CN114933558A - Method for preparing chiral amino compound by catalytic reduction of chiral nitro compound - Google Patents
Method for preparing chiral amino compound by catalytic reduction of chiral nitro compound Download PDFInfo
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Abstract
The invention discloses a method for preparing a chiral amino compound by catalytic reduction of a chiral nitro compound, which comprises the following steps: in the hydrogen atmosphere, under the action of a reaction solvent and an additive, the chiral nitro compound I is subjected to catalytic hydrogenation reaction under the catalytic action of a catalyst to generate a chiral amino compound II. Compared with the prior art, the method provided by the invention has the advantages of relatively simple operation, mild conditions, high chiral purity of the product, obviously improved yield and better application prospect.
Description
Technical Field
The invention relates to the field of chemical synthesis methods, in particular to a method for preparing a chiral amino compound by catalytic reduction of a chiral nitro compound.
Background
Chirality (Chirality) is one of the essential properties of nature. Biological macromolecules, such as proteins, polysaccharides, nucleic acids, enzymes and the like, which are important bases of life activities, are almost all chiral, and these small molecules often have important physiological functions in vivo. Most of the currently used drugs are organic small molecules consisting of less than 50 atoms, most of the drugs have chirality, and the pharmacological action of the drugs is realized through strict chiral matching and molecular recognition with macromolecules in vivo. The enantiomers of chemical drugs containing chiral factors have significant differences in pharmacological activity, metabolic processes and toxicity in the human body. The study of chiral drugs has become one of the major directions in the international research of new drugs. Chiral pharmacy is the leading-edge field of the pharmaceutical industry, and chiral drugs refer to a pair of enantiomers which are real and mirror images of each other and are obtained after a chiral center is introduced into a drug molecular structure. When a chiral compound enters a living organism, its two enantiomers often exhibit different biological activities. For chiral drugs, one isomer may be effective, while the other isomer may be ineffective or even harmful. The chiral pharmaceutical is based on the principle of compound, and can develop medicine with high curative effect and less side effect.
In recent years, in addition to natural product extraction and racemate resolution, chemical synthesis has become one of the key techniques for chiral drug synthesis. For example, a chiral amino compound, (2R) -1- (1H-indol-3-yl) propane-2-amine (CAS: 7795-52-0) is a key chiral intermediate of a medicament for clinically treating diseases such as advanced breast cancer, and the like, and the conventional synthetic method is to reduce the chiral intermediate by using achiral lithium aluminum hydride and then rely on chemical resolution to obtain the chiral intermediate. The method has the advantages of low atom economy, high price, very low yield, and high risk of safety in storage and use of the lithium aluminum hydride. None of the currently commercialized enzymes, as well as the natural enzymes, is able to produce the desired 2R configuration, or the stereospecificity for producing this configuration is not high enough (typically < 50%). The prior art specifically starts from 3- [ (2-nitro-1-propenyl ] -1H-indole (CAS: 22693-51-2), forms (1H-indol-3-yl) propane-2-amine with mixed stereo configuration by achiral lithium aluminum hydride reduction, and obtains (2R) -1- (1H-indol-3-yl) propane-2-amine salt with enriched required configuration by one or more times of recrystallization in the presence of chiral alkali and other resolving agents, the prior art obtains the required product with enriched stereo configuration by chiral resolution, the product with the reverse configuration is discarded in the process, the theoretical separation yield is lower than 50%, and actually, the yield is lower than 30% in order to obtain enough high stereo purity, more than equivalent chiral resolving agents are needed in the process, the price is high, and the atom economy is not high enough; the process needs strict temperature control, and the operation is more complex; a large amount of organic solvent is needed, and the environment is not environment-friendly enough.
According to the prior art, chiral amines are usually prepared by catalytic hydrogenation based on chiral nitro compounds, but due to the special properties of nitro compounds, various intermediate states exist in the reduction process, the process is complicated, and chiral loss can be caused. Therefore, in the process of reducing the nitro compound to amino, the control of chirality is extremely important, and further condition optimization is required to obtain the required result.
Therefore, there is a need in the art for a method for preparing a chiral amino compound by catalytic reduction of a chiral nitro compound, which can maintain or even provide the chirality of a chiral amine, ensure excellent chemical purity, and at the same time, is easy to control, has a high overall yield, and is suitable for large-scale industrial production.
