CN101092338A - Method for prepring compound of beta hydroxyketone in supercritical liquid of carbon dioxide - Google Patents
Method for prepring compound of beta hydroxyketone in supercritical liquid of carbon dioxide Download PDFInfo
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Abstract
This invention discloses a method for preparing beta-hydroxy ketones in supercritical CO2 fluid. The method comprises: preparing crude beta-hydroxy ketone compounds, separating and purifying. The method performs asymmetric aldol condensation reaction on acetone and different aldehyde compounds catalyzed by L-proline in supercritical CO2 fluid. The method solves the problems serious environmental pollution and complex post treatment faced by traditional organic solvent method. The method has such advantages as no need for organic solvent, little environmental pollution, high productivity and high enantio selectivity of the catalyst. The proton NMR spectrum of the product is identical to that of 4-(4-nitrophenyl)-4-hydroxyl-2-butanone. The method has such advantages as reasonable design, simple process, little pollution, high yield, and high enantio selectivity of the catalyst.
Description
Technical field
The invention belongs to synthetic beta-hydroxy ketone, α, beta-unsaturated carbonyl compound and 1, organism intermediary material technical fields such as 2-glycol are specifically related to the preparation method of beta-hydroxy ketone compound in supercritical carbon dioxide fluid.
Background technology
The chiral beta-hydroxy ketone compound is the important intermediate of a lot of natural product asymmetric synthesis.Carbonyl and hydroxyl are active group, can change into adjacent glycol, beta-amino ketones and other functional group.
Aldol reaction is the important reaction that a class forms C-C, can be used for synthesizing beta-hydroxy ketone, α, beta-unsaturated carbonyl compound and 1, organism such as 2-glycol.In natural product synthetic, asymmetric aldol reaction has obtained using very widely.
The commercial run of the aldehydes of synthetic beta-hydroxy ketone compound and the aldol reaction of ketone has used catalyzer, as the dilute solution of potassium hydroxide and sodium hydroxide.But last what react, it is very difficult separating these catalyzer, needs to add acid solution, especially sulfuric acid, catalyzer is converted into corresponding salt, and will removes the salt that has generated, and this is very big in industrial investment.The proline(Pro) small molecules has shown the chiral catalysis performance of the asymmetric direct aldol reaction of good catalysis ketone and aldehyde, but all research all carries out in organic solvent, and in the reaction of organic solvent, major part is all used dimethyl sulfoxide (DMSO).The solvability of proline(Pro) in dimethyl sulfoxide (DMSO) is bad, has limited the speed and the catalytic efficiency of this reaction.And dimethyl sulfoxide (DMSO) makes solvent because its boiling point is higher, handles complicatedly in the purification of product and purge process, has with an organic solvent polluted environment.Use ionic liquid as solvent, because its complex synthetic route, and price is more expensive, thereby it is applied in the research of present stage and also is restricted.
Asymmetry catalysis is the most effective cheap important method that obtains chipal compounds, although it has many good qualities, but the practical application of asymmetry catalysis still is restricted, and high enantioselectivity can only obtain in some specific solvent, and a lot of solvents pollute environment.Supercutical fluid uniqueness and potential advantage are exactly that character such as its density, polarity, diffustivity can change with pressure or variation of temperature, and the reaction medium of the new non-environmental-pollution of a class is provided for chemical reaction.Therefore, as reaction medium, the preparation organic compound has great importance for the Sustainable development of the industry such as chemical industry, pharmacy and the whole society with supercritical carbon dioxide fluid.
Summary of the invention
Technical problem to be solved by this invention is to overcome the shortcoming of above-mentioned beta-hydroxy ketone compounds process for production thereof, provides that a kind of processing step is simple, environmental pollution is little, the preparation method of the enantioselectivity of productive rate and catalyzer is high in supercritical carbon dioxide fluid beta-hydroxy ketone compound.
