Catalyst for preparing chiral beta-amino alcohol and method for preparing chiral beta-amino alcohol using same

Abstract

The invention provides a catalyst for preparing chiral beta-amino alcohol and a method for preparing chiral beta-amino alcohol by using the catalyst. The chiral beta-amino alcohol is shown as a formula (4). According to the method, carbonyl-containing compounds (such as aldehydes and ketones) are used as raw materials, and in the presence of a chemical catalyst, an enzyme catalyst and a solvent, the chiral beta-amino alcohol is prepared by a one-pot method combining chemical catalysis and biological catalysis. Compared with the prior art, one-pot preparation of chiral beta-amino alcohol, especially L-phenylglycinol, is realized through coupling of chemical catalysis and biological catalysis, and the method has the advantages of low raw material cost, mild conditions, low reaction temperature, high safety, high yield, continuous operation and the like. According to the reaction route adopted by the invention, 87% benzaldehyde can be converted into L-phenylglycinol in one pot, the highest yield can reach 83.5%, and the reaction efficiency is greatly improved. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the fields of biocatalysis and chemical catalysis, and relates to a catalyst for preparing chiral β - amino alcohols and a method for preparing chiral β - amino alcohols using the same. Background Art

[0002] Chiral β - amino alcohols are a very important class of compounds and are the main source of chiral compounds in asymmetric synthesis. β - aromatic amino alcohols are key intermediates for synthesizing various drugs and active ingredients, including the anticonvulsant drug cinobezide, antifungal agents otioconazole, itraconazole, fluconazole, miconazole, ketoconazole, the fungicide imazalil, and the transient receptor potential canonical channel antagonist SKF 96365, etc. As a kind of chiral amino alcohol, chiral phenylglycinol is an important chiral intermediate and chiral reagent, and is widely used in the fields of pharmaceuticals, fine chemicals, etc. Chiral phenylglycinol plays a crucial role as a pharmaceutical intermediate. For example, (R)-2 - amino - 2 - phenyl ethanol is a component of a 3 - phosphoinositide - dependent protein kinase - 1 inhibitor. The traditional preparation process of L - phenylglycinol starts from L - phenylglycine and is reduced by sodium borohydride plus drop - wise addition of concentrated sulfuric acid to obtain L - phenylglycinol. This process generates a large amount of borane. Borane is highly toxic and prone to spontaneous combustion, bringing great pressure to production safety and labor protection at the operation site. The biological method for preparing L - phenylglycinol has high selectivity, strong specificity, and mild reaction conditions, but usually adopts multi - enzyme cascade catalysis reactions, resulting in disadvantages such as low conversion rate, low yield, and high cost, which is not conducive to industrial production. Summary of the Invention

[0003] In view of the above - mentioned application deficiencies and technical requirements of chiral phenylglycinol, the present invention has developed a reaction route for preparing chiral β - amino alcohols by a one - pot method combining chemical catalysis and biocatalysis using a carbonyl - containing compound (such as aldehydes, ketones) as a raw material.

[0004] One technical object of the present invention is to provide a catalyst for preparing 2 - nitro - 2 - phenyl - ethanol and its analogs and a preparation method thereof. The catalyst can efficiently catalyze the synthesis of 2 - nitro - 2 - phenyl - ethanol and its analogs using aldehydes, ammonia, and hydrogen peroxide as raw materials.

[0005] Another technical object of the present invention is to provide a method for preparing 2 - nitro - 2 - phenyl - ethanol and its analogs using the above - mentioned catalyst.

[0006] Still another technical object of the present invention is to provide a supported enzyme catalyst for preparing chiral β - amino alcohols (especially L - phenylglycinol) and a preparation method thereof.

[0007] Another technical object of the present invention is to provide a method for preparing chiral β - amino alcohols (especially L - phenylglycinol).

[0008] Another technical object of the present invention is to provide a one - pot method for preparing chiral β - amino alcohols (especially L - phenylglycinol).

[0009] On the one hand, the present invention provides a preparation method of a catalyst for preparing a compound of formula (3) as follows,

[0010]

[0011] In formula (3), R is H or an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl, propyl); R 1 , R 2 , R 3 , R 4 and R 5 are each independently H or an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl, propyl),

[0012] The method includes:

[0013] S1, dissolving a silicon source in water to prepare an aqueous silicon - containing solution with a Si 4+ concentration of 0.3 - 0.6 M; dissolving a zirconium source in water to prepare an aqueous zirconium - containing solution with a Zr 4+ concentration of 0.3 - 0.6 M; adding the aqueous zirconium - containing solution to the aqueous silicon - containing solution under mechanical stirring; subsequently, dropping an alkaline aqueous solution (such as an aqueous NaOH solution) until the pH of the solution is greater than 9 to obtain a precipitate, and filtering, washing, and drying the precipitate to prepare a silicon - zirconium gel;

[0014] S2, generating a silica - aluminate gel by mixing sodium aluminate, water glass, and an alkali solution to obtain a directing agent with a molar ratio of Al 2 O 3 :(5 - 20)SiO 2 :(20 - 50)Na 2 O:(15 - 25)K 2 O:(800 - 1000)H 2 O, and aging the directing agent at room temperature for 10 - 20 h to obtain a directing gel;

