CN111298834A - Preparation method of pharmaceutical intermediate for department of respiration - Google Patents
Preparation method of pharmaceutical intermediate for department of respiration Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical medicines, and particularly relates to a preparation method of a pharmaceutical intermediate for a respiratory department. The invention takes modified montmorillonite as a carrier for the first time and 1-aminoethyl-3-methylimidazole hexafluorophosphate to prepare the supported alkaline ionic liquid; and the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone and chloroacetyl chloride are catalyzed by replacing inorganic base to prepare the key intermediate 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -ketone of the medicine for treating chronic obstructive pulmonary disease. The method has high yield and simple reaction conditions, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a preparation method of a pharmaceutical intermediate for a respiratory department.
Background
Ondaterol (Olodaterol) is a long-acting β 2 receptor agonist developed by Boringer Invitrogen, Germany, and is approved by the FDA in U.S. 7 months of 2014 for marketing under the trade name Streverdii Respimat for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD).
The 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone is a key intermediate for preparing the odaterol, and the compound is prepared by the ring closure reaction of 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone and chloroacetyl chloride under the alkaline condition.
In the ring closing reaction reported at present, potassium carbonate is mostly used as a base and reacts in acetonitrile, but the yield of the reaction system is low; for example, in Bioorganic & Medicinal Chemistry Letters 20(2010) 1410-; in US2005/0267106A1, the reaction conditions are similar to those of Bioorganic & Medicinal Chemistry Letters 20(2010) 1410-1414, the post-treatment adopts silica gel column chromatography, and then the pure product is obtained by pulping and purifying by using isopropanol/diisopropyl ether, but the yield is only 50%; in CN 107188865A, the reaction temperature and the reagent dosage are changed, the post-treatment adopts silica gel column chromatography, and then isopropanol/methylcyclohexane is adopted for recrystallization to obtain the product, wherein the yield is only 37%.
In conclusion, the traditional inorganic base (potassium carbonate) adopted at present has poor catalytic effect on the condensation reaction, so that the defects of complicated post-treatment, low reaction yield and the like are caused, the production amplification of the bulk drug of the odaterol is influenced, and the production cost of the bulk drug is improved to a certain extent.
Disclosure of Invention
The invention aims to overcome the defects of low yield and complicated post-treatment of an Oldham key intermediate 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone in the prior art for treating Chronic Obstructive Pulmonary Disease (COPD); the invention adopts the alkaline ionic liquid to replace potassium carbonate to catalyze and prepare 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone, the yield of the catalytic system is high, and the alkaline ionic liquid loaded by the modified bentonite can be recycled, thereby reducing the production cost to a certain extent.
According to one aspect of the invention, the invention provides a preparation method of a supported basic ionic liquid, wherein a carrier in the supported basic ionic liquid is modified bentonite, and the basic ionic liquid is 1-aminoethyl-3-methylimidazolium hexafluorophosphate; the modified bentonite is obtained by sequentially treating bentonite with hydrochloric acid aqueous solution and sodium hydroxide aqueous solution;
the preparation method of the supported alkaline ionic liquid specifically comprises the following steps:
1) preparing a modified bentonite carrier:
acid treatment: placing bentonite into 1-2mol/L hydrochloric acid aqueous solution, stirring and dispersing for 4-8h at 60-80 ℃, then filtering, washing with water until filtrate does not contain chloride ions, collecting filter cakes, and drying to constant weight to obtain acid-treated bentonite; the acid treatment is adopted to increase the specific surface area of the bentonite;
alkali treatment: dispersing acid-treated bentonite into a saturated aqueous solution of calcium hydroxide, performing reflux reaction overnight for ion exchange, then filtering, washing with water until the filtrate is neutral, and drying to obtain modified bentonite;
2) preparation of ionic liquid:
1-methylimidazole (0.10mol) and 2-bromoethylamine hydrobromide (0.10mol) are subjected to reflux reaction in 50ml of acetonitrile for 4 hours; removing acetonitrile from the reaction solution under reduced pressure, adding 30ml of ethanol, ultrasonically dispersing uniformly, and then adding 40ml of acetonitrile aqueous solution (1: 1) and KPF6(0.1mol) stirring at room temperature overnight, finally adding sodium hydroxide (0.1mol) to adjust the pH of the system, and desolventizing to obtain an oily substance; sequentially extracting the oily substance by using diethyl ether and n-heptane, collecting an ionic liquid layer after liquid separation, and drying the ionic liquid layer at 60-80 ℃ under reduced pressure to obtain 1-aminoethyl-3-methylimidazolium hexafluorophosphate ionic liquid;
3) loading of ionic liquids
Stirring and dispersing 10-50mmol of 1-aminoethyl-3-methylimidazolium hexafluorophosphate ionic liquid in anhydrous toluene, then adding 10g of modified bentonite, refluxing and reacting for 24-48 h, cooling to room temperature, filtering, and drying to obtain the load type alkaline ionic liquid.