Disclosure of Invention
In order to solve the technical problems, the invention provides the following technical scheme:
a method for preparing a chiral amino compound by catalytic reduction of a chiral nitro compound comprises the steps of carrying out catalytic hydrogenation reaction on a chiral nitro compound I under the catalytic action of a catalyst under the action of a reaction solvent and an additive in a hydrogen atmosphere to generate a chiral amino compound II;
the reaction formula is as follows:
wherein the content of the first and second substances,
the R is 1 Is H;
the R is 2 Is methyl or ethyl;
the R is 3 Is a first nine-membered heteroaryl group or a second nine-membered heteroaryl group, the heteroatom of the first nine-membered heteroaryl group being selected from N, and the number of heteroatoms of the first nine-membered heteroaryl group being 1 or 2, the heteroatom of the second nine-membered heteroaryl group also being selected from N, and the number of heteroatoms of the second nine-membered heteroaryl group being 1, the second nine-membered heteroaryl group being substituted with R L Substituted, said R L Is H, OH, OMe, F, Cl, Br or NH 2 ；
Specifically, the catalyst is one of palladium carbon, platinum vanadium carbon or palladium hydroxide carbon.
Preferably, the catalyst is palladium on carbon or palladium hydroxide on carbon.
Specifically, the mass of the catalyst is 0.01-2 times of that of the chiral nitro compound I.
Preferably, the mass of the catalyst is 0.01 to 0.03 times of that of the chiral nitro compound I.
Specifically, the reaction solvent is one or more selected from methanol, ethanol, ethyl acetate, methyl tert-butyl ether, heptane and dioxane.
Preferably, the reaction solvent is methanol.
Specifically, the mass concentration of the chiral nitro compound I in the reaction solvent is 2-100 mg/mL.
Specifically, the additive is one or more selected from diisopropylethylamine, pyridine, acetic acid and hydrochloric acid.
Preferably, the additive is acetic acid.
Specifically, the mass of the chiral nitro compound I is 1-10 times of that of the additive.
Preferably, the mass of the chiral nitro compound I is 1-4 times that of the additive.
Specifically, the hydrogen pressure under the hydrogen atmosphere is 1 to 50 bar.
Preferably, the hydrogen pressure under the hydrogen atmosphere is 20 to 40 bar.
Specifically, the reaction temperature of the catalytic hydrogenation reaction is 10-50 ℃, and the reaction time of the catalytic hydrogenation reaction is 0.5-72 h.
Preferably, the reaction temperature of the catalytic hydrogenation reaction is 20-40 ℃, and the reaction time of the catalytic hydrogenation reaction is 6-48 h.
Specifically, the method comprises the following steps:
step 2, setting reaction conditions: replacing gas in a hydrogenation bottle with nitrogen for 3 times, replacing nitrogen with hydrogen for 3 times, adjusting hydrogen pressure to 1-50 bar, and reacting for 0.5-72 h;
and step 3, post-treatment: after the reaction is finished, extracting by using an extracting agent and water, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, wherein the using amount of the extracting agent and the water is 1:1, the extracting agent is selected from one or more of dichloromethane, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, toluene, n-heptane and methyl tert-butyl ether, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying and filtering, and concentrating the filtrate under reduced pressure to obtain a chiral amino compound II.
Preferably, the extractant is dichloromethane.
The beneficial effects of the invention include:
1) the method has reasonable reaction process design, obtains the target product chiral amino compound by using a hydrogenation catalysis method, and has relatively simple operation, mild conditions, high chiral purity of the product and obviously improved yield compared with the method of reducing by using lithium aluminum hydride and obtaining the product by relying on chemical resolution in the prior art.
2) The method has the advantages of low price and easy obtainment of raw materials, low price and effective saving of production cost, and the reaction solvent, the catalyst, the additive and the extractant are all easy to obtain in the field.