[0015] S3. Add water to the silicon-zirconium gel obtained in S1 in a mass ratio of silicon-zirconium gel to water of 1:2 - 1:4. Then add a pore-forming agent and an organic template agent, and then add 0.5 - 2 wt% of the guiding gel obtained in S2 based on the weight of the silicon-zirconium gel at room temperature, and stir for 1 - 4 hours to obtain a mixture. Transfer the mixture to a hydrothermal reaction kettle, age at 50 - 100 °C for 3 - 8 hours, and then put the reaction kettle into an oven at 150 - 200 °C for static crystallization for 10 - 50 hours. Filter, wash, and dry the sample obtained by crystallization, and then calcine at 400 - 600 °C for 5 - 10 hours, and add an acid solution (such as HCl aqueous solution) for pickling for 1 - 4 hours to obtain the catalyst Zr-MFI zeolite.

[0016] The present invention also provides a catalyst for preparing the compound of formula (3) prepared by the above method.

[0017] In some embodiments, the compound of formula (3) is the following compound of formula III:

[0018]

[0019] In some embodiments, in S1, the silicon source is selected from sodium silicate (such as Na 2 SiO 3 ·9H 2 O), tetraethyl orthosilicate, sodium aluminosilicate, etc.

[0020] In some embodiments, in S1, the zirconium source is selected from zirconium oxychloride (such as ZrOCl 2 ·8H 2 O), tetraethoxy zirconium, dichlorodicyclopentadienyl zirconium, zirconium nitrate, etc.

[0021] In some embodiments, in S1, the addition of the silicon source and the zirconium source makes the molar ratio of silicon to zirconium 1:1.

[0022] In some embodiments, in S1, the alkaline aqueous solution can be selected from NaOH aqueous solution, KOH aqueous solution, Na 2 CO 3 aqueous solution, NaHCO 3 aqueous solution.

[0023] In some embodiments, in S2, the alkali solution is an aqueous solution containing NaOH and KOH in a molar ratio of 2:1 - 1:1.

[0024] In some embodiments, in S2, the chemical composition of the guiding agent conforms to the following molar ratio: Al 2 O 3 :(10 - 15)SiO 2 :(30 - 40)Na2 O: (15 - 25)K 2 O: (800 - 1000)H 2 O。

[0025] In some embodiments, in S2, the chemical composition of the guiding agent conforms to the following molar ratio: Al 2 O 3 : 12SiO 2 : 36Na 2 O: 20K 2 O: 950H 2 O。

[0026] In some embodiments, in S3, the crystallization formula is: H 2 O / SiO 2 = 40 - 10, organic template agent / SiO 2 = 0.1 - 0.3, SiO 2 / ZrO 2 = 80 - 150. SiO 2 and ZrO 2 contents can be determined by chemical analysis, such as X-ray fluorescence spectrometry.

[0027] In some embodiments, in S3, the mass ratio of the pore-forming agent to the silicon-zirconium gel in the feed is 1:15 - 1:50, such as 1:20, 1:30, 1:40, etc.

[0028] In some embodiments, in S3, the pore-forming agent is selected from sodium carbonate, sodium bicarbonate, starch, ethylenediaminetetraacetic acid, preferably sodium bicarbonate.

[0029] In some embodiments, in S3, the pore-forming agent is added in the form of an aqueous solution.

[0030] In some embodiments, in S3, the mass ratio of the organic template agent to the silicon-zirconium gel in the feed is 1:20 - 1:5.

[0031] In some embodiments, in S3, the organic template agent is selected from 1,8-octanediamine, methyltriethylammonium chloride, hexamethyleneimine, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, preferably hexamethyleneimine.

[0032] In some embodiments, in S3, the organic template agent is added in the form of an aqueous solution.

[0033] On the other hand, the present invention provides a method for preparing a compound of the following formula (3),

[0034]

[0035] which includes the following reaction route:

[0036]

[0037] Among them, R is H or an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl, propyl); R 1 , R 2 , R 3 , R 4 and R 5 are each independently H or an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl, propyl),

[0038] including the following steps:

[0039] In the presence of a catalyst for preparing the compound of formula (3), subject the compound of formula (1) as a substrate to a nitration reaction with ammonia and hydrogen peroxide at 30 - 80 °C to obtain the nitro-substituted intermediate compound of formula (2); the compound of formula (2) undergoes a nucleophilic reaction with formaldehyde in the presence of ammonia water to form the target product, the compound of formula (3).

[0040] In some embodiments, the compound of formula (3) is the following compound of formula III:

[0041]

[0042] The method includes the following reaction route:

[0043]

[0044] including the following steps:

[0045] In the presence of a catalyst for preparing the compound of formula III, subject the compound of formula I to a nitration reaction with ammonia and hydrogen peroxide at 30 - 80 °C to obtain the nitro-substituted intermediate compound of formula II; the compound of formula II undergoes a nucleophilic reaction with formaldehyde in the presence of ammonia water to form the target product, the compound of formula III.

