CN1762968A - 2-(9-anthryl)-2-carbonylethyl acetate solid phase synthesis method - Google Patents
2-(9-anthryl)-2-carbonylethyl acetate solid phase synthesis method Download PDFInfo
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Abstract
The solid phase 2-(9-anthryl)-2-carbonyl ethyl acetate synthesis process includes the steps of pre-treatment in drying reaction case, solid phase reaction, separation and purification and inspection. It is superior to available liquid phase synthesis process and may be used in mass preparation of the matter. Co-catalyst 1-methyl-2-pyrrolidone is added into the reactant to raise yield from below 10 % to 92.5 %. The present invention has the advantages of short reaction period, simple post-treatment, low product cost, high yield, high product purity, less environmental pollution, etc.
Description
Technical field
The invention belongs to
Base only connects the preparation of the compound of carbon or hydrogen atom; The preparing technical field of the inner complex of this compounds, the Friedel-Crafts that is specifically related to condensation reacts.
Technical background
2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is the anthracene derivant of a kind of structure shown in 1 formula.
Above-claimed cpd is mainly used in optically active substance 2-(9-anthryl)-2-hydroxyl ethyl acetate (2 formula) and 2-(9-anthryl)-2-methoxyacetic acid (3 formula) synthetic raw material.
Optically active compounds 2-(9-anthryl)-2-hydroxyl ethyl acetate and 2-(9-anthryl)-2-methoxyacetic acid are two kinds of important chiral auxiliary reagents, and they can be used for the mensuration of unsymmetrical carbon absolute configuration in some chipal compounds.The absolute configuration of chiral carbon atom assisting down in the carboxylic acid of unknown absolute configuration, the alkohol and amine compounds at optically pure 2-(9-anthryl)-2-hydroxyl ethyl acetate or 2-(9-anthryl)-2-methoxyacetic acid, utilize magnetic nuclear resonance method or circular dichroism spectrum exciton chirality method to be determined, this is based on these chiral auxiliary reagents has due to the strong absorption at ultraviolet region the anisotropy of magnetic and anthracene nuclear.In many chiral drug molecules, have carboxyl, hydroxyl and amido functional group, make such chiral auxiliary reagent have application widely aspect the sign of chiral drug molecule and some other chipal compounds steric configurations.
In the chipal compounds unsymmetrical carbon absolute configuration determine it is stereochemical important research content, also be one of the problem that must illustrate of chiral drug molecule.Drug molecule with different steric configurations has huge difference to the physiologically active that living organism showed.For many chiral drugs, its biological activity is often only proprietary by a kind of enantiomorph of specific absolute configuration, their pharmacological action be by and body between the biomacromolecule chirality coupling and the molecular recognition of strictness realize.There is significant difference in the enantiomorph of chiral drug at aspects such as the intravital pharmacologically active of people, metabolic process and toxicity.In the research process again of new drug development or existing chiral drug, the chirality three-dimensional arrangement of determining physiologically active substance for the drug quality inspection with understand different steric isomers activity difference in vivo and all have crucial meaning.These all show the importance of synthesis of chiral auxiliary reagent 2-(9-anthryl)-2-hydroxyl ethyl acetate and 2-(9-anthryl)-compounds such as 2-methoxyacetic acid.
For synthesizing of synthetic these chiral auxiliary reagents essential raw material 2-(9-anthryl) of institute-2-carbonylic acetic acid ethyl ester, former report seldom.R.Riguera once delivered about synthetic (the Journal of Organic Chemistry of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester in nineteen ninety-five, 1995,60,504-515), it has only reported that this compound is to be obtained by anthracene and monoethyl oxalate one acyl chloride reaction, but concrete reaction process and preparation method is not described.