Solving the problems of the technologies described above the technical scheme that is adopted comprises the steps:
1, preparation beta-hydroxy ketone compound crude product
In the supercritical, high pressure reactor, add acetone and different substrate aldehyde compounds, the mol ratio of different substrate aldehyde compounds and acetone is 1: 10～30, add catalyzer L-proline(Pro), the mol ratio of different substrate aldehyde compounds and L-proline(Pro) is 1: 0.05～0.3, sealed reactor charges into CO with the high pressure micro-injection pump
2It is 10～35MPa that liquid is charged to pressure, and 30～60 ℃ were reacted 15～36 hours, and chemical equation is as follows:
(1) R is p-nitrophenyl or m-nitro base or ortho-nitrophenyl base or phenyl or to bromophenyl or rubigan or p-methoxyphenyl or 2-naphthyl in the formula, R is preferably p-nitrophenyl or m-nitro base or ortho-nitrophenyl base rubigan, and R the best is a p-nitrophenyl.After reaction is finished, emit CO
2, ethyl acetate is joined reactor to reaction product dissolve, take out solution, remove by filter catalyzer L-proline(Pro), filtrate at 40 ℃ of rotary evaporations, is prepared into beta-hydroxy ketone compound crude product with Rotary Evaporators.
2, separate purification
The beta-hydroxy ketone compound crude product of step 1 preparation is separated with the column chromatography chromatogram partition method, and 20～60 ℃, vacuum tightness are 0.09MPa, dry 12 hours in vacuum drying oven, are prepared into the beta-hydroxy ketone compound.
In the preparation beta-hydroxy ketone compound crude product 1 of the present invention, in the supercritical, high pressure reactor, add acetone and different substrate aldehyde compounds, the preferred molar ratio of different substrate aldehyde compounds and acetone is 1: 20～30, add catalyzer L-proline(Pro), the preferred molar ratio of different substrate aldehyde compounds and L-proline(Pro) is 1: 0.1～0.3, sealed reactor charges into CO with the high pressure micro-injection pump
2Liquid is charged to pressure and is preferably 20～35MPa, 40～60 ℃ of preferred reaction 24～36 hours.
In the preparation beta-hydroxy ketone compound crude product 1 of the present invention, in the supercritical, high pressure reactor, add acetone and different substrate aldehyde compounds, the optimum mole ratio of different substrate aldehyde compounds and acetone is 1: 30, add catalyzer L-proline(Pro), the optimum mole ratio of different substrate aldehyde compounds and L-proline(Pro) is 1: 0.15, sealed reactor charges into CO with the high pressure micro-injection pump
2Liquid is charged to that pressure is best to be 35MPa, 50 ℃ of optimum responses 30 hours.
The present invention carries out the asymmetric aldol reaction of L-proline(Pro) catalysis acetone and different substrate aldehyde compounds in supercritical carbon dioxide fluid, overcome the shortcoming of conventional organic solvents environmental pollution, aftertreatment technology step complexity, do not add any organic solvent, reduced pollution, improved the enantioselectivity of productive rate and catalyzer environment.Adopt the product superconduction fourier numeralization nmr determination of the embodiment of the invention 1 preparation, the hydrogen nuclear magnetic resonance spectrogram is consistent with 4-(4-nitrophenyl)-4-hydroxyl-2-butanone structure.That the present invention has is reasonable in design, technology is simple, environmental pollution is little, the enantioselectivity advantages of higher of productive rate and catalyzer, can be used for preparing the beta-hydroxy ketone compound.
Description of drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram that adopts 4-(4-the nitrophenyl)-4-hydroxyl-2-butanone of the embodiment of the invention 1 preparation.
Embodiment
The present invention is described in more detail below in conjunction with drawings and Examples, but the invention is not restricted to these embodiment.