[0046] In some embodiments, a reaction solvent is used, and the reaction solvent is one or more selected from water, methanol, ethanol, isopropanol, and tert-butanol, preferably ethanol.

[0047] In some embodiments, the ammonia can be ammonia gas or ammonia water.

[0048] On the other hand, the present invention provides a method for preparing a supported enzyme catalyst for preparing a chiral β-amino alcohol represented by the following formula (4),

[0049]

[0050] Among them, R is H or an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl, propyl); R1 、R 2 、R 3 、R 4 and R 5 are each independently H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl),

[0051] The method includes:

[0052] A1. Preparation of β-cyclodextrin polymer

[0053] Take an N-methylpyrrolidone solution (concentration: 20 - 40 g / L), β-cyclodextrin and a silane coupling agent, stir and dissolve them, then add NaHCO 3 , to obtain a prepared solution, wherein, N-methylpyrrolidone accounts for 7 - 14 wt%, β-cyclodextrin accounts for 20 - 40 wt%, the silane coupling agent accounts for 45 - 55 wt%, and NaHCO 3 accounts for 1 - 5 wt%. Then, continuously stir the prepared solution at 40 - 80 °C for 8 - 15 hours. The solution turns yellow. After the reaction ends and the solution cools, pour it into acetone and stir for 10 - 30 min to produce a white precipitate. After vacuum filtration, repeatedly rinse it with acetone to form a cheese-like substance. Finally, place the sample in a vacuum drying oven and dry it at 30 - 50 °C for 4 - 7 hours to obtain a white powder of β-cyclodextrin polymer, and then take it out and grind it to obtain β-cyclodextrin polymer;

[0054] A2. Preparation of β-cyclodextrin-loaded enzyme catalyst

[0055] Prepare a 30 - 50 g / L solution of β-cyclodextrin polymer with deionized water, add PBS to adjust the pH value to 4 - 7, stir it at 25 - 40 °C for 10 - 30 hours, then add an enzyme (where the molar ratio of the enzyme to β-cyclodextrin polymer in the feed is 8:1 - 2:1), let it stand, centrifuge, remove the supernatant, and wash the obtained white precipitate to obtain the supported enzyme catalyst.

[0056] The present invention also provides a supported enzyme catalyst prepared by the above method.

[0057] In some embodiments, the compound of formula (4) is the following compound of formula IV (L-phenylglycinol):

[0058]

[0059] In some embodiments, in A1, the molar ratio of β-cyclodextrin to the silane coupling agent in the feed is 1:3 - 1:8, such as 1:4, 1:5, 1:6 or 1:7.

[0060] In some embodiments, in A2, the enzyme is one selected from ammonia dehydrogenase, transaminase, amidase, and nitroreductase, preferably nitroreductase.

[0061] On the other hand, the present invention provides a method for preparing a chiral β - amino alcohol represented by the following formula (4),

[0062]

[0063] wherein, R is H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl); R 1 , R 2 , R 3 , R 4 and R 5 are each independently H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl),

[0064] which includes the following reaction route:

[0065]

[0066] including the following steps:

[0067] At 30 - 70 °C, in the presence of the supported enzyme catalyst for preparing the chiral β - amino alcohol represented by formula (4), the substrate compound of formula (3) reacts to form the chiral β - amino alcohol represented by formula (4).

[0068] In some embodiments, the chiral β - amino alcohol represented by formula (4) is the following formula IV compound (L - phenylglycinol):

[0069]

[0070] The method includes the following reaction route:

[0071]

[0072] including the following steps:

[0073] At 30 - 70 °C, in the presence of the supported enzyme catalyst for preparing the chiral β - amino alcohol represented by formula IV, the substrate compound of formula III reacts to form the chiral β - amino alcohol represented by formula IV.

[0074] In some embodiments, a reaction solvent is used, and the reaction solvent is one or more selected from water, methanol, ethanol, isopropanol, or tert - butanol, preferably ethanol.

[0075] On another aspect, the present invention provides a one - pot method for preparing a chiral β - amino alcohol represented by formula (4),

[0076]

[0077] It includes the following reaction routes:

[0078]

[0079] Wherein, R is H or an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl, propyl); R 1 , R 2 , R 3 , R 4 and R 5 are each independently H or an alkyl group having 1 to 3 carbon atoms (for example, methyl, ethyl, propyl),

[0080] It includes the following steps:

[0081] Add the catalyst for preparing the compound of formula (3), the supported enzyme catalyst for preparing the chiral β-amino alcohol as shown in formula (4), and the solvent into a reactor. After mixing evenly, heat up to 35 - 60 °C (for example, 40 °C), and add the reaction substrate, the compound of formula (1), formaldehyde, ammonia, and hydrogen peroxide into the reactor. React for 30 - 55 h to obtain the chiral β-amino alcohol as shown in formula (4).