Drawings
FIG. 1 is a chromatogram obtained by separating R/S chirality by liquid chromatography of the product obtained in the first embodiment of the invention;
FIG. 2 is a chromatogram obtained after R/S chirality separation by liquid chromatography of the product obtained in example two of the present invention;
FIG. 3 is a chromatogram obtained after R/S chirality separation by liquid chromatography of the product obtained in the third embodiment of the present invention;
FIG. 4 is a chromatogram obtained after R/S chirality separation by liquid chromatography of the resulting product of example four of the present invention;
FIG. 5 is a chromatogram obtained after R/S chirality separation by liquid chromatography of the product obtained in comparative example one of the present invention;
FIG. 6 is a chromatogram obtained after R/S chirality separation by liquid chromatography of the resulting product of comparative example of the present invention;
FIG. 7 is a chromatogram obtained after R/S chirality separation by liquid chromatography of the resulting product of comparative example three of the present invention;
FIG. 8 is a chromatogram obtained after separating R/S chirality by liquid chromatography of the product obtained in comparative example four of the present invention;
in the figure, the abscissa is time in minutes and the ordinate is absorbance in AU.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
In all the following examples, the chiral nitro compound I is (2R) -3- (2-nitropropyl) -1H-indole, of the formula:
the chiral amino compound II is (2R) -1- (1H-indol-3-yl) propane-2-amine, and has the following chemical formula:
example one
The method for preparing the chiral amino compound by catalytic reduction of the chiral nitro compound has the advantages that the chiral nitro compound I is subjected to catalytic hydrogenation reaction under the catalytic action of a catalyst under the action of a reaction solvent and an additive in a hydrogen atmosphere to generate a chiral amino compound II;
the reaction formula is as follows:
wherein the content of the first and second substances,
R 1 is H;
R 2 is methyl or ethyl;
R 3 is a first nine-membered heteroaryl group or a second nine-membered heteroaryl group, the heteroatom of the first nine-membered heteroaryl group being selected from N and the number of heteroatoms of the first nine-membered heteroaryl group being 1 or 2, the heteroatom of the second nine-membered heteroaryl group also being selected from N and the number of heteroatoms of the second nine-membered heteroaryl group being 1, the second nine-membered heteroaryl group being substituted with R L Substituted, R L Is H, OH, OMe, F, Cl, Br or NH 2 ；
In this embodiment, the chiral nitro compound I is (2R) -3- (2-nitropropyl) -1H-indole, and the formula is shown as follows:
the chiral amino compound II is (2R) -1- (1H-indol-3-yl) propane-2-amine, and the molecular formula is shown as follows:
0.5 mL of methanol, 50 mg of chiral nitro compound I, i.e., (2R) -3- (2-nitropropyl) -1H-indole, and 10 mg of palladium on carbon (10%) were added to a hydrogenation flask, and the temperature was adjusted to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the usage amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying, filtering to remove the sodium sulfate and heterogeneous catalyst palladium carbon, and concentrating the filtrate under reduced pressure to obtain a product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, wherein the yield is 99%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value according to a peak area, wherein the calculation formula of the e.e. value is as follows:
Example two
0.5 mL of methanol, 50 mg of chiral nitro compound I, i.e., (2R) -3- (2-nitropropyl) -1H-indole, and 10 mg of palladium on carbon (20%) were added to a hydrogenation flask, and the temperature was adjusted to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the usage amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying, filtering to remove the sodium sulfate and heterogeneous catalyst palladium hydroxide carbon, and concentrating the filtrate under reduced pressure to obtain a product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine 50 mg, wherein the yield is 99%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value according to a peak area, wherein the calculation formula of the e.e. value is as follows:
wherein R is the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, S is another chiral molecule opposite to R, namely (2S) -1- (1H-indol-3-yl) propane-2-amine, as shown in figure 2, the retention time of the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine in a chromatographic column is 3.681min, the retention time of the corresponding other chiral compound (2S) -1- (1H-indol-3-yl) propane-2-amine in the chromatographic column is 4.310min according to two chiralitiesThe peak area of the compound was calculated to give e.e.>95 percent, the chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, obtained in the example has higher chiral purity.
EXAMPLE III
0.5 mL of methanol, 50 mg of chiral nitro compound I, i.e., (2R) -3- (2-nitropropyl) -1H-indole, 15mg of acetic acid and 10 mg of palladium on carbon hydroxide (20%) were added to a hydrogenation flask, and the temperature was adjusted to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the usage amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying, filtering to remove the sodium sulfate and heterogeneous catalyst palladium hydroxide carbon, and concentrating the filtrate under reduced pressure to obtain a product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine 39 mg, wherein the yield is 78%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value according to a peak area, wherein the calculation formula of the e.e. value is as follows:
wherein R is the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, S is another chiral molecule opposite to R, namely (2S) -1- (1H-indol-3-yl) propane-2-amine, as shown in figure 3, the retention time of the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine in a chromatographic column is 3.681min, the retention time of the other corresponding chiral compound (2S) -1- (1H-indol-3-yl) propane-2-amine in the chromatographic column is 4.309min, and e.e. = 91 percent is calculated according to the peak areas of the two chiral compounds, as can be seen, the chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, obtained in the example has higher chiral purity.
