Method for photocatalytic synthesis of beta-amino alcohol compound

Abstract

The invention belongs to the field of chemical synthesis, and provides a method for photocatalytic synthesis of beta-amino alcohol compounds. A semiconductor photocatalyst is used, cheap and easily available amine and aldehyde are used as initial raw materials, the reaction inertia of a benzylamine alpha C-H bond is broken through under an illumination condition, asymmetric addition of the benzylamine alpha C-H bond to the aldehyde is realized under a mild condition, and an important compound beta-amino alcohol is efficiently constructed. A series of beta-amino alcohol chemicals with high added value can be obtained by utilizing the process, the energy consumption in the reaction process is low, the product selectivity is high, the separation is simple, the pollutant emission is less, the energy is saved, the emission is reduced, and the industrial application prospect is wide.

Description

Technical Field

[0001] The invention belongs to the field of preparation of synthetic beta-amino alcohol compounds, and in particular relates to a method for photocatalytically synthesizing beta-amino alcohol compounds. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] β-Amino alcohols are very important chiral building blocks that are widely present in natural products, bioactive molecules, ligands and catalyst structures, including more than 2,000 natural products, more than 80 approved drugs and more than 100 candidate drugs, such as β-adrenergic receptor agonists (ractopamine), β-adrenergic receptor antagonists (carteolol), IRAK4 / FLT3 inhibitors (emavusertib), etc. Given the important role of β-amino alcohols, efficient synthesis of β-amino alcohols is of great significance. Over the past few decades, researchers have been committed to the development of efficient synthesis methods for β-amino alcohols. Among them, using excess amines as amine donors to directly react with epoxides for aminolysis is one of the most practical and recognized methods for synthesizing β-amino alcohols. In addition, scientists have also developed chemical methods using various Lewis acids or reacting in different organic solvents to improve the efficiency of epoxide ammonolysis reactions. These methods generally have defects such as high reaction temperature, large amount of catalyst, and catalyst sensitivity to water. In addition, the required raw material epoxide is difficult to prepare and usually requires metal catalysts under harsh reaction conditions. Therefore, it is very necessary to develop a synthesis method with easy-to-obtain raw materials, efficient reaction, high product selectivity, and economical and green. Summary of the invention

[0004] In recent years, visible light-mediated photoredox catalysis has developed into a favorable tool for organic synthesis. The α-amino radicals generated by CH activation have high activity and coupling ability with various electrophilic reagents, but the αC-H bond acidity of benzylamine is extremely low (pKa~42.7), which is difficult to activate. The present invention uses ZnCdS as a catalyst, the most readily available amines and aldehydes as starting materials, breaks through the reaction inertness of the αC-H bond of benzylamine under illumination conditions, realizes the asymmetric addition of the αC-H bond of benzylamine to aldehyde under mild conditions, and efficiently constructs the important compound β-amino alcohol. A series of β-amino alcohol chemicals with high added value can be obtained by using this process. The reaction process has low energy consumption, high product selectivity, simple separation, low pollutant emissions, energy saving and emission reduction, and has broad industrial application prospects.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] The first aspect of the present invention provides a method for photocatalytically synthesizing β-amino alcohol compounds, comprising:

[0007] The β-amino alcohol compounds were synthesized by the following route;

[0008]

[0009] Wherein, R1, R2, and R3 are one of halogen, aromatic hydrocarbon, and alkane;

[0010] The specific steps of the route include:

[0011] N-benzylaniline, benzaldehyde, a photocatalyst, a base and an organic solvent are uniformly mixed, and placed under a light source for reaction under the protection of an inert gas atmosphere to obtain the product.

[0012] Reaction mechanism:

[0013] The present invention synthesizes β-amino alcohol compounds based on semiconductor catalysts, and speculates on the reaction mechanism. First, under light conditions, the heterogeneous photocatalyst ZnCdS undergoes charge separation to generate a redox center. The hydrogen ions at the reducing end obtain electrons to form hydrogen free radicals and combine with aldehydes to form benzyl alcohol free radicals A. The oxidizing end performs oxidative dehydrogenation on N-benzylaniline to form benzyl free radicals B. Free radicals A and B undergo coupling to obtain product 1. Figure 2 shown.