The invention utilizes the characteristic that the lamellar structure of montmorillonite in bentonite can be swelled and dispersed into nano-sized clay particles in an organic solvent, inserts the ionic liquid into the lamellar structure to achieve the purpose of loading the ionic liquid, solves the problem that the ionic liquid is difficult to recover, and has an adjusting effect on the catalytic activity of the ionic liquid.
According to another aspect of the invention, the invention provides a use of a supported basic ionic liquid for catalyzing 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone and chloroacetyl chloride to prepare 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one in the presence of a solvent. The applicant finds that the supported alkaline ionic liquid prepared by the method can be used for replacing potassium carbonate to efficiently catalyze and prepare the key intermediate 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone of the odaterol, has high reaction selectivity, does not generate byproducts, and can react at room temperature. The load type alkaline ionic liquid part prepared by the invention plays a role in base catalysis, is easier to dissolve in a system compared with inorganic base (potassium carbonate), is similar to homogeneous catalysis (potassium carbonate catalysis belongs to typical heterogeneous catalysis), so that the reaction rate is higher, and the reaction can be promoted to convert at room temperature to generate a target product.
Preferably, the solvent is a polar aprotic solvent, which is acetonitrile (CH)3CN), Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA).
Preferably, an acid-binding agent is added into the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone and chloroacetyl chloride for preparing 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone; the acid-binding agent is Triethylamine (TEA), N-Diisopropylethylamine (DIPEA) and 4-Dimethylaminopyridine (DMAP); the addition of the acid-binding agent can greatly improve the conversion rate of the reaction and reduce the dosage of the supported alkaline ionic liquid;
the method specifically comprises the following steps:
1) adding a solvent, 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone, an acid-binding agent and a supported alkaline ionic liquid into a reactor, uniformly stirring, and controlling the temperature to be 0-5 ℃;
2) dropwise adding chloroacetyl chloride into the reactor, and naturally heating to room temperature for reaction after dropwise adding;
3) HPLC detection shows that the reaction is stopped when the area percentage of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone in the reaction liquid is less than 0.5 percent;
4) filtering, and removing the load type alkaline ionic liquid to obtain filtrate;
5) the filtrate is post-treated to obtain 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone.
Preferably, the post-treatment is to drop an anti-solvent into the filtrate for crystallization; the antisolvent is water or any alkane with 1-7 carbon atoms.
Preferably, the acid scavenger is, in terms of molar ratio: 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone is 2-5:1, the invention adopts an acid-binding agent to remove hydrochloric acid which is a co-product generated by a ring-closing reaction, and 2mol of hydrochloric acid is generated per 1mol of substrate, so the molar dosage of the acid-binding agent is 2 times larger than that of the substrate;
preferably, the molar ratio of 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone: chloroacetyl chloride 1: 1.05-1.50;
preferably, the ratio of 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone: the supported basic ionic liquid is 1: 0.1-1.0.
The invention takes modified montmorillonite as a carrier for the first time and 1-aminoethyl-3-methylimidazole hexafluorophosphate to prepare the supported alkaline ionic liquid; and catalyzing 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone with chloroacetyl chloride instead of inorganic base to prepare 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one; compared with the prior art, the method has the following beneficial effects:
1) the prepared load type alkaline ionic liquid has the advantages of both heterogeneous and homogeneous catalysts, part of the ionic liquid can be dissolved in a solvent in the reaction process, which is equivalent to homogeneous catalysis, and excellent catalytic performance can be realized; after the reaction is finished, the catalyst can be recycled and is convenient to separate from the system;
2) the supported alkaline ionic liquid prepared by the method has high catalytic selectivity and basically has no side reaction;
3) the method has simple reaction conditions, the chloroacetyl chloride is dripped at low temperature and then naturally heated to room temperature for reaction, the ring closing reaction can be realized without heating at the later stage, and the reaction time can be generally finished within 4 hours;
4) the acid-binding agent is added into the catalytic system, so that the dosage of the supported alkaline ionic liquid can be effectively reduced, and the substrate is completely converted.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention.