The contriver adopts Friedel-Crafts acylation reaction as follows to carry out the synthetic of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester:
Carry out in order to make to be reflected in the homogeneous system, the contriver considered once that the inert substance that the Friedel-Crafts reaction does not take place with oil of mirbane etc. reacted under anhydrous condition as solvent, but the common drawback of these materials is less to the solubleness of anthracene, makes the reaction volume that reaction needed is bigger.Dithiocarbonic anhydride is better than other solvent to the solubility property of anthracene in selected all solvents.Promptly be to be that solvent reacts with dithiocarbonic anhydride, dissolving 1 gram anthracene just needs 200mL dithiocarbonic anhydride under temperature of reaction, and the yield of target product is less than 10%, and also has the acylate of other position except that the 9-position, makes that the purifying of target product is cumbersome.This preparation method obviously is difficult to adapt to a large amount of preparations of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester, and another drawback of this preparation method is that solvent need carry out drying, makes that operation is more loaded down with trivial details.
Summary of the invention
Technical problem to be solved by this invention is to overcome the shortcoming of above-mentioned 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester liquid phase preparation process, and the solvent-free solid phase synthesis process of a kind of productive rate height, product purity height, with short production cycle, environmental pollution is little, production cost is low, product is easy to separate purification 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is provided.
Solving the problems of the technologies described above the technical scheme that is adopted comprises the steps:
1. the pre-treatment of dry reaction case
500～700g discolour silica gel is put into 0.25m
3The dry reaction case in, remove the moisture in the dry reaction case, making the relative humidity in the dry reaction case is 3～8%RH, puts into the sodium hydroxide of 1.5 times of reactant anthracene weight, with the hydrogen chloride gas that produces in the absorption reaction process.
2. solid state reaction
Mortar is placed in the dry reaction case, take by weighing reactant anthracene and monoethyl oxalate one acyl chlorides, catalyzer aluminum trichloride (anhydrous) and promotor 1-Methyl-2-Pyrrolidone, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1～2: 1～2: 0.1～0.4.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m; Speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 1～3 hour, be ground to mixture particle diameter 10～20 μ m, generate the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Its chemical equation is as follows:
3. separate and purify
Mortar is taken out in the dry reaction case, and the trash ice that adds 7.5 times of anthracene consumptions in mortar makes the complex compound of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride be hydrolyzed by following reaction:
After treating that ice melts fully, suction filtration separates, and filter cake is 2-(9-anthryl)-thick product of 2-carbonylic acetic acid ethyl ester; Acetone with 4.5 times of anthracene consumptions carries out recrystallization to thick product again, gets 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester.Product is placed 40 ℃ of dryings in the vacuum drying oven, weigh, analysed preparation purity is calculated productive rate.
4. check
Quality control standards (QCS) by 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is tested.
In the raw materials used proportioning of the present invention, the preferred molar ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1～2: 1～1.5: 0.1～0.3, preferred 2～3 hours griding reaction time.
In the raw materials used proportioning of the present invention, the optimum mole ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 1.5: 0.2, and 2.5 hours best griding reaction time.
The present invention has set up the solvent-free solid phase synthesis process of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester, compare with liquid-phase synthesis process, overcome the cumbersome procedure that solvent must be handled before use, simplified operation steps, shortened reaction time, reduced the generation of byproduct of reaction, overcome liquid phase reaction and can not be used for a large amount of shortcomings that prepare of this material.In reactant, added the promotor 1-Methyl-2-Pyrrolidone, made former productive rate bring up to 92.5% by being lower than 10%.Through a large amount of experimental study, the result shows, the present invention has short, advantage such as post-reaction treatment is simple, product cost is low, productive rate is high, product purity is high, environmental pollution is little reaction time.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail, but the invention is not restricted to these embodiment.
Embodiment 1
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
1. the pre-treatment of dry reaction case
500～700g discolour silica gel is put into 0.25m
3The dry reaction case in, remove the moisture in the dry reaction case, making the relative humidity in the dry reaction case is 3～8%RH, putting into weight is the sodium hydroxide of 1.5 times of reactant anthracene weight, with the hydrogen chloride gas that produces in the absorption reaction process.
2. solid state reaction
Mortar is placed in the dry reaction case, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 26.7g, reactant monoethyl oxalate one acyl chlorides 20.5g and promotor 1-Methyl-2-Pyrrolidone 2.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 1.5: 0.2.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 2.5 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.