[0082] In some embodiments, the compound of formula (1) is the compound of formula I,

[0083]

[0084] The method includes the following reaction routes:

[0085]

[0086] It includes the following steps:

[0087] Add the catalyst for preparing the compound of formula III, the supported enzyme catalyst for preparing the chiral β-amino alcohol as shown in formula IV, and the solvent into a reactor. After mixing evenly, heat up to 35 - 60 °C (for example, 40 °C), and add the reaction substrate, the compound of formula (1), formaldehyde, ammonia (ammonia gas or ammonia water), and hydrogen peroxide into the reactor. React for 30 - 55 h to obtain the compound of formula IV.

[0088] In some embodiments, the molar ratio of the reaction substrate, the compound of formula (1), formaldehyde, ammonia, and hydrogen peroxide is about 1:(1 - 1.5):(2 - 3):(1 - 2), and particularly, the molar ratio is about 1:1.2:2.5:1.5.

[0089] In some embodiments, the mass feed ratio of the catalyst for preparing the compound of formula (3) to the reaction substrate is about 0.8:1 - 1.2:1; the mass feed ratio of the supported enzyme catalyst for preparing the chiral β-amino alcohol as shown in formula (4) to the reaction substrate is about 0.8:5 - 1.2:5; the mass feed ratio of the solvent to the reaction substrate is about 2:1 - 1.5:1.

[0090] In some embodiments, the ammonia may be ammonia gas or aqueous ammonia.

[0091] Compared with the prior art, the method of the present invention has the following beneficial effects:

[0092] 1) The present invention prepares a chemical catalyst and an enzyme catalyst for preparing chiral β-amino alcohol. Using the catalyst of the present invention to prepare chiral β-amino alcohol has the advantages of simple process, mild conditions, high yield, continuous operation, and being conducive to industrialization. In particular, compared with the existing preparation route of phenylglycine, this route realizes the one-pot preparation of chiral β-amino alcohol (L-phenylglycinol) through chemical catalytic coupling with biocatalysis, and has the advantages of low raw material cost, low reaction temperature, and high safety.

[0093] 2) The reaction route adopted by the present invention can convert 87% of benzaldehyde into L-phenylglycinol in one pot, and the highest yield can reach 83.5%, greatly improving the reaction efficiency. Description of the Drawings

[0094] Figure 1 is the scanning electron micrograph of the 2# molecular sieve catalyst obtained in Preparation Example 1 of the present invention.

[0095] Figure 2 is the scanning electron micrograph of the 1# enzyme catalyst obtained in Preparation Example 2 of the present invention.

[0096] Figure 3 is the standard curve of enzyme activity measured by the p-nitrophenol method in Example 1. Detailed Embodiments

[0097] As mentioned above, in view of the many defects of the prior art, the inventors of this case have put forward the technical solution of the present invention through long-term in-depth research and a large number of practices, which is specifically described as follows.

[0098] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; unless otherwise specified, the reagents, materials, etc. used in the following examples can all be obtained from commercial channels.

[0099] Reagent Sources and Detection Means

[0100] Nitroreductase was purchased from Shanghai Yuanye Bio-Technology Co., Ltd., product number S33787 - 5mg.

[0101] Benzaldehyde, formaldehyde, and ethanol were purchased from Aladdin Reagent Co., Ltd.; PBS buffer solution and hydrogen peroxide were purchased from Titan Technology Co., Ltd.; L-phenylglycinol and sodium bicarbonate were purchased from Sinopharm Reagent Co., Ltd.; β-cyclodextrin was purchased from Seebio Technology Co., Ltd., product number ACJ0063A; silane coupling agent KH560 was purchased from Nanjing Pining Coupling Agent Co., Ltd.

[0102] The crystal morphology of the samples was determined using a Hitachi S-4800 cold field high-resolution emission scanning electron microscope. Using the purified product as a standard, the concentration of substances during the conversion process was measured by high performance liquid chromatography (HPLC). High performance liquid chromatography analysis and quantification (Shimadazu LC-20A HPLC) were performed on a C18 reversed-phase chromatographic column with dimensions of 150×4.6 mm and a particle size of 5 μm. The mobile phase composition was: 15% H 2 O, 10% acetonitrile, 5% formic acid solution (≥98%, AR), and 70% methanol, v / v. The sample peak positions were: benzaldehyde at 14.12 min; formaldehyde at 8.531 min; L-phenylglycinol at 7.14 min.

[0103] Liquid sample detection of the reaction solution and products was carried out on a Bruker-Varian Plus 400 MHz nuclear magnetic resonance spectrometer. The sample to be measured was dissolved in a corresponding internal standard such as DMSO-D 6 to detect the types and numbers of hydrogen atoms in different chemical environments ( 1 1H-NMR).

[0104] Optical testing of chiral substances was carried out using Anton Paar MCP 5500, and the sample tube volume was 0.7 mL.

[0105] Preparation Example 1: Preparation of Zr-MFI zeolite catalyst

[0106] Dissolve Na 2 SiO 3 ·9H 2 O in hot water to prepare a silicon-containing aqueous solution with a Si 4+ concentration of 0.4 M; dissolve ZrOCl 2 ·8H 2 O in water to prepare a zirconium-containing aqueous solution with a Zr 4+ concentration of 0.4 M; under mechanical stirring, slowly add the zirconium-containing aqueous solution to the silicon-containing aqueous solution; then, slowly dropwise add 0.1 mol / L NaOH aqueous solution until the solution pH = 12 to form a precipitate. Filter the resulting mixture under reduced pressure to obtain the precipitate, wash the precipitate with deionized water, and dry it in an oven at 70 °C to prepare the silicon-zirconium gel.