The raw material 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone used in the examples is from Shanghai Kanlukiaceae, Inc., and the HPLC purity is more than 99.8%;
reaction solution HPLC normalization method: chromatography column Agilent C18 column (4.6 mm. times.250 mm,5 μm); mobile phase A: 50mmol/L sodium dihydrogen phosphate aqueous solution, B: acetonitrile, gradient elution (0 → 5 min: A65%; 5 → 20 min: A65% → 35%; 20 → 28 min: A35%; 28 → 35 min: A35% → 65%; 35 → 40 min: A65%); the detection wavelength is 220 nm; the flow rate is 1.0 ml/min; the column temperature was 30 ℃.
Production example 1
Preparing a supported basic ionic liquid:
1) preparing a modified bentonite carrier:
acid treatment: 10.0g of bentonite (Sigma Aldrich Shanghai trade Co., Ltd., product No. 285234, specific surface area 10.21 m)2/g) dispersing in 100ml 1mol/L hydrochloric acid aqueous solution at 60-80 deg.C under stirring for 4-8 hr, filtering, washing with water until the filtrate contains no chloride ion, collecting filter cake, drying to constant weight to obtain acid-treated bentonite (specific surface area of 15.12 m)2/g)；
Alkali treatment: dispersing 1.0g acid-treated bentonite in 50ml saturated aqueous solution of calcium hydroxide, refluxing for overnight reaction for ion exchange, filtering, washing with water until the filtrate is neutral, and drying to obtain modified bentonite (specific surface area of 14.58 m)2/g)；
2) Preparation of ionic liquid:
1-methylimidazole (0.10mol) and 2-bromoethylamine hydrobromide (0.10mol) are subjected to reflux reaction in 50ml of acetonitrile for 4 hours; removing acetonitrile from the reaction solution under reduced pressure, adding 30ml ethanol, ultrasonically dispersing uniformly, and then adding 40ml acetonitrile water solution (acetonitrile/water volume ratio is 1:1), KPF6(0.1mol) stirring at room temperature overnight, finally adding sodium hydroxide (0.1mol) to adjust the pH of the system, and desolventizing to obtain an oily substance; sequentially extracting and washing the oily substance by using diethyl ether and n-heptane, separating the liquid, collecting an ionic liquid layer, and drying the ionic liquid layer at 60-80 ℃ under reduced pressure to obtain 1-aminoethyl-3-methylimidazolium hexafluorophosphate ionic liquid;
taking a small amount of ionic liquid for mass spectrum detection: MS (ESI) M/z 126.1 (100%) [ M-PF6]+,397.2(100％)[2M-PF6]+；
3) Loading of ionic liquids
Stirring and dispersing 30mmol of 1-aminoethyl-3-methylimidazolium hexafluorophosphate ionic liquid in 200ml of anhydrous toluene, then adding 10g of modified bentonite, refluxing and reacting for 24h-48h, cooling to room temperature, filtering, and drying to obtain the supported basic ionic liquid (the theoretical content of the ionic liquid in percentage by weight is 44.8 wt%, and the carrier is 55.2 wt%).
In the invention, alkaline alumina and MCM-41 molecular sieves are respectively tried as carriers (10g of carriers, 30mmol of ionic liquid is loaded according to the method in the step 3) when the 1-aminoethyl-3-methylimidazolium hexafluorophosphate ionic liquid is loaded in the earlier stage, so that the alkaline alumina-loaded ionic liquid and the MCM-41 molecular sieve-loaded ionic liquid are respectively obtained, and the theoretical content of the ionic liquid in the two types of loaded ionic liquids is 44.8 wt%.
