalyst, carry out catalytic hydrogenation, effectively raise yield in low pressure, productive rate can reach more than 90%, the highlyest can reach 96.9%.
(2) present invention employs double-metal composite catalyst, carry out catalytic hydrogenation in low pressure, the effective generation suppressing hydrogenated by-product A, B and C, substantially increases 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, there is wide prospects for commercial application.
(4) the invention provides the simple process for purification of a kind of afloqualone, improve the purity of product, decrease the content of impurity, meet the requirement of GB.
Detailed description of the invention
Embodiment 1
Prepare a double-metal composite catalyst for afloqualone, comprise ruthenium palladium catalyst and activated carbon, 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, will prepare the catalyst of afloqualone above 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, the alcoholic solution containing acid of 3-phthalazone, acid content 0.1N and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02MPa, temperature is 0 DEG C of reaction, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 2 hours used times, filters to obtain ruthenium palladium catalyst and filtrate.
B. with ethanol washing ruthenium palladium catalyst, under the condition of temperature lower than 40 DEG C, 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, stir 2 hours at 20 DEG C, 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 DEG C of crystallization 3 hours, filter and obtain afloqualone.With the afloqualone before recrystallization for benchmark, 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 the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:5.
In steps A, the alcoholic solution containing acid comprises sulfuric acid and absolute methanol.Wherein, the volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcoholic solution of acid 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 efficient 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, are adjusted to pH to 5.5 with phosphoric acid,diluted, gets in 600 milliliters of these solution and adds 400 milliliters of acetonitriles.In addition, column temperature controls at 40 DEG C of constant temperature; Determined wavelength selects 254nm; Flow rate of mobile phase controls at 1.0ml/min.
Embodiment 2
Prepare a double-metal composite catalyst for afloqualone, comprise ruthenium palladium catalyst and activated carbon, 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, will prepare the catalyst of afloqualone above 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 the alcohol-ester mixed solution containing acid and the double-metal composite catalyst of 0.1N 0.3N, Hydrogen Vapor Pressure is 0.02MPa, temperature is 5 DEG C of reactions, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 10 hours used times, filters to obtain ruthenium palladium catalyst and filtrate.
B. with ethanol washing ruthenium palladium catalyst, under the condition of temperature lower than 40 DEG C, 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, stir 2 hours at 20 DEG C, 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 DEG C of crystallizations 5 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:10.
In steps A, the alcohol-ester mixed solution containing acid comprises sulfuric acid, amylalcohol and ethyl acetate; Wherein, amylalcohol and ethyl acetate mix with arbitrary proportion.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcohol-ester mixed solution of acid 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
Prepare a double-metal composite catalyst for afloqualone, comprise ruthenium palladium catalyst and aluminium oxide, 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, will prepare the catalyst of afloqualone above 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 the alcohol-ester mixed solution containing acid and the double-metal composite catalyst of 0.3N, Hydrogen Vapor Pressure is 0.4MPa, temperature is 70 DEG C of reactions, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 20 hours used times, filters to obtain ruthenium palladium catalyst and filtrate.
B. with ethanol washing ruthenium palladium catalyst, under the condition of temperature lower than 40 DEG C, 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, stir 2 hours at 20 ~ 25 DEG C, 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 DEG C of crystallizations 7 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:10.
In steps A, the alcohol-ester mixed solution containing acid comprises 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.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcohol-ester mixed solution of acid 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
Prepare a double-metal composite catalyst for afloqualone, comprise palladium platinum catalyst and aluminium oxide, 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, will prepare the catalyst of afloqualone above 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, the alcoholic solution containing acid of 3-phthalazone, acid content 0.4N and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.4MPa, temperature is 70 DEG C of reactions, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 20 hours used times, filters to obtain palladium platinum catalyst and filtrate.
B. with ethanol washing palladium platinum catalyst, under the condition of temperature lower than 40 DEG C, 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, stir 2 hours at 25 DEG C, 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 DEG C of crystallizations 8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:20.