[0107] After dissolving 20 g of industrial sodium metaaluminate in 100 ml of water, 40 ml of 0.1 mol / L NaOH solution and 40 ml of 0.1 mol / L KOH solution were added, and the mixture was stirred and dissolved thoroughly with magnetic stirring. Then 30 g of water glass was quickly poured into it to obtain a directing agent, and the directing agent was aged at room temperature for 14 h to obtain a directing gel.

[0108] In the above step, the directing agent is a aluminosilicate gel formed by the reaction of sodium metaaluminate, water glass and an alkali solution. Its chemical composition conforms to the following molar ratio: Al 2 O 3 :12SiO 2 :36Na 2 O:20K 2 O:950H 2 O.

[0109] To 5 g of the dried silica-zirconia gel, 20 mL of water was added, then 10 mL of 0.2 mol / L sodium bicarbonate aqueous solution and 15 mL of 5 wt% hexamethyleneimine aqueous solution were added. Then, based on the weight of the silica-zirconia gel, 0.8 wt% of the directing gel was added at room temperature and stirred for 3 h to obtain a mixture; the obtained mixture was transferred to a polytetrafluoroethylene autoclave, aged at 80 °C for 4 h, and finally crystallized statically in an oven at 160 °C for 12 h, 24 h, and 36 h respectively; the samples obtained by crystallization were filtered under reduced pressure, washed with deionized water, and dried in an oven at 70 °C; calcined at 500 °C for 7 h and pickled with 0.5 M HCl solution for 2 h to obtain Zr-MFI molecular sieve.

[0110] Among them, the crystallization formula is: H 2 O / SiO 2 =20, hexamethyleneimine / SiO 2 =0.2, SiO 2 / ZrO 2 =100;

[0111] Among them, the mass ratio of the pore-forming agent sodium bicarbonate to the silica-zirconia gel added is 1:5; the crystallization time is 12 h, 24 h, and 36 h;

[0112] The molecular sieve obtained with a crystallization time of 12 h is 1# molecular sieve, the molecular sieve obtained with a crystallization time of 24 h is 2# molecular sieve, and the molecular sieve obtained with a crystallization time of 36 h is 3# molecular sieve.

[0113] The specific surface area (S BET ) of the molecular sieve was obtained by the Brunner-Emmet-Teller method.

[0114] The external surface area (Sext ) and micropore volume (V micro );

[0115] The mesopore volume (V meso ) of the molecular sieve is obtained by BJH desorption;

[0116] The silicon-aluminum ratio (Si / Al) of the molecular sieve is detected by ICP;

[0117] Conversion-1h is the conversion rate of the substrate obtained by the following calculation formula by adding 20 mg of 1#, 2#, and 3# catalysts to three identical 10 ml 5 mol / L formaldehyde (substrate) solutions respectively, reacting for 1 hour, and then testing the content of the remaining formaldehyde (substrate) in the solution by high performance liquid chromatography.

[0118] The calculation formula is as follows:

[0119]

[0120] Table 1. Physicochemical properties of some molecular sieve catalyst samples

[0121]

[0122] Figure 1 is the scanning electron micrograph of the 2# molecular sieve catalyst obtained in Preparation Example 1 of the present invention.

[0123] Preparation Example 2: Preparation of cyclodextrin-immobilized enzyme catalyst

[0124] (1) Preparation of β-cyclodextrin polymer

[0125] Take 40 mL of N-methylpyrrolidone solution (30 g / L), weigh 4 g of β-cyclodextrin and 6 g of silane coupling agent KH560 according to a molar ratio of 1:5, pour them into a beaker and mix, stir to dissolve, add 0.3 g of NaHCO 3 , then put the prepared solution into a constant temperature water bath and stir continuously at 50 °C for 10 h. The solution turns yellow. After the reaction ends and the solution cools, quickly pour it into acetone and stir rapidly for 20 min. A large amount of white precipitate is found. After vacuum filtration, rinse repeatedly with acetone to form a cheese-like substance. Finally, put the sample into a vacuum drying oven and dry it at 35 °C for 5 h to obtain a white powder of β-cyclodextrin polymer, and then take it out and grind it to obtain β-cyclodextrin polymer.

[0126] (2) Preparation of β-cyclodextrin-immobilized enzyme catalyst

[0127] Weigh 4.0 g of β-cyclodextrin polymer, dissolve it with deionized water, and prepare a 40 g / L solution in a 100 mL volumetric flask. Weigh 10 mL of the above solution, add 10 mL of PBS solution to adjust the pH value to 5, stir it magnetically at high speed at 30 °C for 13 h, then add nitroreductase, let it stand, and centrifuge (4000 r·min -1 , 5 min), remove the supernatant, wash the obtained white precipitate with PBS solution three times, collect the precipitate, and that's it.