Embodiment 1
Used raw material paranitrobenzaldehyde 0.5g is that example used other raw material and processing step are as follows with preparation 4-(4-nitrophenyl)-4-hydroxyl-2-butanone:
1, preparation beta-hydroxy ketone compound crude product
In the supercritical, high pressure reactor, add acetone 5.76g and paranitrobenzaldehyde 0.5g, the mol ratio of paranitrobenzaldehyde 0.5g and acetone is 1: 30, add catalyzer L-proline(Pro) 0.057g, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) is 1: 0.15, sealed reactor charges into CO with the high pressure micro-injection pump
2It is 35MPa that liquid is charged to pressure, and 50 ℃ were reacted 30 hours, and chemical equation is as follows:
After reaction is finished, emit CO
2, ethyl acetate is joined reactor to reaction product dissolve, take out solution, remove by filter catalyzer L-proline(Pro), filtrate at 40 ℃ of rotary evaporations, is prepared into 4-(4-nitrophenyl)-4-hydroxyl-2-butanone crude product with Rotary Evaporators.
2, separate purification
4-(4-nitrophenyl)-4-hydroxyl-2-butanone crude product of step 1 preparation is separated with the column chromatography chromatogram partition method, and 20～60 ℃, vacuum tightness are 0.09MPa, dry 12 hours in vacuum drying oven, are prepared into 4-(4-nitrophenyl)-4-hydroxyl-2-butanone.
Embodiment 2
Used raw material paranitrobenzaldehyde 0.5g is that example used other raw material and processing step are as follows with preparation 4-(4-nitrophenyl)-4-hydroxyl-2-butanone:
In preparation beta-hydroxy ketone compound crude product processing step 1, in the supercritical, high pressure reactor, add acetone 1.92g and paranitrobenzaldehyde 0.5g, the mol ratio of paranitrobenzaldehyde 0.5g and acetone is 1: 10, add catalyzer L-proline(Pro) 0.114g, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) is 1: 0.3, sealed reactor charges into CO with the high pressure micro-injection pump
2It is 20MPa that liquid is charged to pressure, and 60 ℃ were reacted 15 hours.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Embodiment 3
Used raw material paranitrobenzaldehyde 0.5g is that example used other raw material and processing step are as follows with preparation 4-(4-nitrophenyl)-4-hydroxyl-2-butanone:
In preparation beta-hydroxy ketone compound crude product processing step 1, in the supercritical, high pressure reactor, add acetone 3.84g and paranitrobenzaldehyde 0.5g, the mol ratio of paranitrobenzaldehyde and acetone is 1: 20, add catalyzer L-proline(Pro) 0.02g, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) is 1: 0.05, sealed reactor charges into CO with the high pressure micro-injection pump
2It is 10MPa that liquid is charged to pressure, and 30 ℃ were reacted 36 hours.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Embodiment 4
Used stock yard nitrobenzaldehyde 0.5g is that example used other raw material and processing step are as follows with preparation 4-(3-nitrophenyl)-4-hydroxyl-2-butanone:
In the preparation beta-hydroxy ketone compound crude product processing step 1 of embodiment 1～3, used raw material paranitrobenzaldehyde is replaced with m-nitrobenzaldehyde, consumption is 0.5g, and the consumption of acetone is identical with respective embodiments, and promptly m-nitrobenzaldehyde is identical with the mol ratio and the respective embodiments of acetone.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Embodiment 5
Used raw material Ortho Nitro Benzaldehyde 0.5g is that example used other raw material and processing step are as follows with preparation 4-(2-nitrophenyl)-4-hydroxyl-2-butanone:
In the preparation beta-hydroxy ketone compound crude product processing step 1 of embodiment 1～3, used raw material paranitrobenzaldehyde is replaced with Ortho Nitro Benzaldehyde, consumption is 0.5g, and the consumption of acetone is identical with respective embodiments, and promptly Ortho Nitro Benzaldehyde is identical with the mol ratio and the respective embodiments of acetone.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Embodiment 6
Phenyl-the used benzene feedstock formaldehyde 0.35g of 4-hydroxyl-2-butanone is that example used other raw material and processing step are as follows with preparation 4-:
In the preparation beta-hydroxy ketone compound crude product processing step 1 of embodiment 1～3, used raw material paranitrobenzaldehyde is replaced with phenyl aldehyde, consumption is 0.35g, and the consumption of acetone is identical with respective embodiments, and promptly phenyl aldehyde is identical with the mol ratio and the respective embodiments of acetone.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Embodiment 7