In steps A, the alcoholic solution containing acid comprise hydrochloric acid and containing water quality to be mass percent be 70% hydrous ethanol solution.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcoholic solution of acid 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
Prepare a double-metal composite catalyst for afloqualone, comprise palladium platinum catalyst and aluminium oxide, 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, will prepare the catalyst of afloqualone above 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 the alcohol-ester mixed solution containing acid and the double-metal composite catalyst of 0.4N, Hydrogen Vapor Pressure is 0.2MPa, temperature is 50 DEG C of reactions, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 2 hours used times, filters to obtain palladium platinum catalyst and filtrate.
B. with ethanol washing palladium platinum catalyst, under the condition of temperature lower than 40 DEG C, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 11.0, stir 2 hours at 25 DEG C, 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 DEG C of crystallizations 3 ~ 8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:20.
In steps A, the alcohol-ester mixed solution containing acid comprises 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.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcohol-ester mixed solution of acid is 20ml.
In step D, in recrystallization solvent, alcoholic solution (III) is 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
Prepare a double-metal composite catalyst for afloqualone, comprise palladium platinum catalyst and activated carbon, 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, will prepare the catalyst of afloqualone above as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the alcohol-ester mixed solution containing acid of 3-phthalazone, 0.3N and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.4MPa, temperature is 70 DEG C of reactions, react after 20 hours, filter to obtain palladium platinum catalyst and filtrate.
B. with ethanol washing palladium platinum catalyst, under the condition of temperature lower than 40 DEG C, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 10.2, stir 2 hours at 20 DEG C, 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 DEG C of crystallization 3 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:5.
In steps A, the alcohol-ester mixed solution containing acid comprises 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.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcohol-ester mixed solution of acid 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
Prepare a double-metal composite catalyst for afloqualone, comprise platinum ruthenium catalyst and zeolite, 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, will prepare the catalyst of afloqualone above 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, the alcoholic solution containing acid of 3-phthalazone, 0.3N and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.1MPa, temperature is 60 DEG C of reactions, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 10 hours used times, filters to obtain platinum ruthenium catalyst and filtrate.
B. with ethanol washing platinum ruthenium catalyst, under the condition of temperature lower than 40 DEG C, 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, stir 2 hours at 23 DEG C, 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 DEG C of crystallization 3 ~ 8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:5 ~ 20.
In steps A, the alcoholic solution containing acid comprises sulfuric acid and alcoholic solution (I), and alcoholic solution (I) is with isopropyl alcohol and the butanols arbitrarily than mixing.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcoholic solution of acid 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
Prepare a double-metal composite catalyst for afloqualone, comprise palladium ruthenium catalyst and zeolite, 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, will prepare the catalyst of afloqualone above as catalyst, comprises the following steps:
A. in hydrogenation apparatus, add 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1, the alcohol-ester mixed solution containing acid of 3-phthalazone, 0.4N and double-metal composite catalyst, Hydrogen Vapor Pressure is 0.02MPa, temperature is 5 DEG C of reactions, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 2 hours used times, filters to obtain palladium ruthenium catalyst and filtrate.
B. with ethanol washing palladium ruthenium catalyst, under the condition of temperature lower than 40 DEG C, 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, stir 2 hours at 20 ~ 25 DEG C, 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 DEG C of crystallization 3 ~ 8 hours, filter and obtain afloqualone.
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:5.
In steps A, the alcohol-ester mixed solution containing acid comprises 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.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcohol-ester mixed solution of acid 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
Prepare a double-metal composite catalyst for afloqualone, comprise palladium ruthenium catalyst and zeolite, 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, will prepare the catalyst of afloqualone above 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 the alcoholic solution containing acid and the double-metal composite catalyst of 0.3N, Hydrogen Vapor Pressure is 0.02MPa, temperature is 70 DEG C of reactions, reaction is followed the tracks of by liquid chromatogram, when raw material reaction is complete, reaction terminates, and altogether 10 hours used times, filters to obtain palladium ruthenium catalyst and filtrate.
B. with ethanol washing palladium ruthenium catalyst, under the condition of temperature lower than 40 DEG C, decompression obtains solution (I).