[0128] The catalyst obtained with a molar ratio of nitroreductase to β-cyclodextrin polymer of 3:1 is denoted as 1# enzyme catalyst, the catalyst obtained with a molar ratio of nitroreductase to β-cyclodextrin polymer of 5:1 is denoted as 2# enzyme catalyst, and the catalyst obtained with a molar ratio of nitroreductase to β-cyclodextrin polymer of 7:1 is denoted as 3# enzyme catalyst. Figure 2 This is the scanning electron micrograph of the 1# enzyme catalyst obtained in Preparation Example 2 of the present invention. Figure 2 It proves that the enzyme penetrates and distributes on the surface of β-cyclodextrin, and β-cyclodextrin has significant enzyme loading capacity.

[0129] Determination of enzyme activity

[0130] Standard curve for enzyme activity determination by p-nitrophenol method

[0131] Stock solution preparation: Weigh 5 mg of p-nitrophenol and dissolve it in 20 mL of PBS (pH 6.5, 0.01 M), 1 mL of acetonitrile, and 20 mL of acetone;

[0132] Diluent preparation: Measure 20 mL of PBS (pH 6.5, 0.01 M), 1 mL of acetonitrile, and 20 mL of acetone. Then dilute the stock solution of p-nitrophenol concentration to 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, and then measure the ultraviolet absorption value at 405 nm with a protein analyzer. Finally, with the p-nitrophenol concentration as the ordinate and the OD 405 ultraviolet light absorption value as the abscissa, draw a standard curve. The blank control solution is 5 mL of the diluent.

[0133] Determination of enzyme activity: Take 50 μL of enzyme solution (nitroreductase, purchased from Shanghai Yuanye Bio-Technology Co., Ltd., product number S33787-5mg) and add it to 2 mL of PBS (100 mM, pH 6.5). This solution is incubated at 37 °C in a shaker at 150 rpm for 5 minutes. Then add 4-nitrophenyl acetate (50 μL, 50 mM), shake for 5 minutes. Finally, add 2 mL of acetone to terminate the reaction and immediately measure its absorbance at 405 nm.

[0134] Figure 3This is the standard curve of enzyme activity measured by the p-nitrophenol method. From Figure 3 the obtained standard curve is y = 49.3203x + 0.2888, and its regression coefficient is 0.9998.

[0135] Example 1

[0136] (1) Take 10 g of 1# molecular sieve and add it to a 500 mL autoclave, and then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it up to 60 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is about 1:1.2:2.5:1.5) into the reactor. After reacting for 24 h and detecting, 142 g of 2-nitro-2-phenylethanol is obtained. The conversion rate of benzaldehyde is about 93%, and the molar yield of 2-nitro-2-phenylethanol based on benzaldehyde is about 92.5%. After 1 1H-NMR detection, the peak positions of the product are δ 7.0 ppm, 5H; δ 3.8 ppm, 2H; δ 3.6 ppm, 1H; δ 3.2 ppm, 1H.

[0137] (2) Take 20 g of 1# enzyme catalyst and add it to a 500 mL autoclave, and then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it up to 40 °C. Add 100 g of the product 2-nitro-2-phenylethanol obtained in (1) into the reactor. After reacting for 18 h and detecting, 72 g of L-phenylglycinol is obtained. The molar yield of L-phenylglycinol based on 2-nitro-2-phenylethanol is about 88%. After chiral optical testing, its specific rotation is about +33.5°; after 1 1H-NMR detection, the peak positions of the product are δ 7.2 ppm, 5H; δ 3.7 ppm, 2H; δ 4.0 ppm, 1H; δ 2.4 ppm, 1H; δ 2.0 ppm, 2H.

[0138] Example 2

[0139] Take 10 g of 1# molecular sieve and add it to a 500 mL autoclave, take 20 g of 1# enzyme catalyst and add it to a 500 mL autoclave, and then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it up to 40 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is about 1:1.2:2.5:1.5) into the reactor. After reacting for 42 h and detecting, 86 g of L-phenylglycinol is obtained. The conversion rate of benzaldehyde is about 79%, and the molar yield of L-phenylglycinol based on benzaldehyde is about 80%.

[0140] After chiral optical testing, its specific rotation is about +33.0°; after 1The peak positions of the product obtained by \(^1\)H-NMR detection are δ 7.4 ppm, 5H; δ 3.8 ppm, 2H; δ 4.2 ppm, 1H; δ 2.6 ppm, 1H; δ 2.2 ppm, 2H.

[0141] Example 3

[0142] (1) Take 10 g of 2# molecular sieve and add it to a 500 mL autoclave, then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it to 60 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is about 1:1.2:2.5:1.5) into the reactor. After reacting for 24 h and detecting, 149 g of 2-nitro-2-phenylethanol product is obtained. The conversion rate of benzaldehyde is about 96%, and the molar yield of 2-nitro-2-phenylethanol based on benzaldehyde is 93.4%. After 1 The peak positions of the product obtained by \(^1\)H-NMR detection are δ 7.5 ppm, 5H; δ 3.8 ppm, 2H; δ 3.5 ppm, 1H; δ 3.0 ppm, 1H.