Used raw material p-bromobenzaldehyde 0.61g is that example used other raw material and processing step are as follows with preparation 4-(4-bromophenyl)-4-hydroxyl-2-butanone:
In the preparation beta-hydroxy ketone compound crude product processing step 1 of embodiment 1～3, used raw material paranitrobenzaldehyde is replaced with p-bromobenzaldehyde, consumption is 0.61g, and the consumption of acetone is identical with respective embodiments, and promptly p-bromobenzaldehyde is identical with the mol ratio and the respective embodiments of acetone.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Used raw material 4-chloro-benzaldehyde 0.46g is that example used other raw material and processing step are as follows with preparation 4-(4-chloro-phenyl-)-4-hydroxyl-2-butanone:
In the preparation beta-hydroxy ketone compound crude product processing step 1 of embodiment 1～3, used raw material paranitrobenzaldehyde is replaced with 4-chloro-benzaldehyde, consumption is 0.46g, and the consumption of acetone is identical with respective embodiments, and promptly 4-chloro-benzaldehyde is identical with the mol ratio and the respective embodiments of acetone.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Embodiment 9
Used raw material aubepine 0.45g is that example used other raw material and processing step are as follows with preparation 4-(4-p-methoxy-phenyl)-4-hydroxyl-2-butanone:
In the preparation beta-hydroxy ketone compound crude product processing step 1 of embodiment 1～3, used raw material paranitrobenzaldehyde is replaced with aubepine, consumption is 0.45g, the consumption of acetone is identical with respective embodiments, and promptly aubepine is identical with the mol ratio and the respective embodiments of acetone.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
Used raw material 2-naphthaldehyde 0.52g is that example used other raw material and processing step are as follows with preparation 4-(2-naphthyl)-4-hydroxyl-2-butanone:
In the preparation beta-hydroxy ketone compound crude product processing step 1 of embodiment 1～3, used raw material paranitrobenzaldehyde is replaced with the 2-naphthaldehyde, consumption is 0.52g, and the consumption of acetone is identical with respective embodiments, and promptly the 2-naphthaldehyde is identical with the mol ratio and the respective embodiments of acetone.Other step in this processing step is identical with embodiment 1.
Other step is identical with embodiment 1.
In order to determine the processing step of the best of the present invention, the contriver has carried out a large amount of laboratory study tests, and various test situation are as follows:
Laboratory apparatus: SF-400 type autoclave, Powerise Science and Technology Ltd. is closed in Beijing four; Superconduction fourier numeralization nuclear magnetic resonance analyser, model is AVANCF300MHZ, is produced by Switzerland Bruker company; High pressure liquid chromatograph, model are CO325P977M, are produced by U.S. waters company; Chiral separation post, model are AS-H, are produced by Japanese Daicel Chemical Industries.
1, the selection of proportioning raw materials
The contriver has investigated the influence of reactant acetone with different proportionings right title aldol reaction in supercritical carbon dioxide fluid of paranitrobenzaldehyde.
With acetone and paranitrobenzaldehyde is reactant, in the supercritical, high pressure reactor, add paranitrobenzaldehyde 0.5g, take by weighing acetone 0.958g, 1.917g, 3.833g, 5.75g respectively, the mol ratio of paranitrobenzaldehyde and acetone is 1: 5,1: 10,1: 20,1: 30, add catalyzer L-proline(Pro) 0.114g again, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) is 1: 0.15, and sealed reactor charges into CO with the high pressure micro-injection pump
2It is 35MPa that liquid is charged to pressure, and temperature of reaction is 40 ℃, and the reaction times is 30 hours, investigates the influence of the different proportionings with acetone of paranitrobenzaldehyde right title aldol reaction in supercritical carbon dioxide fluid.Prepared product is tested with high performance liquid chromatograph, and enantiomeric excess value is calculated as follows:
ee＝(R-S)/(R+S)×100％ (3)
In formula (3), ee is an enantiomeric excess value, and R is the concentration of cis-product, and S is the concentration of trans product.
Test and calculation result inspection the results are shown in Table 1.