Example four
0.5 mL of methanol, 50 mg of chiral nitro compound I, i.e., (2R) -3- (2-nitropropyl) -1H-indole, 15mg of acetic acid and 10 mg of palladium on carbon (10%) were added to a hydrogenation flask, and the temperature was adjusted to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the usage amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying and filtering to remove the sodium sulfate and heterogeneous catalyst palladium carbon, and concentrating the filtrate under reduced pressure to obtain a product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, 32 mg, the yield is 64%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value according to a peak area, wherein the calculation formula of the e.e. value is as follows:
wherein R is the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, S is another chiral molecule opposite to R, namely (2S) -1- (1H-indol-3-yl) propane-2-amine, as shown in figure 4, the retention time of the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine in a chromatographic column is 3.680min, the retention time of the other corresponding chiral compound (2S) -1- (1H-indol-3-yl) propane-2-amine in the chromatographic column is 4.309min, and e.e. = 87% is calculated according to the peak areas of the two chiral compounds, as can be seen, the yield of the product chiral amino compound II, i.e., (2R) -1- (1H-indol-3-yl) propane-2-amine, obtained in this example is slightly lower than that obtained in examples 1-3, but the chiral purity remains high.
Comparative example 1
0.5 mL of methanol, 50 mg of chiral nitro compound I, i.e., (2R) -3- (2-nitropropyl) -1H-indole, 15mg of acetic acid and 10 mg of palladium hydroxide (20%) were added to a hydrogenation flask, and the temperature was adjusted to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the usage amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying and filtering to remove the sodium sulfate and heterogeneous catalyst palladium carbon, and concentrating the filtrate under reduced pressure to obtain a product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, wherein the yield is 61%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value according to a peak area, wherein the calculation formula of the e.e. value is as follows:
wherein R is the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, S is another chiral molecule opposite to R, namely (2S) -1- (1H-indol-3-yl) propane-2-amine, as shown in figure 5, the retention time of the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine in a chromatographic column is 3.683min, the retention time of the other corresponding chiral compound (2S) -1- (1H-indol-3-yl) propane-2-amine in the chromatographic column is 4.315min, and e.e. = 81.9 percent is calculated according to the peak areas of the two chiral compounds, it can be seen that the chiral purity of the product chiral amino compound II, i.e. (2R) -1- (1H-indol-3-yl) propane-2-amine, obtained in this comparative example is relatively low compared to the chiral purity of the products of the four preceding examples.
The reaction system provided by the first comparative example is different from the reaction system provided by the third example in that palladium hydroxide carbon (20%) is selected as a reaction catalyst in the reaction system provided by the third example, and palladium hydroxide (20%) is selected as a reaction catalyst in the reaction system provided by the first comparative example, and compared with the product yield and the e.e. value in the two examples, it can be seen that the difference of the catalysts has a more obvious influence on the yield and chiral purity of the product.
Comparative example No. two
Adding 0.5 m of ethanol, 50 mg of chiral nitro compound I, namely (2R) -3- (2-nitropropyl) -1H-indole and 10 mg of palladium hydroxide carbon (20%) into a hydrogenation bottle, and adjusting the temperature to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the usage amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying and filtering to remove the sodium sulfate and heterogeneous catalyst palladium carbon, concentrating the filtrate under reduced pressure to obtain a product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, wherein the conversion rate is 99%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value according to a peak area, wherein the calculation formula of the e.e. value is as follows:
wherein R is the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, S is another chiral molecule opposite to R, namely (2S) -1- (1H-indol-3-yl) propane-2-amine, as shown in figure 6, the retention time of the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine in a chromatographic column is 3.683min, the retention time of the other corresponding chiral compound (2S) -1- (1H-indol-3-yl) propane-2-amine in the chromatographic column is 4.314min, and e.e. = 48.8 percent is calculated according to the peak areas of the two chiral compounds, the chiral purity of the product chiral amino compound II, namely, (2R) -1- (1H-indol-3-yl) propane-2-amine, obtained in this comparative example is significantly lower than that of the products of the preceding four examples, and the e.e. value is reduced to almost half of that of the preceding example.