[0143] (2) Take 20 g of 2# enzyme catalyst and add it to a 500 mL autoclave, then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it to 40 °C. Add 100 g of the product 2-nitro-2-phenylethanol obtained in (1) into the reactor. After reacting for 18 h and detecting, 68 g of L-phenylglycinol is obtained. The molar yield of L-phenylglycinol based on 2-nitro-2-phenylethanol is about 84%. After chiral optical testing, its specific rotation is about +31.9°; after 1 The peak positions of the product obtained by \(^1\)H-NMR detection are δ 7.3 ppm, 5H; δ 3.8 ppm, 2H; δ 4.0 ppm, 1H; δ 2.3 ppm, 1H; δ 2.1 ppm, 2H.

[0144] Example 4

[0145] Take 10 g of 2# molecular sieve and add it to a 500 mL autoclave, take 20 g of 2# enzyme catalyst and add it to a 500 mL autoclave, then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it to 40 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is about 1:1.2:2.5:1.5) into the reactor. After reacting for 42 h and detecting, 90 g of L-phenylglycinol is obtained. The conversion rate of benzaldehyde is about 82%, and the molar yield of L-phenylglycinol based on benzaldehyde is about 80.8%.

[0146] After chiral optical testing, its specific rotation is about +31.7°; after 1The peak positions of the product obtained by \(^1H\)-NMR detection are δ 7.2 ppm, 5H; δ 3.6 ppm, 2H; δ 4.2 ppm, 1H; δ 2.7 ppm, 1H; δ 2.0 ppm, 2H.

[0147] Example 5

[0148] (1) Take 10 g of 3# molecular sieve and add it to a 500 mL autoclave, then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it to 60 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is approximately 1:1.2:2.5:1.5) into the reactor. After reacting for 24 h and detecting, 128 g of 2-nitro-2-phenylethanol product is obtained. The conversion rate of benzaldehyde is approximately 85%, and the molar yield of 2-nitro-2-phenylethanol based on benzaldehyde is 91%. After 1 The peak positions of the product obtained by \(^1H\)-NMR detection are δ 7.2 ppm, 5H; δ 3.8 ppm, 2H; δ 3.4 ppm, 1H; δ 3.7 ppm, 1H.

[0149] (2) Take 20 g of 3# enzyme catalyst and add it to a 500 mL autoclave, then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it to 40 °C. Add 100 g of the product 2-nitro-2-phenylethanol obtained in (1) into the reactor. After reacting for 18 h and detecting, 61 g of L-phenylglycinol is obtained. The molar yield of L-phenylglycinol based on 2-nitro-2-phenylethanol is approximately 76%. After chiral optical testing, its specific rotation is approximately +32.5°; after 1 The peak positions of the product obtained by \(^1H\)-NMR detection are δ 7.4 ppm, 5H; δ 3.5 ppm, 2H; δ 4.0 ppm, 1H; δ 2.5 ppm, 1H; δ 2.0 ppm, 2H.

[0150] Example 6

[0151] Take 10 g of 3# molecular sieve and add it to a 500 mL autoclave, take 20 g of 3# enzyme catalyst and add it to a 500 mL autoclave, then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it to 40 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is approximately 1:1.2:2.5:1.5) into the reactor. After reacting for 42 h and detecting, 74 g of L-phenylglycinol is obtained. The conversion rate of benzaldehyde is approximately 73%, and the molar yield of L-phenylglycinol based on benzaldehyde is approximately 74.5%.

[0152] After chiral optical testing, its specific rotation is approximately +32.0°; after 1The peak positions of the product obtained by \(^1\)H-NMR detection are δ 7.3 ppm, 5H; δ 3.7 ppm, 2H; δ 4.1 ppm, 1H; δ 2.3 ppm, 1H; δ 1.9 ppm, 2H.

[0153] Example 7

[0154] Take 10 g of 2# molecular sieve and add it to a 500 mL autoclave. Take 20 g of 1# enzyme catalyst and add it to a 500 mL autoclave, and then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it up to 40 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is about 1:1.2:2.5:1.5) into the reactor. After reacting for 42 h and detecting, 98 g of L-phenylglycinol is obtained. The conversion rate of benzaldehyde is about 87%, and the molar yield of L-phenylglycinol based on benzaldehyde is about 83.5%.

[0155] The specific rotation obtained by chiral optical test is about +32.5°; by 1 The peak positions of the product obtained by \(^1\)H-NMR detection are δ 7.2 ppm, 5H; δ 3.6 ppm, 2H; δ 4.0 ppm, 1H; δ 2.2 ppm, 1H; δ 1.7 ppm, 2H.

[0156] Comparative Example 1

[0157] An uncrystallized sample of Zr-MFI molecular sieve was prepared in the same manner as in Preparation Example 1 except that the crystallization step was not carried out.