[0014] In some embodiments, the mass ratio of N-benzylaniline to benzaldehyde, photocatalyst, base and organic solvent is 0.8-2:0.2-0.5:0.5-1:1000-3000.

[0015] In some embodiments, the photocatalyst is an inorganic semiconductor catalyst.

[0016] Preferably, the inorganic semiconductor catalyst is selected from at least one of TiO2, ZnO, ZnS, CdS, CdSe, and ZnCdS.

[0017] In some embodiments, the base is selected from at least one of NaHCO3, K2CO3, Na2CO3, K3PO4, NaOAc, Cs2CO3, NaOH, KHCO3, and tBuONa.

[0018] In some embodiments, the organic solvent is selected from at least one of tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, and dichloroethane.

[0019] In some embodiments, the reaction temperature is 20-80°C;

[0020] In some embodiments, the reaction time is 10-24 hours.

[0021] In some embodiments, the wavelength of the light source is 200-2000nm and the power is 5-30w;

[0022] Preferably, the light source is 420nm light with a power of 10W.

[0023] The second aspect of the present invention provides β-amino alcohol compounds prepared by the above method.

[0024] The third aspect of the present invention provides the use of the above-mentioned β-amino alcohol compounds in the preparation of medicines.

[0025] Beneficial Effects of the Invention

[0026] (1) The present invention uses N-benzylaniline and benzaldehyde as raw materials to prepare β-amino alcohol chemicals at room temperature and pressure under photocatalytic conditions. The method of the present invention avoids the use of highly toxic and dangerous reagents, reduces pollution and waste, reduces costs, and is suitable for large-scale industrial production.

[0027] (2) The present invention uses N-benzylaniline and benzaldehyde as raw materials, and synthesizes β-amino alcohol chemicals by activating the CH bond through a photocatalyst. The method is simple, highly practical, and easy to promote. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0029] Figure 1 Diagram for catalyst recycling.

[0030] Figure 2 The reaction mechanism diagram.

[0031] Figure 3 This is the H NMR spectrum of β-amino alcohol 1.

[0032] Figure 4 This is the carbon NMR spectrum of β-amino alcohol 1.

[0033] Figure 5 This is the H NMR spectrum of β-amino alcohol 2.

[0034] Figure 6 This is the carbon NMR spectrum of β-amino alcohol 2.

[0035] Figure 7 This is the H NMR spectrum of β-amino alcohol 3.

[0036] Figure 8 This is the carbon NMR spectrum of β-amino alcohol 3.

[0037] Fig. 9 This is the H NMR spectrum of β-amino alcohol 4.

[0038] Fig.10 This is the carbon NMR spectrum of β-amino alcohol 4. DETAILED DESCRIPTION

[0039] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0040] The present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are intended to explain the present invention rather than to limit it.

[0041] Example 1

[0042] Synthesis of β-amino alcohol 1

[0043]

[0044] Weigh 0.5mmol 92mg N-benzylaniline, 0.6mmol 64mg benzaldehyde, 20mg ZnCdS photocatalyst and 50mg NaHCO3 respectively and add them to a 10mL reaction bottle, add 4mL anhydrous acetonitrile, replace the reaction system with argon protection, and then place the reaction bottle under a 420nm light source for illumination reaction for 12 hours. After the reaction is completed, remove the light source, filter the reaction mixture with diatomaceous earth, and then extract with 5.0mL CH2Cl2. Dry the extract with anhydrous sodium sulfate and concentrate to obtain a colorless liquid. Rotate to evaporate the solvent, and then use column chromatography (developing solvent: petroleum ether / ethyl acetate) to obtain the pure target product with a yield of 89% and a purity of 95%. 1 HNMR, 13 C-NMR and other tests confirmed the structure. 1H NMR (400MHz, CDCl3) δ7.34–7.22(m,8H),7.17(dd,J=6.7,2.9Hz,1H),7.15–7.04(m,3H),6.69(t,J=7.3Hz,1H),6.62–6.51(m,2H),5.09(d,J=3 .9Hz,0.5H),4.90(d,J=5.8Hz,0.5H),4.70(d,J=4.8Hz,0.5H),4.56(d,J=5.9Hz,0.5H),4.50(brs,1H),2.62(brs,0.5H),2.39(brs,0.5H).13C NMR (100MHz, CDCl3) δ147.3,146.8,140.6,140.3,140.0,138.5,129.1,129.1,128.6,128.3,128.3,128.3,128.1, 127.9,127.6,127.5,127.3,126.6,126.6,117.9(d,J=1.3Hz),114.2,114.0,78.1,77.2,64.7,63.7.HRMS(ESI)m / z Calcd.for C20H19NO[M+H] + 301.0335; found, 301.0320.