The reaction system provided by the comparative example II is different from the reaction system provided by the example I in that methanol is selected as a reaction solvent in the reaction system provided by the example I, ethanol is selected as a reaction solvent in the reaction system provided by the comparative example II, and the product yield and the e.e. value of the two examples are compared, so that the difference of the reaction solvents has small influence on the yield of the product, but has large influence on the chiral purity of the product, and the e.e. value is sharply reduced to about half of that of the reaction solvent when methanol is used as the reaction solvent when ethanol is selected as the reaction solvent.
Comparative example No. three
0.5 mL of tetrahydrofuran, 50 mg of chiral nitro compound I, i.e., (2R) -3- (2-nitropropyl) -1H-indole, 15mg of triethylamine and 10 mg of palladium on carbon (10%) were added to a hydrogenation flask, and the temperature was adjusted to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the usage amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying, filtering to remove the sodium sulfate and heterogeneous catalyst palladium carbon, concentrating the filtrate under reduced pressure to obtain a product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, wherein the conversion rate is 58%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value according to a peak area, wherein the calculation formula of the e.e. value is as follows:
wherein R is the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, S is another chiral molecule opposite to R, namely (2S) -1- (1H-indol-3-yl) propane-2-amine, as shown in figure 7, the retention time of the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine in a chromatographic column is 3.683min, the retention time of the other corresponding chiral compound (2S) -1- (1H-indol-3-yl) propane-2-amine in the chromatographic column is 4.313min, and e.e. = 38.5 percent is calculated according to the peak areas of the two chiral compounds, the product obtained in this comparative example is the chiral amino compound II (2R) -1- (1H-indol-3-yl) propaneThe chiral purity of the alk-2-amines is significantly lower and poorer than the chiral purity of the products of the four preceding examples.
Comparing the reaction system provided by the third comparative example with the reaction system provided by the fourth example, the reaction system provided by the fourth example selects methanol as the reaction solvent, the reaction system provided by the third comparative example selects tetrahydrofuran as the reaction solvent, the reaction system provided by the fourth example selects acetic acid as the additive, the reaction system provided by the third comparative example selects triethylamine as the additive, and comparing the product yield and the e.e. value of the two examples, it can be seen that the third comparative example can also realize the preparation of the chiral amino compound II, namely, (2R) -1- (1H-indol-3-yl) propane-2-amine, and can maintain a certain degree of chiral purity, but the e.e. value of the third comparative example with better comparison effect is only 38.5%, and the conversion rate is only 58%, compared with the 87% e.e. value and the 64% yield value in the fourth example, the method is obviously lower, and the difference of the reaction solvent and the additive has obvious influence on the yield and the chiral purity of the product.
Comparative example No. four
0.5 mL of tetrahydrofuran, 50 mg of chiral nitro compound I, i.e., (2R) -3- (2-nitropropyl) -1H-indole, 30mg of triethylamine and 10 mg of palladium on carbon (10%) were added to a hydrogenation flask, and the temperature was adjusted to 20-25 ℃. The air in the hydrogenation bottle is replaced by nitrogen for 3 times, and then the nitrogen is replaced by hydrogen for 3 times, so that the hydrogen reduction atmosphere in the hydrogenation bottle is ensured. The reaction was carried out for 48 hours under a hydrogen atmosphere of 30 bar.
After the reaction is finished, extracting by using a dichloromethane extracting agent and water, wherein the using amount of the dichloromethane extracting agent and the water is 1:1, extracting a reaction byproduct dissolved in water into a water phase by using water, extracting a main product into an organic phase, separating the water phase from the organic phase by using a separating funnel after the extraction is finished, adding sodium sulfate into the organic phase for drying and filtering to remove the sodium sulfate and heterogeneous catalyst palladium carbon, concentrating the filtrate under reduced pressure to obtain a chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, wherein the conversion rate is 95%, separating chiral isomers by using a chiral chromatographic column, and calculating an e.e. value and an e.e. value according to peak areasThe calculation formula is as follows:
wherein R is the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine, S is another chiral molecule opposite to R, namely (2S) -1- (1H-indol-3-yl) propane-2-amine, as shown in figure 8, the retention time of the product chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine in a chromatographic column is 3.682min, the retention time of the other corresponding chiral compound (2S) -1- (1H-indol-3-yl) propane-2-amine in the chromatographic column is 4.310min, and e.e. = 2.7 percent is calculated according to the peak areas of the two chiral compounds, the chiral purity of the product chiral amino compound II, namely, (2R) -1- (1H-indol-3-yl) propane-2-amine obtained in the comparative example is obviously lower than that of the products obtained in the previous four examples, namely, the chiral purity is only 2.7%, and the chiral purity is extremely poor.