3. separate and purify
Mortar is taken out in the dry reaction case, the trash ice that adds 130g in reaction mixture makes the complex compound hydrolysis of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride, after treating that ice melts fully, suction filtration separates, and filter cake is 2-(9-anthryl)-thick product of 2-carbonylic acetic acid ethyl ester; Acetone with 100ml carries out recrystallization to thick product again, gets 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester.Product is placed 40 ℃ of dryings in the vacuum drying oven, get product 25.6g, productive rate is 92.1%.With tlc analysed preparation purity, also available liquid-phase chromatography method analysed preparation purity.
4. check
Quality control standards (QCS) by 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is tested.
Embodiment 2
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 13.4g, reactant monoethyl oxalate one acyl chlorides 13.6g and promotor 1-Methyl-2-Pyrrolidone 1.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1: 1: 0.1.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 3 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 17.6g, productive rate is 63.3%.
Embodiment 3
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 26.7g, reactant monoethyl oxalate one acyl chlorides 27.3g and promotor 1-Methyl-2-Pyrrolidone 4.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 2: 0.4.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 2 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 25.2g, productive rate is 90.6%.
Embodiment 4
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 13.4g, reactant monoethyl oxalate one acyl chlorides 13.6g and promotor 1-Methyl-2-Pyrrolidone 4.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1: 1: 0.4.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 2 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 20.2g, productive rate is 72.7%.
Embodiment 5
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 26.7g, reactant monoethyl oxalate one acyl chlorides 13.6g and promotor 1-Methyl-2-Pyrrolidone 1.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 1: 0.1.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 1 hour, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 19.5g, productive rate is 70.1%.
Embodiment 6
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 26.7g, reactant monoethyl oxalate one acyl chlorides 27.3g and promotor 1-Methyl-2-Pyrrolidone 1.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 2: 0.1.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 2 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 23.8g, productive rate is 85.6%.
Embodiment 7
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 13.4g, reactant monoethyl oxalate one acyl chlorides 27.3g and promotor 1-Methyl-2-Pyrrolidone 4.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1: 2: 0.4.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 3 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 25.3g, productive rate is 91.0%.
Embodiment 8
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 13.4g, reactant monoethyl oxalate one acyl chlorides 27.3g and promotor 1-Methyl-2-Pyrrolidone 1.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1: 2: 0.1.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 1.5 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 19.6g, productive rate is 70.5%.
Embodiment 9
With reaction raw materials anthracene charging capacity is that 0.1 mole of preparation 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is an example, and used raw material and preparation method thereof is as follows:
In the solid state reaction step 2 of present embodiment, take by weighing reactant anthracene 17.8g, catalyzer aluminum trichloride (anhydrous) 26.7g, reactant monoethyl oxalate one acyl chlorides 13.6g and promotor 1-Methyl-2-Pyrrolidone 4.0g, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 1: 0.4.Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m, speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 2.5 hours, being ground to the reaction mixture particle diameter is 10～20 μ m, generates the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride.Other step is identical with embodiment 1.Get product 24.4g, productive rate is 87.7%.
In order to determine the processing step of the best of the present invention, the contriver under 0.1 mole the situation, has carried out a large amount of laboratory study tests, and various test situation are as follows:
Experimental drug: anthracene, chemical pure, the Beijing Chemical Plant produces; Monoethyl oxalate one acyl chlorides, self-control; Aluminum trichloride (anhydrous), analytical pure, experiment reagent company limited in Shanghai produces; 1-Methyl-2-Pyrrolidone, chemical pure, the supply of Shanghai chemical reagents corporation of Chinese Medicine group.
Laboratory apparatus: dry reaction case; Accurate Hygrothermograph is produced by the Fuan City Guangyuan Electromechanical Co.,Ltd, Fujian; Superconduction fourier numeralization nuclear magnetic resonance analyser (300MHz) is produced by Switzerland Bruker company; UV-1 type ultraviolet analysis instrument for three purposed is produced by Shanghai Gu Cun electric light instrument plant; WRS-1B type numeral fusing point instrument is produced by Shanghai Precision Scientific Apparatus Co., Ltd; Fourier transformation infrared spectrometer is produced by German Bruker company.