[0045] Example 2

[0046] Synthesis of β-amino alcohol 1

[0047]

[0048] Weigh 0.5mmol 92mg N-benzylaniline, 0.6mmol 64mg benzaldehyde, 20mg CdS photocatalyst and 50mg NaHCO3 respectively and add them to a 10mL reaction bottle, add 4mL anhydrous acetonitrile, replace the reaction system with argon protection, and then place the reaction bottle under a 420nm light source for 12 hours of light reaction. After the reaction is completed, remove the light source, filter the reaction mixture with diatomaceous earth, and then extract with 5.0mL CH2Cl2. The extract is dried with anhydrous sodium sulfate and concentrated to obtain a colorless liquid. Rotate to evaporate the solvent, and then obtain the pure target product through column chromatography (developing solvent: petroleum ether / ethyl acetate). 1 HNMR, 13 C-NMR and other tests confirmed that the structure was the same as that in Example 1, with a yield of 65% and a purity of 95%.

[0049] Example 3

[0050] Synthesis of β-amino alcohol 1

[0051]

[0052] Weigh 0.5mmol 92mg N-benzylaniline, 0.6mmol 64mg benzaldehyde, 20mg ZnCdS photocatalyst and 50mg K2CO3 respectively and add them to a 10mL reaction bottle, add 4mL anhydrous acetonitrile, replace the reaction system with argon protection, and then place the reaction bottle under a 420nm light source for 12 hours of light reaction. After the reaction is completed, remove the light source, filter the reaction mixture with diatomaceous earth, and then extract with 5.0mL CH2Cl2. The extract is dried with anhydrous sodium sulfate and concentrated to obtain a colorless liquid. Rotate to evaporate the solvent, and then obtain the pure target product through column chromatography (developing solvent: petroleum ether / ethyl acetate). 1 HNMR, 13 C-NMR and other tests confirmed that the structure was the same as that in Example 1, with a yield of 52% and a purity of 95%.

[0053] Example 4

[0054] Synthesis of β-amino alcohol 1

[0055]

[0056] Weigh 0.5mmol 92mg N-benzylaniline, 0.6mmol 64mg benzaldehyde, 20mg ZnCdS photocatalyst and 50mg NaHCO3 respectively and add them to a 10mL reaction bottle, add 4mL anhydrous acetonitrile, replace the reaction system with argon protection, and then place the reaction bottle under a 390nm light source for 12 hours of light reaction. After the reaction is completed, remove the light source, filter the reaction mixture with diatomaceous earth, and then extract with 5.0mL CH2Cl2. The extract is dried with anhydrous sodium sulfate and concentrated to obtain a colorless liquid. Rotate to evaporate the solvent, and then obtain the pure target product through column chromatography (developing solvent: petroleum ether / ethyl acetate). 1 HNMR, 13 C-NMR and other tests confirmed that the structure was the same as that in Example 1, with a yield of 46% and a purity of 95%.

[0057] Example 5

[0058] Synthesis of β-amino alcohol 2

[0059]