The reaction system provided in the fourth comparative example is different from the reaction system provided in the fourth example in that methanol is selected as a reaction solvent in the reaction system provided in the fourth example, tetrahydrofuran is selected as a reaction solvent in the reaction system provided in the fourth comparative example, acetic acid is selected as an additive in the reaction system provided in the fourth example, triethylamine is selected as an additive in the reaction system provided in the fourth comparative example, the amount of triethylamine used as the additive is increased from 15mg to 30mg, and according to the result, although the fourth comparative example can also realize the preparation of the chiral amino compound II, namely, (2R) -1- (1H-indol-3-yl) propane-2-amine, the chiral purity is obviously poor, and the e.e. value is only 2.7%, so that the selection of the additive and the reaction solvent can be seen, and the dosage of the additive and the reaction solvent have obvious influence on the chiral purity of the chiral amino compound II, namely (2R) -1- (1H-indol-3-yl) propane-2-amine.
In summary, the above embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. The method for preparing the chiral amino compound by catalytic reduction of the chiral nitro compound is characterized in that the chiral nitro compound I is subjected to catalytic hydrogenation reaction under the catalytic action of a catalyst under the hydrogen atmosphere and under the action of a reaction solvent and an additive to generate a chiral amino compound II;
the reaction formula is as follows:
wherein, the first and the second end of the pipe are connected with each other,
the R is 1 Is H;
the R is 2 Is methyl or ethyl;
the R is 3 Is a first nine-membered heteroaryl group or a second nine-membered heteroaryl group, the heteroatom of the first nine-membered heteroaryl group being selected from N, and the number of heteroatoms of the first nine-membered heteroaryl group being 1 or 2, the heteroatom of the second nine-membered heteroaryl group also being selected from N, and the number of heteroatoms of the second nine-membered heteroaryl group being 1, the second nine-membered heteroaryl group being substituted with R L Substituted, said R L Is H, OH, OMe, F, Cl, Br or NH 2 。
2. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound according to claim 1, wherein the catalyst is one of palladium carbon, platinum vanadium carbon or palladium hydroxide carbon.
3. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound as claimed in claim 1, wherein the mass of the catalyst is 0.01-2 times of the mass of the chiral nitro compound i.
4. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound as claimed in claim 1, wherein the reaction solvent is selected from one or more of methanol, ethanol, ethyl acetate, methyl tert-butyl ether, heptane, dioxane.
5. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound as claimed in claim 1, wherein the mass concentration of the chiral nitro compound i in the reaction solvent is 2-100 mg/mL.
6. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound as claimed in claim 1, wherein the additive is selected from one or more of diisopropylethylamine, pyridine, acetic acid, hydrochloric acid.
7. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound of claim 1, wherein the mass of the chiral nitro compound i is 1-10 times of the mass of the additive.
8. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound according to claim 1, wherein the hydrogen pressure under hydrogen atmosphere is 1-50 bar.
9. The method for preparing chiral amino compound by catalytic reduction of chiral nitro compound according to claim 1, wherein the reaction temperature of the catalytic hydrogenation reaction is 10-50 ℃, and the reaction time of the catalytic hydrogenation reaction is 0.5-72 h.
10. The process for the catalytic reduction of chiral nitro compounds to chiral amino compounds according to claim 1, comprising the steps of:
step 1, adding reactants: adding a reaction solvent, a chiral nitro compound I, an additive and a catalyst into a hydrogenation bottle, and adjusting the temperature to 10-50 ℃;
step 2, setting reaction conditions: replacing gas in a hydrogenation bottle with nitrogen for 3 times, replacing nitrogen with hydrogen for 3 times, adjusting hydrogen pressure to 1-50 bar, and reacting for 0.5-72 h;
and step 3, post-treatment: after the reaction is finished, extracting by using an extracting agent and water, wherein the using amount of the extracting agent and the water is 1:1, the extracting agent is selected from one or more of dichloromethane, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, toluene, n-heptane and methyl tert-butyl ether, after the extraction is finished, separating a water phase from an organic phase by using a separating funnel, adding sodium sulfate into the organic phase for drying and filtering, and concentrating the filtrate under reduced pressure to obtain a chiral amino compound II.
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