1. the selection of promotor
Promotor of the present invention is the following pyrrolidones of structural formula, and wherein R can be methyl, ethyl, octyl group, dodecyl, hydroxyethyl.
At normal temperatures and pressures, reacted 2 hours, the mol ratio of getting anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-R-2-pyrrolidone is 1: 2: 1.5:, carried out the influence experiment of different promotors to reaction yield at 0.2 o'clock.
Experimental result sees Table 1.
The different promotor of table 1 is to the influence of reaction yield
| R | Methyl | Ethyl | Octyl group | Dodecyl | Hydroxyethyl |
| Reaction yield | 90.3％ | 78.3％ | 75.2％ | 72.4％ | 65.3％ |
The result shows: under identical reaction conditions, each material mol ratio of participating in reaction is identical, and when R was methyl, reaction yield was 90.3%.Therefore the preferred promotor of the present invention is a 1-Methyl-2-Pyrrolidone, claims the N-N-methyl-2-2-pyrrolidone N-again.Following experimental study all is that promotor carries out condition optimizing with the 1-Methyl-2-Pyrrolidone.
2. the selection of reactant ratio
At normal temperatures and pressures, in 2 hours reaction times, carried out of the influence experiment of the mol ratio of chemical reaction raw material anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone to reaction yield.
Experimental result sees Table 2.
Table 2 chemical reactant mol ratio is to the influence of reaction yield
| Each material mol ratio | 1∶0.5∶0.5∶0.05 | 1∶0.6∶0.8∶0.08 | 1∶1∶1∶0.1 | 1∶2∶1∶0.1 | 1∶2∶1∶0.2 | 1∶2∶1∶0.4 |
| Reaction yield | 35.6％ | 41.3％ | 62.8％ | 71.5％ | 79.9％ | 80.5％ |
| Each material mol ratio | 1∶2∶1.5∶0.1 | 1∶2∶1.5∶0.2 | 1∶2∶1.5∶0.4 | 1∶2∶2∶0.4 | 1∶2.5∶2.5∶0.5 | 1∶3∶2.8∶0.8 |
| Reaction yield | 85.6％ | 90.3％ | 90.7％ | 90.6％ | 90.8％ | 90.7％ |
The result shows: under the normal temperature and pressure, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is lower than 1: 1: 1: 0.1 o'clock, productive rate was lower than 62.8%; The mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 1.5: 0.2 o'clock, productive rate was 90.3%; Increase the consumption of aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone on this basis, productive rate is not significantly improved.The molar ratio range of chemical reaction raw material anthracene that is adopted among the present invention and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1～2: 1～2: 0.1～0.4.
3. the selection of chemical time
At normal temperatures and pressures, the mol ratio of getting anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 1.5:, carried out the influence experiment of chemical time to reaction yield at 0.2 o'clock.
Experimental result sees Table 3.
Table 3 chemical time is to the influence of reaction yield
| Reaction times | 0.5 hour | 1 hour | 1.5 hour | 2 hours | 2.5 hour | 3 hours | 4 hours |
| Reaction yield | 45.8％ | 70.1％ | 72.7％ | 90.3％ | 92.1％ | 92.4％ | 92.5％ |
The result shows: under identical reaction conditions, each material mol ratio of participating in reaction is identical, and along with the prolongation in reaction times, reaction yield increases; The griding reaction time is less than 1 hour, and productive rate is lower; The griding reaction time surpassed after 2.5 hours, and gain in yield is not obvious.The griding reaction time range that is adopted among the present invention is 1～3 hour, and the best griding reaction time is 2.5 hours.