The influence of table 1 paranitrobenzaldehyde and the right title aldol reaction of different proportionings of acetone
| Numbering | Paranitrobenzaldehyde and acetone mol ratio | Productive rate (%) | Enantiomeric excess value (%) |
| 1 | 1∶5 | 13.0 | 78.2 |
| 2 | 1∶10 | 42.1 | 79.3 |
| 3 | 1∶20 | 50.0 | 77.0 |
| 4 | 1∶30 | 68.1 | 80.0 |
By table 1 as seen, under identical reaction conditions, the mol ratio of paranitrobenzaldehyde and acetone is 1: 10～30 o'clock, productive rate and enantioselectivity be higher, wherein mol ratio is that 1: 30 o'clock productive rate and enantioselectivity are the highest, the present invention select paranitrobenzaldehyde and acetone rub than be 1: 10～30, the best is 1: 30.
2, the selection of catalyzer L-proline(Pro) consumption
The contriver has investigated the influence of different catalyzer L-proline(Pro) consumption asymmetric aldol reactions of catalysis in supercritical carbon dioxide fluid to paranitrobenzaldehyde and acetone.
With paranitrobenzaldehyde and acetone is reactant, with the L-proline(Pro) is catalyzer, in the supercritical, high pressure reactor, add acetone 3.83g, paranitrobenzaldehyde 0.5g, the mol ratio of paranitrobenzaldehyde and acetone is 1: 20, the consumption of L-proline(Pro) is respectively 0.004,0.019,0.038,0.057,0.076,0.114, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) was respectively 1: 0.01,1: 0.05,1: 0.1,1: 0.15,1: 0.2,1: 0.3, reaction pressure is 35MPa, temperature of reaction is 50 ℃, in 30 hours reaction times, it is 1 identical that used equipment and other step and the selection of proportioning raw materials are tested.The influence of the different amounts of having investigated the L-proline(Pro) asymmetric aldol reaction of L-proline(Pro) catalysis acetone and paranitrobenzaldehyde in supercritical carbon dioxide fluid.Enantiomeric excess value calculates by formula (3).Test and calculation result inspection the results are shown in Table 2.
The influence of the right title aldol reaction of table 2 catalyst consumption
| Numbering | Catalyst levels (g) | Productive rate (%) | Enantiomeric excess value (%) |
| 1 | 0.004 | 6.70 | 75.0 |
| 2 | 0.019 | 34.3 | 74.0 |
| 3 | 0.038 | 53.0 | 78.6 |
| 4 | 0.057 | 62.1 | 79.2 |
| 5 | 0.076 | 50.0 | 77.0 |
| 6 | 0.114 | 48.1 | 80.0 |
By table 2 as seen, under identical reaction conditions, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) is 1: 0.05～1: 0.3 o'clock, productive rate and enantioselectivity are higher, wherein the mol ratio of paranitrobenzaldehyde and catalyzer L-proline(Pro) is 1: 0.15 o'clock, productive rate is the highest, enantiomeric excess value is 79.2, and it is that 1: 0.05～1: 0.3, optimum mole ratio are 1: 0.15 that the present invention selects the mol ratio of paranitrobenzaldehyde and L-proline(Pro).
3, the selection in reaction times
The contriver has investigated the influence of reaction times to the asymmetric aldol reaction of catalyzer L-proline(Pro) catalysis acetone and paranitrobenzaldehyde in supercritical carbon dioxide fluid.
With acetone and paranitrobenzaldehyde is reactant, in the supercritical, high pressure reactor, add acetone 3.83g and paranitrobenzaldehyde 0.5g, the mol ratio of paranitrobenzaldehyde and acetone is 1: 20, add catalyzer L-proline(Pro) 0.114g, the mol ratio of paranitrobenzaldehyde and catalyzer L-proline(Pro) is 1: 0.3, and reaction pressure is 20MPa, and temperature of reaction is 40 ℃, in 5,10,15,20,24,30,36 hours reaction times, used equipment is identical with the selection of proportioning raw materials with other step.Investigate of the influence of differential responses time to the asymmetric aldol reaction of L-proline(Pro) catalysis acetone and paranitrobenzaldehyde in the supercritical carbon dioxide fluid.Prepared product 4-(4-nitrophenyl)-4-hydroxyl-2-butanone is tested with high performance liquid chromatograph, and enantiomeric excess value calculates by (4) formula, and transformation efficiency is calculated as follows:
In the formula (4), C is a transformation efficiency, M
1Weight, M for the paranitrobenzaldehyde that adds
2Weight for unreacted paranitrobenzaldehyde.Test and calculation result see Table 3.