[0060] Weigh 0.5mmol 92mg N-benzylaniline, 0.6mmol 84mg p-bromobenzaldehyde, 20mg ZnCdS photocatalyst and 50mg NaHCO3 respectively and add them to a 10mL reaction bottle, add 4mL anhydrous acetonitrile, replace the reaction system with argon protection, and then place the reaction bottle under a 420nm light source for illumination reaction for 12 hours. After the reaction is completed, remove the light source, filter the reaction mixture with diatomaceous earth, and then extract with 5.0mL CH2Cl2. Dry the extract with anhydrous sodium sulfate and concentrate to obtain a colorless liquid. Rotate to evaporate the solvent, and then use column chromatography (developing solvent: petroleum ether / ethyl acetate) to obtain the pure target product with a yield of 86% and a purity of 93%. 1 HNMR, 13 C-NMR and other tests confirmed the structure. 1 H NMR (500MHz, CDCl3) δ7.33–7.25(m,5H),7.22(dt,J=11.3,6.5Hz,2H),7.17–7.07(m,3H),7.02(d,J=8.4Hz,1H),6.71(t,J=7.3Hz,1H),6.58(t,J =7.3Hz,2H),5.09(d,J=4.6Hz,0.5H),4.86(d,J=6.1Hz,0.5H),4.68(d,J=4.6Hz,0.5H),4.50(d,J=6.1Hz,0.5H),4.50(brs,1H),2.93(brs,1H). 13 C NMR (125MHz, CDCl3) δ147.0,146.6,139.8,139.1,138.6,138.0,133.7,133.6,129.2,129.2,128.7,128.4,128.4,1 28.3,128.0,127.9,127.9,127.8,127.7,127.3,118.3,118.2,114.3,114.1,77.4,76.4,64.9,63.6.HRMS(ESI)m / z Calcd.for C20H18ClNO[M+H]+301.0335; found,301.0320.

[0061] Example 6

[0062] Synthesis of β-amino alcohol 3

[0063]

[0064] Weigh 0.5mmol 104mg 4-anilinobenzonitrile, 0.6mmol 64mg benzaldehyde, 20mg ZnCdS photocatalyst and 50mg NaHCO3 respectively and add them to a 10mL reaction bottle, add 4mL anhydrous acetonitrile, replace the reaction system with argon protection, and then place the reaction bottle under a 420nm light source for light reaction for 12 hours. After the reaction is completed, remove the light source, filter the reaction mixture with diatomaceous earth, and then extract with 5.0mL CH2Cl2. The extract is dried with anhydrous sodium sulfate and concentrated to obtain a colorless liquid. The solvent is removed by rotary evaporation, and then the pure target product is obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate), with a yield of 76% and a purity of 94%. 1 HNMR, 13 C-NMR and other tests confirmed the structure. 1 H NMR (500MHz, CDCl3) δ7.47 (dd, J=13.0, 8.3Hz, 2H), 7.34–7.28 (m, 4H), 7.25– 7.19(m,2H),7.15–7.04(m,3H),6.73(t,J=7.3Hz,1H),6.52(d,J=8.4Hz,2H), 5.16(d,J=4.1Hz,0.5H),4.88(brs,1H),4.79(d,J=6.4Hz,0.5H),4.69(d,J=3 .3Hz,0.5H),4.57(d,J=6.5Hz,0.5H),3.14(brs,0.5H),2.93(brs,0.5H).13C NMR (126MHz, CDCl3) δ146.8,146.4,146.3,144.7,140.2,139.9,132.4,132.2,131.7,129.3,129.2,129.1,128.5,128.4,128.4,1 28.3,128.2,127.1,126.8,126.4,119.0,118.9,118.4,118.3,114.1,113.8,111.0,110.9,77.8,76.5,64.7,63.4.HRMS(ESI)m / z Calcd.for C21H18N2O[M+H]+301.0335; found,301.0320.

[0065] Example 7

[0066] Synthesis of β-amino alcohol 4

[0067]

[0068] Weigh 0.5mmol 108mg N-benzyl-4-chloroaniline, 0.6mmol 64mg benzaldehyde, 20mg ZnCdS photocatalyst and 50mg NaHCO3 respectively and add them to a 10mL reaction bottle, add 4mL anhydrous acetonitrile, replace the reaction system with argon protection, and then place the reaction bottle under a 420nm light source for illumination reaction for 12 hours. After the reaction is completed, remove the light source, filter the reaction mixture with diatomaceous earth, and then extract with 5.0mL CH2Cl2. Dry the extract with anhydrous sodium sulfate and concentrate to obtain a colorless liquid. Rotate to evaporate the solvent, and then use column chromatography (developing solvent: petroleum ether / ethyl acetate) to obtain the pure target product with a yield of 83% and a purity of 95%. 1 HNMR, 13 C-NMR and other tests confirmed the structure. 1 H NMR (500MHz, CDCl3) δ7.38–7.26(m,7H),7.24(dd,J=6.4,4.8Hz,1H),7.17–7.08(m,2H),7.03(dd,J=8.9,3.7Hz,2H),6.46(dd,J=8.9,3.3Hz,2H),5.08 (d,J=4.3Hz,0.45H),4.88(d,J=5.7Hz,0.55H),4.69(brs,1H),4.64(d,J=4 .7Hz,0.45H),4.51(d,J=5.7Hz,0.55H),2.60(brs,0.55H),2.41(s,0.45H). 13 C NMR (125MHz, CDCl3) δ145.9,145.4,140.5,139.9,138.0,129.0,128.9,128.7,128.4,128.3,128.2,128. 0,127.9,127.8,127.7,127.3,126.5,122.5,122.4,115.2,115.1,78.0,77.2,64.7,63.8.HRMS(ESI)m / z Calcd.for C20H18ClNO[M+H]+301.0335; found,301.0320.