In order to verify beneficial effect of the present invention, the contriver adopts 2-(9-the anthryl)-2-carbonylic acetic acid ethyl ester of the embodiment of the invention 1 preparation to test, and various test situation are as follows:
1. use the structure of superconduction fourier numeralization nuclear magnetic resonance analyser test chemical reaction product
With the structure of superconduction fourier numeralization nuclear magnetic resonance analyser test reaction product, test result is as follows:
1H NMR(300MHz，(CD
3)
2CO)δ(ppm)：1.30(t，3H)，4.37(q，2H)，7.61(m，2H)，7.67(m，2H)，7.99(m，2H)，8.19(m，2H)，8.79(t，1H)。
13C NMR(300MHz，(CD
3)
2CO)δ(ppm)：14.3，63.5，124.8，126.8，129.1，130.0，130.1，131.2，131.9，132.1，162.8，193.1。
2. test the structure of chemical reaction product with Fourier transformation infrared spectrometer
With the structure of Fourier transformation infrared spectrometer test reaction product, test result is as follows:
IR(KBr)3051，2948，2301，1725，1600，1451，1400，1302，1250，1100cm
-1。
3. product property is identified
2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is pale brown look solid, and recording fusing point with WRS-1B type numeral fusing point instrument is 83.8-84.7 ℃, dissolves in acetone and other organic solvent.Adopt silica gel thin-layer chromatography that the synthetic 2-of institute (9-anthryl)-2-carbonylic acetic acid ethyl ester is carried out the product purity analysis.With tlc silica gel GF
254The phase that fixes, under the situation with toluene or chloroform give developping agent, the Rf value of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is respectively 0.51 or 0.62; 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is being viewed as a glassy yellow spot under visible light on the chromatographic sheet, at wavelength be to be viewed as a blackening under the UV-1 type ultraviolet analysis instrument for three purposed of 254nm.
Claims (3)
1. the solid phase synthesis process of a 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is characterized in that it comprises the steps:
(1) pre-treatment of dry reaction case
500～700g discolour silica gel is put into 0.25m
3The dry reaction case in, the relative humidity in the control dry reaction case is 3～8%RH, puts into the sodium hydroxide of 1.5 times of reactant anthracene weight;
(2) solid state reaction
Mortar is placed in the dry reaction case, take by weighing reactant anthracene and monoethyl oxalate one acyl chlorides, catalyzer aluminum trichloride (anhydrous) and promotor 1-Methyl-2-Pyrrolidone, the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1～2: 1～2: 0.1～0.4; Earlier anthracene and aluminum trichloride (anhydrous) are placed in the mortar and grind, grind evenly, being ground to particle diameter is 10～20 μ m; Speed with 3～5 of per minutes alternately drips monoethyl oxalate one acyl chlorides and 1-Methyl-2-Pyrrolidone, grind while dripping, griding reaction 1～3 hour, being ground to the mixture particle diameter is 10～20 μ m, generate the complex compound and the hydrogen chloride gas of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride, its chemical equation is as follows:
(3) separate purification
Mortar is taken out in the dry reaction case, the trash ice that adds 7.5 times of anthracene consumptions in reaction mixture makes the complex compound hydrolysis of 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester and aluminum chloride, after treating that ice melts fully, suction filtration separates, and filter cake is 2-(9-anthryl)-thick product of 2-carbonylic acetic acid ethyl ester; Acetone with 4.5 times of anthracene consumptions carries out recrystallization to thick product again, gets 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester; Product is placed 40 ℃ of dryings in the vacuum drying oven, weigh, analysed preparation purity is calculated productive rate;
(4) check
Quality control standards (QCS) by 2-(9-anthryl)-2-carbonylic acetic acid ethyl ester is tested.
2. according to the solid phase synthesis process of the described 2-of claim 1 (9-anthryl)-2-carbonylic acetic acid ethyl ester, it is characterized in that: in proportioning raw materials, wherein the mol ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 1～2: 1～1.5: 0.1～0.3, and wherein griding reaction is 2～3 hours.
3. according to the solid phase synthesis process of the described 2-of claim 1 (9-anthryl)-2-carbonylic acetic acid ethyl ester, it is characterized in that: in proportioning raw materials, wherein the optimum mole ratio of anthracene and aluminum trichloride (anhydrous), monoethyl oxalate one acyl chlorides, 1-Methyl-2-Pyrrolidone is 1: 2: 1.5: 0.2, and 2.5 hours best griding reaction time.
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