By table 3 as seen, under identical reaction conditions, along with the increase in reaction times, transformation efficiency increases gradually, and the reaction times is 30,36 hours, and transformation efficiency reaches 100%.The selective reaction time of the present invention is 15～36 hours, and optimum reacting time is 30 hours.
The table 3 differential responses time is to the influence of aldol reaction
| Numbering | Time (hour) | Transformation efficiency (%) | Productive rate (%) | Enantiomeric excess value (%) |
| 1 | 5 | 11 | 2.1 | 74.0 |
| 2 | 10 | 20 | 5.6 | 76.4 |
| 3 | 15 | 64 | 13.9 | 75.5 |
| 4 | 20 | 83 | 15.3 | 76.3 |
| 5 | 24 | 92 | 22.7 | 78.0 |
| 6 | 30 | 100 | 48.1 | 76.0 |
| 7 | 36 | 100 | 50.1 | 80.0 |
Transformation efficiency in the table refers to the transformation efficiency of paranitrobenzaldehyde.
4, the selection of temperature of reaction
The contriver has investigated temperature of reaction 0～60 ℃ of influence to the asymmetric aldol reaction of catalyzer L-proline(Pro) catalysis acetone and paranitrobenzaldehyde in supercritical carbon dioxide fluid.
With acetone and paranitrobenzaldehyde is reactant, in the supercritical, high pressure reactor, add acetone 3.83g, paranitrobenzaldehyde 0.5g, the mol ratio of paranitrobenzaldehyde and acetone is 1: 20, add L-proline(Pro) 0.114g, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) is 1: 0.3, reaction pressure is 20MPa, and temperature of reaction is respectively 0,10,18,30,35,40,50,60 ℃, and the reaction times is 30 hours.It is 1 identical that used equipment and other step and the selection of proportioning raw materials are tested.Investigate the influence of temperature to the asymmetric aldol reaction of L-proline(Pro) catalysis acetone and paranitrobenzaldehyde in the supercritical carbon dioxide fluid.Prepared product 4-(4-nitrophenyl)-4-hydroxyl-2-butanone is tested with high performance liquid chromatograph, and enantiomeric excess value calculates by (3).Test sees Table 4 with calculation result.
The influence of the right title aldol reaction of table 4 temperature of reaction
| Numbering | Temperature (℃) | Productive rate (%) | Enantiomeric excess value (%) |
| 1 | 0 | 0 | 0 |
| 2 | 10 | 0 | 0 |
| 3 | 18 | 13.9 | 75.5 |
| 4 | 30 | 15.3 | 76.3 |
| 5 | 35 | 22.7 | 78.0 |
| 6 | 40 | 48.1 | 76.0 |
| 7 | 50 | 53.0 | 80.0 |
| 8 | 60 | 38.0 | 73.0 |
By table 2 as seen, under identical reaction conditions, temperature of reaction productive rate in 30～60 ℃ is higher, and 50 ℃ of productive rates are the highest, and enantioselectivity is also the highest, and selective reaction temperature of the present invention is at 30～60 ℃, and 50 ℃ is optimal reaction temperature.
5, the selection of reaction pressure
The contriver has investigated the influence of pressure 10～35MPa asymmetric aldol reaction of catalyzer L-proline(Pro) catalysis acetone and paranitrobenzaldehyde in supercritical carbon dioxide fluid.