[0069] Example 8

[0070] Photocatalyst cycling stability

[0071] The specific operations are:

[0072] The reaction was carried out according to Example 1. After the reaction was completed, the mixture was centrifuged. The supernatant was taken and water and ethyl acetate were added to extract the organic phase. The extract was dried over anhydrous sodium sulfate and concentrated to obtain a colorless liquid. The yield was calculated after column chromatography separation and purification (recorded as the first reaction yield). The precipitated photocatalyst obtained by centrifugation was dried and repeated in Example 1. The product was separated and purified and the yield was calculated (recorded as the first reaction yield). This cycle was repeated for five rounds. The cyclic stability of the catalyst was obtained. The results are shown in FIG. Figure 1 ,Depend on Figure 1 The visible light catalyst has good stability and the reaction yield remains stable.

[0073] In summary, the present invention provides a method for preparing a β-amino alcohol compound. In the present invention, N-benzylaniline and benzaldehyde are used as raw materials, N-benzylaniline is subjected to CH activation under the action of photocatalysis and a coupling reaction occurs with benzaldehyde, thereby preparing a β-amino alcohol compound. Compared with the previous synthesis method, the method of the present invention has the advantages of easier raw material acquisition, lower price, milder reaction conditions and environmental friendliness, and is suitable for large-scale production of β-amino alcohol compounds.

[0074] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for photocatalytic synthesis of β-amino alcohol compounds, characterized in that: include: The β-amino alcohol compounds were synthesized by the following route; Wherein, R1, R2, and R3 are one of halogen, aromatic hydrocarbon, and alkane; The specific steps of the route include: N-benzylaniline, benzaldehyde, a photocatalyst, a base and an organic solvent are uniformly mixed, and placed under a light source for reaction under the protection of an inert gas atmosphere to obtain the product.

2. The method for photocatalytic synthesis of β-amino alcohol compounds according to claim 1, characterized in that: The mass ratio of the N-benzylaniline to benzaldehyde, the photocatalyst, the base and the organic solvent is 0.8-2:0.2-0.5:0.5-1:1000-3000.

3. The method for photocatalytic synthesis of β-amino alcohol compounds according to claim 1, characterized in that: The photocatalyst is an inorganic semiconductor catalyst.

4. The method for photocatalytic synthesis of β-amino alcohol compounds according to claim 3, characterized in that: The inorganic semiconductor catalyst is selected from at least one of TiO2, ZnO, ZnS, CdS, CdSe, and ZnCdS.

5. The method for photocatalytic synthesis of β-amino alcohol compounds according to claim 1, characterized in that: The base is selected from at least one of NaHCO3, K2CO3, Na2CO3, K3PO4, NaOAc, Cs2CO3, NaOH, KHCO3, and tBuONa.

6. The method for photocatalytic synthesis of β-amino alcohol compounds according to claim 1, characterized in that: The organic solvent is selected from at least one of tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide and dichloroethane.

7. The method for photocatalytic synthesis of β-amino alcohol compounds according to claim 1, characterized in that: The reaction temperature is 20-80°C; Or, the reaction time is 10-24h.

8. The method for photocatalytic synthesis of β-amino alcohol compounds according to claim 1, characterized in that: The wavelength of the light source is 200-2000nm, and the power is 5-30w; Or, the light source is 420nm light with a power of 10W.

9. β-amino alcohol compounds prepared by the method according to any one of claims 1 to 8.

10. Use of the β-amino alcohol compound according to claim 9 in the preparation of medicines.

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