Example 1
Catalyzing 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone and chloroacetyl chloride by using different carrier-supported basic ionic liquids prepared in example 1 to prepare 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one; the specific conditions are as follows:
adding a substrate 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone (10mmol, 2.57g) into 50ml of acetonitrile, stirring, adding a supported ionic liquid (6.0g, 10mmol of 1-aminoethyl-3-methylimidazolium hexafluorophosphate), uniformly stirring, controlling the temperature at 0-5 ℃, slowly dropwise adding chloroacetyl chloride (12mmol), heating to room temperature after dropwise adding, reacting, detecting by HPLC (high performance liquid chromatography) that the area percentage of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone in the reaction solution is not changed any more, counting the reaction equilibrium time of the reaction system, the conversion rate of the substrate (the percentage of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone left after the reaction to the weight before the reaction, the weight remaining after the reaction was calculated from the mass concentration after the reaction), selectivity of the product 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one (ratio of moles of product formed by the reaction to moles of substrate reacted), and the results are shown in table 1:
TABLE 1 catalytic Effect of Ionic liquids obtained by different Supports
| Carrier | Reaction time/h | Conversion rate/% | Selectivity/%) |
| — | 3 | 52.4 | 99.2 |
| Modified bentonite | 5 | 68.2 | 99.1 |
| Basic alumina | 5 | 49.2 | 99.3 |
| MCM-41 | 6 | 53.1 | 99.2 |
And the injection is to load the 1-aminoethyl-3-methylimidazole hexafluorophosphate ionic liquid by using 10mmol of ionic liquid without using a carrier.
Test results show that the 1-aminoethyl-3-methylimidazole hexafluorophosphate ionic liquid prepared by the method can replace inorganic base potassium carbonate to catalyze 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone and chloroacetyl chloride to prepare 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -one, and the product selectivity is up to more than 99%; in addition, the carrier has certain influence on the activity of the ionic liquid, and the supported alkaline ionic liquid prepared by adopting the modified bentonite as the carrier has better catalytic effect than alkaline alumina and mesoporous molecular sieve MCM-41.
Example 2
The result of example 1 shows that the supported basic ionic liquid prepared in preparation example 1 of the present invention is used as a catalyst to replace inorganic base potassium carbonate, the selectivity of the target product of the catalytic reaction is high, and no by-product is generated; but the conversion rate of the raw materials is only 68.2 percent, and the industrial production cannot be realized; considering that two molecules of hydrochloric acid are generated in the ring closing reaction, the invention tries to add an acid binding agent to break the reaction balance, and the specific method is as follows:
adding a substrate 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone (10mmol, 2.57g) into 50ml of acetonitrile, stirring, adding a supported ionic liquid (6.0g, 10mmol of 1-aminoethyl-3-methylimidazolium hexafluorophosphate) and an acid-binding agent (20mmol), uniformly stirring, controlling the temperature at 0-5 ℃, slowly dropwise adding chloroacetyl chloride (12mmol), heating to room temperature after dropwise adding, reacting, detecting by HPLC (high performance liquid chromatography) that the area percentage of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone in a reaction solution is not changed, counting the reaction equilibrium time of a reaction system, and counting the conversion rate of the substrate (the percentage of the weight of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone left after the reaction to the weight before the reaction and the weight of the reaction The weight remaining after the reaction was calculated from the mass concentration after the reaction), selectivity of the product 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one (ratio of the number of moles of the product formed by the reaction to the number of moles of the substrate reacted), and the results are shown in table 2:
TABLE 2 Effect of different acid-binding agent species on the reaction
| Acid-binding agent/mmol | Reaction time/h | Conversion rate/% | Selectivity/%) |
| K2CO3/20 | 5 | 72.3 | 99.1 |
| Cs2CO3/20 | 6 | 83.4 | 99.2 |
| TEA/20 | 4 | 96.8 | 99.4 |
| DIPEA/20 | 4 | 99.2 | 99.3 |
| DMAP/20 | 4 | 98.1 | 99.2 |
Note: TEA for triethylamine, DIPEA for N, N-diisopropylethylamine, DMAP for 4-dimethylaminopyridine.
Test results show that the conversion rate can be improved after the acid-binding agent is added, but the inorganic base acid-binding agent has a poor effect compared with the organic base acid-binding agent, probably because the inorganic base cannot be dissolved in an acetonitrile system, if the inorganic base is simply added to be used as a catalyst and/or the acid-binding agent, heating is often needed in the later period, and the reason that the reaction cannot be completely converted at room temperature is explained; the inventor finds that good conversion rate can be obtained by using organic base as an acid-binding agent and the synergistic action of the organic base and the ionic liquid, wherein the effect of N, N-Diisopropylethylamine (DIPEA) is the best.