With acetone and paranitrobenzaldehyde is reactant, in the supercritical, high pressure reactor, add acetone 3.83g, paranitrobenzaldehyde 0.5g, L-proline(Pro) 0.114g, the mol ratio of paranitrobenzaldehyde and acetone is 1: 20, the mol ratio of paranitrobenzaldehyde and L-proline(Pro) is 1: 0.3, reaction pressure is respectively 10,15,20,25,30,35MPa, temperature of reaction is 50 ℃, 30 hours reaction times, and it is 1 identical that used equipment and other step and the selection of proportioning raw materials are tested.Investigate the influence of different reaction pressures asymmetric aldol reaction of L-proline(Pro) catalysis acetone and paranitrobenzaldehyde in supercritical carbon dioxide fluid.Enantiomeric excess value calculates by formula (3), and test and calculation result see Table 5.
The influence of the right title aldol reaction of table 5 different pressures
| Numbering | Reaction pressure (MPa) | Productive rate (%) | Enantiomeric excess value (%) |
| 1 | 10 | 30.0 | 73.0 |
| 2 | 15 | 35.0 | 73.5 |
| 3 | 20 | 53.0 | 80.3 |
| 4 | 25 | 55.0 | 79.2 |
| 5 | 30 | 61.0 | 80.0 |
| 6 | 35 | 65.0 | 80.5 |
By table 5 as seen, under identical reaction conditions, reaction pressure is in 10～35MPa scope, increase along with pressure, the productive rate of product and enantioselectivity portion increase, reaction pressure productive rate and enantioselectivity when 35MPa is the highest, and selective reaction pressure of the present invention is 10～35MPa, and optimum response pressure is 35MPa.
6.L-the asymmetric aldol reaction of catalytic different substrate aldehyde compounds of proline(Pro) and acetone
The contriver has investigated acetone and different substrate aldehyde compounds asymmetric aldol reaction of L-proline(Pro) catalysis in supercritical carbon dioxide fluid.
Is reactant with acetone with different substrate aldehyde compounds, in the supercritical, high pressure reactor, add different substrate aldehyde compound paranitrobenzaldehydes respectively, Ortho Nitro Benzaldehyde, m-nitrobenzaldehyde, phenyl aldehyde, 4-chloro-benzaldehyde, p-bromobenzaldehyde, the 2-naphthaldehyde, each 0.5g of aubepine, the adding weight of corresponding acetone is respectively 5.76g, 5.76g, 5.76g, 8.21g, 6.2g, 4.71g, 5.58g, 6.40g, 7.31g, rubbing than being 1: 30 of different substrate aldehyde compounds and acetone, the mol ratio of different substrate aldehyde compounds and L-proline(Pro) is 1: 0.15, reaction pressure is 35MPa in supercritical carbon dioxide fluid, temperature of reaction is 40 ℃, in 30 hours reaction times, it is 1 identical that used equipment and other step and the selection of proportioning raw materials are tested.Investigate of the influence of different substrate aldehyde compounds to L-proline(Pro) asymmetric aldol reaction of catalysis in supercritical carbon dioxide fluid.Enantiomeric excess value calculates by formula (3).Test and calculation result inspection the results are shown in Table 7.
The asymmetric aldol reaction result of different substrate aldehyde compounds of table 7 L-proline(Pro) catalysis and acetone
| Numbering | Aldehyde compound (0.5g) | Productive rate (%) | Enantiomeric excess value (%) |
| 1 | Paranitrobenzaldehyde | 68.1 | 80.0 |
| 2 | Ortho Nitro Benzaldehyde | 78.3 | 81.0 |
| 3 | M-nitrobenzaldehyde | 79.4 | 80.6 |
| 4 | Phenyl aldehyde | 63.4 | 75.0 |
| 5 | 4-chloro-benzaldehyde | 67.8 | 79.5 |
| 6 | P-bromobenzaldehyde | 61.3 | 75.0 |
| 7 | The 2-naphthaldehyde | 67.0 | 74.0 |
| 8 | Aubepine | 30.0 | 76.0 |
By table 7 as seen, under identical reaction conditions, the productive rate of the phenyl aldehyde generation product that phenyl aldehyde that nitro replaces and chlorine replace is higher, and its enantioselectivity of the compound of contraposition is low than adjacent.