C. in filtrate and solution (I), add water, add 0.1N sodium hydroxide solution, regulate pH to 11.0, stir 2 hours at 20 DEG C, 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 DEG C of crystallizations 4 hours, filter and obtain afloqualone.With the afloqualone before recrystallization for benchmark, 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 the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:10.
In steps A, the alcoholic solution containing acid comprises glacial acetic acid and alcoholic solution (I), and alcoholic solution (I) is with the tert-butyl alcohol and the amylalcohol arbitrarily than mixing.The volume added in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone containing the alcoholic solution of acid 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 done 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 (8)
1. the preparation method of afloqualone, is characterized in that: the double-metal composite catalyst 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;
Preparing in the process of afloqualone, using preparing the catalyst of afloqualone as double-metal composite catalyst, comprising 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 DEG C of reaction, react after 2 ~ 20 hours, filter to obtain double-metal composite catalyst and filtrate;
B. wash double-metal composite catalyst with ethanol, under the condition of temperature lower than 40 DEG C, 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, stir 2 hours at 20 ~ 25 DEG C, filter to obtain afloqualone crude product;
D. in afloqualone crude product, add recrystallization solvent, in every gram of afloqualone crude product, add the recrystallization solvent of 5 ~ 15ml, 0 ~ 40 DEG C of crystallization 3 ~ 8 hours, filter and obtain afloqualone;
Wherein, in steps A, the quality of double-metal composite catalyst and the mass ratio of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone are 1:5 ~ 20;
In steps A, the volume adding catalytic hydrogenation solvent in every gram of 6-nitro-2-(methyl fluoride)-3-(2-aminomethyl phenyl)-4-(3H)-1,3-phthalazone is 8 ~ 20ml;
In steps A, the alcoholic solution containing acid of catalytic hydrogenation solvent to be acid content be 0.1 ~ 0.4N or acid content are the alcohol-ester mixed solution containing acid of 0.1 ~ 0.4N;
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.
2. the preparation method of afloqualone according to claim 1, is characterized in that: the alcoholic solution containing acid comprises acid solution and alcoholic solution (I), and acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (I) is methyl alcohol, in ethanol, isopropyl alcohol, butanols, amylalcohol one or both.
3. the preparation method of afloqualone according to claim 1, is characterized in that: the alcohol-ester mixed solution containing acid comprises acid solution, alcoholic solution (II) and ester solution (I); Acid solution is sulfuric acid or hydrochloric acid or glacial acetic acid; Alcoholic solution (II) is methyl alcohol, in ethanol, isopropyl alcohol, butanols, 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.
4. the preparation method of afloqualone according to claim 1, is characterized in that: alcoholic solution (III) is methyl alcohol, in ethanol, propyl alcohol more than one; Ester solution (II) is ethyl acetate or propyl acetate or butyl acetate or Ethyl formate or propyl formate or butyl formate.
5. the preparation method of afloqualone according to claim 1, is characterized in that: the quality of bimetallic catalyst is 5 ~ 8% of carrier quality.
6. the preparation method of 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.
7. the preparation method of 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.
8. the preparation method of 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.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5371275A (en) * | 1990-10-05 | 1994-12-06 | Korean Research Institute Of Chemical Technology | Methods for preparing ethylidene diacetate |
| CN101239923A (en) * | 2007-12-31 | 2008-08-13 | 浙江工业大学 | Method for preparing (S,S)N-(1-ethoxycarbonyl-3-phenylpropyl)-L-amino acid derivatives and refining method thereof |
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| US5371275A (en) * | 1990-10-05 | 1994-12-06 | Korean Research Institute Of Chemical Technology | Methods for preparing ethylidene diacetate |
| CN101239923A (en) * | 2007-12-31 | 2008-08-13 | 浙江工业大学 | Method for preparing (S,S)N-(1-ethoxycarbonyl-3-phenylpropyl)-L-amino acid derivatives and refining method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 氟喹酮的合成;肖瑞琪等;《华西药学杂志》;20061231;第21卷(第2期);第160-162页 * |
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