Example 3
N, N-Diisopropylethylamine (DIPEA) is selected as an acid-binding agent, and the reaction solvent is further optimized by the method, and the specific method comprises the following steps:
adding a substrate 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone (10mmol, 2.57g) into 50ml of a solvent, stirring, adding a supported ionic liquid (6.0g, 10mmol of 1-aminoethyl-3-methylimidazolium hexafluorophosphate) and an acid-binding agent (20mmol), uniformly stirring, controlling the temperature at 0-5 ℃, slowly dropwise adding chloroacetyl chloride (12mmol), heating to room temperature after dropwise adding, reacting, detecting by HPLC (high performance liquid chromatography) that the area percentage of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone in a reaction solution is not changed any more, counting the reaction equilibrium time of a reaction system, and counting the conversion rate of the substrate (the percentage of the weight of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone left after the reaction to the weight before the reaction and the conversion rate of the substrate The weight remaining after the reaction was calculated from the mass concentration after the reaction), selectivity of the product 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one (ratio of the number of moles of the product formed by the reaction to the number of moles of the substrate reacted), and the results are shown in table 3:
TABLE 3 influence of solvent type on the reaction
| Solvent(s) | Reaction time/h | Conversion rate/% | Selectivity/%) |
| Methanol | 12 | 82.1 | 99.4 |
| Ethanol | 15 | 86.4 | 99.2 |
| Ethyl acetate | 24 | 68.7 | 99.1 |
| Acetonitrile | 4 | 99.2 | 99.3 |
| DMF | 3 | 100 | 99.3 |
| DMSO | 3 | 98.6 | 99.2 |
| HMPA | 3 | 100 | 99.1 |
The test result shows that the reaction conversion rate of the aprotic solvent is higher than that of the protic solvent, wherein the reaction effect of DMF and HMPA is the best, the substrate can be completely converted, and the invention adopts DMF as the solvent in consideration of the fact that the cost of hexamethylphosphoric triamide (HMPA) is higher than that of Dimethylformamide (DMF).
The invention optimizes the dosage of the load type alkaline ionic liquid, and finds that the dosage of the load type alkaline ionic liquid can be reduced on the premise of adding the acid-binding agent; when the molar dosage of the acid-binding agent is twice of that of the substrate 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone, the complete conversion of the substrate can be realized when the dosage of the supported alkaline ionic liquid is 40% of the weight of the substrate 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone.
Example 4
The invention carries out laboratory scale amplification on the optimization method to verify the feasibility of the process, and the specific method is as follows:
1) adding 2L of DMF solvent, 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone (257g, 1mol), acid-binding agent DIPEA (2mol) and supported alkaline ionic liquid (prepared in preparation example 1, 103g, the theoretical content of the ionic liquid is about 0.17mol) into a reactor, uniformly stirring, and controlling the temperature to be 0-5 ℃;
2) dropwise adding chloroacetyl chloride (1.2mol) into the reactor, and naturally heating to room temperature for reaction after dropwise adding;
3) after 4h, taking reaction liquid for HPLC detection (normalization method), and stopping the reaction when the area percentage of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone in the reaction liquid is 0.12%;
4) filtering, and removing the load type alkaline ionic liquid to obtain filtrate;
5) transferring the filtrate to a crystallization kettle, heating to 45-50 ℃ to obtain a homogeneous transparent solution, then dropwise adding n-heptane until the system becomes turbid, keeping the temperature, stirring for 20-30min to grow crystals, continuously dropwise adding n-heptane until the concentration of 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -one in the solution is not reduced (1.62L of n-heptane is added in total), precipitating a large amount of solid particles, naturally cooling to room temperature, filtering, and drying a filter cake under reduced pressure to obtain 272.6g of white solid with the yield of 91.8%.
Taking a small amount of sample, and carrying out HPLC purity detection to obtain 99.81% (normalization method); ESI-MS (M/z):298[ M + H]+；1H-NMR(400MHz,DMSO-d6)δ:10.81(s,1H), 7.40～7.44(d,2H),7.37～7.39(t,2H),7.32～7.34(dd,1H),6.85～ 6.86(d,1H),6.73～6.74(d,1H),5.05(s,2H),4.63(s,2H),2.53(s,3H).