In order to verify beneficial effect of the present invention, the contriver adopts the structure of 4-(4-the nitrophenyl)-4-hydroxyl-2-butanone of the embodiment of the invention 1 preparation superconduction fourier numeralization nmr determination, the results are shown in Figure 1.
1H NMR(CDCl
3δ2.23(s，3H，CH
3)，2.85-2.86(m，2H，CH
2)，3.59(d，J＝2.9Hz，1H，OH)，5.26-5.28(m，1H，-CH-)，7.55(d，J＝8.1Hz，2H，ArH)，8.22(d，J＝8.1Hz，2H，ArH)。
As seen from Figure 1, the hydrogen nuclear magnetic resonance spectrogram of prepared compound is consistent with 4-(4-nitrophenyl)-4-hydroxyl-2-butanone structure.
Claims (5)
1, a kind of in supercritical carbon dioxide fluid the preparation method of beta-hydroxy ketone compound, it is characterized in that it comprises the steps:
(1) preparation beta-hydroxy ketone compound crude product
In the supercritical, high pressure reactor, add acetone and different substrate aldehyde compounds, the mol ratio of different substrate aldehyde compounds and acetone is 1: 10～30, add catalyzer L-proline(Pro), the mol ratio of different substrate aldehyde compounds and L-proline(Pro) is 1: 0.05～0.3, sealed reactor charges into CO with the high pressure micro-injection pump
2It is 10～35MPa that liquid is charged to pressure, and 30～60 ℃ were reacted 15～36 hours, and chemical equation is as follows:
(1) R is p-nitrophenyl or m-nitro base or ortho-nitrophenyl base or phenyl or to bromophenyl or rubigan or p-methoxyphenyl or 2-naphthyl in the formula, after reaction is finished, emits CO
2, ethyl acetate is joined reactor to reaction product dissolve, take out solution, remove by filter catalyzer L-proline(Pro), filtrate at 40 ℃ of rotary evaporations, is prepared into beta-hydroxy ketone compound crude product with Rotary Evaporators;
(2) separate purification
The beta-hydroxy ketone compound crude product of step (1) preparation is separated with the column chromatography chromatogram partition method, and 20～60 ℃, vacuum tightness are 0.09MPa, dry 12 hours in vacuum drying oven, are prepared into the beta-hydroxy ketone compound.
2, according to claim 1 described in supercritical carbon dioxide fluid the preparation method of beta-hydroxy ketone compound, it is characterized in that: said in preparation beta-hydroxy ketone compound crude product (1), in the supercritical, high pressure reactor, add acetone and different substrate aldehyde compounds, the mol ratio of different substrate aldehyde compounds and acetone wherein is 1: 20～30, add catalyzer L-proline(Pro), the mol ratio of different substrate aldehyde compounds and L-proline(Pro) wherein is 1: 0.1～0.3, sealed reactor charges into CO with the high pressure micro-injection pump
2It wherein is 20～35MPa that liquid is charged to pressure, and 40～60 ℃ were wherein reacted 24～36 hours.
3, according to claim 1 described in supercritical carbon dioxide fluid the preparation method of beta-hydroxy ketone compound, it is characterized in that: in the said preparation beta-hydroxy ketone compound crude product (1), in the supercritical, high pressure reactor, add acetone and different substrate aldehyde compounds, the mol ratio of different substrate aldehyde compounds and acetone wherein is 1: 30, add catalyzer L-proline(Pro), the mol ratio of different substrate aldehyde compounds and L-proline(Pro) wherein is 1: 0.15, sealed reactor charges into CO with the high pressure micro-injection pump
2Liquid is charged to pressure and wherein is 35MPa, and 50 ℃ were wherein reacted 30 hours.
4, according to claim 1 described in supercritical carbon dioxide fluid the preparation method of beta-hydroxy ketone compound, it is characterized in that: R wherein is p-nitrophenyl or m-nitro base or ortho-nitrophenyl base rubigan in said chemical equation (1) formula.
5, according to claim 1 described in supercritical carbon dioxide fluid the preparation method of beta-hydroxy ketone compound, it is characterized in that: R wherein is p-nitrophenyl in said chemical equation (1) formula.
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