The supported alkaline ionic liquid obtained by filtration and recovery is dried to constant weight after being ultrasonically washed by DMF, and is recovered and applied mechanically, and the result shows that the conversion rate of more than 99.5 percent and the selectivity of more than 99.1 percent of the substrate can still be realized after the supported alkaline ionic liquid is continuously used for 2 times; but when used to the fifth time, the conversion was only 89.3% and the selectivity was still 99.2%.
Although the embodiments of the present invention have been described in detail, it should be understood that various changes, substitutions, and alterations can be made hereto without departing from the spirit and scope of the invention.
Claims (10)
1. A preparation method of a supported alkaline ionic liquid is characterized by comprising the following steps: the carrier in the load type alkaline ionic liquid is modified bentonite, and the alkaline ionic liquid is 1-aminoethyl-3-methylimidazole hexafluorophosphate; the modified bentonite is obtained by sequentially treating bentonite with hydrochloric acid aqueous solution and sodium hydroxide aqueous solution.
2. The method of claim 1, wherein: the method specifically comprises the following steps:
1) preparing a modified bentonite carrier:
acid treatment: placing bentonite in hydrochloric acid water solution, stirring and dispersing at 60-80 ℃, then filtering, washing with water until filtrate does not contain chloride ions, collecting filter cakes, and drying to constant weight to obtain acid-treated bentonite;
alkali treatment: dispersing acid-treated bentonite into a saturated aqueous solution of calcium hydroxide, performing reflux reaction overnight for ion exchange, then filtering, washing with water until the filtrate is neutral, and drying to obtain modified bentonite;
2) preparation of ionic liquid:
carrying out reflux reaction on 1-methylimidazole and 2-bromoethylamine hydrobromide in acetonitrile; removing acetonitrile from the reaction solution under reduced pressure, adding ethanol, ultrasonically dispersing uniformly, and then adding acetonitrile water solution and KPF6Stirring at room temperature overnight, finally adding sodium hydroxide to adjust the pH of the system, and desolventizing to obtain an oily substance; sequentially extracting the oily substance by using diethyl ether and n-heptane, collecting an ionic liquid layer, and drying under reduced pressure at the temperature of 60-80 ℃ to obtain 1-aminoethyl-3-methylimidazole hexafluorophosphate ionic liquid;
calculated according to molar ratio, the 1-methylimidazole, the 2-bromoethylamine hydrobromide and the KPF6The mole number of the sodium hydroxide is the same;
3) loading of ionic liquids
Stirring and dispersing the 1-aminoethyl-3-methylimidazole hexafluorophosphate ionic liquid in anhydrous toluene, adding modified bentonite for reflux reaction, cooling to room temperature, filtering, and drying to obtain the supported alkaline ionic liquid.
3. The use of the supported basic ionic liquid prepared by the preparation method of claim 1, which is characterized in that: in the presence of a solvent, the method is used for catalyzing 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone and chloroacetyl chloride to prepare the intermediate 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone of the odaterol.
4. Use according to claim 3, characterized in that: an acid-binding agent is also added in the catalysis process.
5. The method of claim 4, wherein: the acid-binding agent is triethylamine, N-diisopropylethylamine or 4-dimethylaminopyridine.
6. The method of claim 4, wherein: the solvent is a polar aprotic solvent.
7. The method of claim 6, wherein: the polar aprotic solvent is acetonitrile, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide.
8. Use according to any one of claims 4 to 7, characterized in that: the method comprises the following steps:
1) adding a solvent, 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone, an acid-binding agent and a supported alkaline ionic liquid into a reactor, uniformly stirring, and controlling the temperature to be 0-5 ℃;
2) dropwise adding chloroacetyl chloride into the reactor, and naturally heating to room temperature for reaction after dropwise adding;
3) HPLC detection shows that the reaction is stopped when the area percentage of the 1- [ 2-hydroxy-3-amino-5- (benzyloxy) phenyl ] ethanone in the reaction liquid is less than 0.5 percent;
4) filtering, and removing the load type alkaline ionic liquid to obtain filtrate;
5) the filtrate is post-treated to obtain 8-acetyl-6- (benzyloxy) -2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone.
9. Use according to claim 8, characterized in that: and the post-treatment is to drop an anti-solvent into the filtrate for crystallization.
10. Use according to claim 9, characterized in that: the antisolvent is water or any alkane with 1-7 carbon atoms.
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