[0158] Add 10 g of the uncrystallized sample of Zr-MFI molecular sieve to a 500 mL autoclave, and then add 180 g of solvent ethanol. After stirring and mixing evenly, heat it up to 60 °C. Continuously add 106 g of benzaldehyde, 36 g of formaldehyde, 88 g of ammonia water, and 51 g of 50% hydrogen peroxide (the molar ratio of the materials is about 1:1.2:2.5:1.5) into the reactor. After reacting for 24 h and detecting, 52 g of 2-nitro-2-phenylethanol product is obtained. The conversion rate of benzaldehyde is about 35%, and the molar yield of 2-nitro-2-phenylethanol based on benzaldehyde is 37%. By 1 The peak positions of the product obtained by \(^1\)H-NMR detection are δ 7.5 ppm, 5H; δ 4.0 ppm, 2H; δ 3.0 ppm, 1H; δ 3.3 ppm, 1H.

[0159] It shows that the activity of the uncrystallized molecular sieve catalyst is very low, and the crystallization step can greatly improve the activity of the molecular sieve catalyst.

[0160] Comparative Example 2

[0161] 20 g of β-cyclodextrin polymer without supported enzyme catalyst was added to a 500 mL autoclave, and 180 g of solvent ethanol was added. After stirring and mixing evenly, the temperature was raised to 40 °C. 100 g of 2-nitro-2-phenyl-ethanol was added into the reactor. After reacting for 18 h and detection, 0 g of L-phenylglycinol was obtained, and the molar yield of L-phenylglycinol based on 2-nitro-2-phenyl-ethanol was about 0%.

[0162] It shows that the enzyme-catalyzed step cannot proceed by directly adding β-cyclodextrin polymer.

[0163] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention, rather than limiting them; although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing examples, or perform equivalent replacements for some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a catalyst for preparing a compound of formula (3), In formula (3), R is H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl); R1, R2, R3, R4 and R5 are each independently H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl), Preferably, the compound of formula (3) is a compound of formula III: The method comprises: S1, dissolve the silicon source in water to form Si 4+ A silicon-containing aqueous solution with a concentration of 0.3-0.6M; dissolve the zirconium source in water to prepare Zr 4+ A zirconium-containing aqueous solution with a concentration of 0.3-0.6M; under mechanical stirring, the zirconium-containing aqueous solution is added to the silicon-containing aqueous solution; subsequently, an alkaline aqueous solution is added dropwise thereto until the pH of the solution is greater than 9 to obtain a precipitate, and the precipitate is filtered, washed, and dried to prepare a silicon-zirconium gel; S2, by mixing sodium aluminate, water glass and alkaline solution to generate aluminosilicate gel to obtain a guiding agent with a molar ratio of Al2O3: (5-20) SiO2: (20-50) Na2O: (15-25) K2O: (800-1000) H2O, aging the guiding agent at room temperature for 10-20 hours to obtain a guiding glue; S3, adding water to the silica-zirconium gel obtained in S1 at a mass ratio of 1:2-1:4 between the silica-zirconium gel and water, then adding a pore-forming agent and an organic template, and then adding 0.5-2wt% of the guiding glue obtained in S2 based on the weight of the silica-zirconium gel at room temperature, stirring for 1-4 hours to obtain a mixture; transferring the mixture to a hydrothermal reactor, aging at 50-100°C for 3-8 hours, and then placing the reactor in an oven at 150-200°C for static crystallization for 10-50 hours; filtering, washing, and drying the crystallized sample, and then calcining at 400-600°C for 5-10 hours, adding an acid solution (such as an aqueous HCl solution) for acid washing for 1-4 hours to obtain a catalyst Zr-MFI zeolite.

2. The preparation method according to claim 1, wherein: In S1, the silicon source is selected from sodium silicate, tetraethyl silicate, sodium aluminum silicate; and / or In S1, the zirconium source is selected from zirconium oxychloride (e.g., ZrOCl2·8H2O), tetraethoxy zirconium, zirconocene dichloride, zirconium nitrate; and / or In S1, the silicon source and the zirconium source are added so that the molar ratio of silicon to zirconium is 1:1; and / or In S1, the alkaline aqueous solution can be selected from NaOH aqueous solution, KOH aqueous solution, Na2CO3 aqueous solution, NaHCO3 aqueous solution; and / or In S2, the alkaline solution is an aqueous solution containing NaOH and KOH in a molar ratio of 2:1 to 1:1; and / or In S2, the chemical composition of the directing agent conforms to the following molar ratio: Al2O3: (10-15) SiO2: (30-40) Na2O: (15-25) K2O: (800-1000) H2O, more preferably, the chemical composition of the directing agent conforms to the following molar ratio: Al2O3: 12SiO2: 36Na2O: 20K2O: 950H2O; and / or In S3, the crystallization formula is: H2O / SiO2=40-10, organic template / SiO2=0.1-0.3, SiO2 / ZrO2=80-150; and / or In S3, the mass ratio of the pore-forming agent to the silicon-zirconium gel is 1:15-1:50; and / or In S3, the pore-forming agent is selected from sodium carbonate, sodium bicarbonate, starch, ethylenediaminetetraacetic acid, preferably sodium bicarbonate; and / or In S3, the pore former is added in the form of an aqueous solution; and / or In S3, the mass ratio of the organic template to the silicon zirconium gel is 1:20-1:5; and / or In S3, the organic template is selected from 1,8-octanediamine, methyltriethylammonium chloride, hexamethyleneimine, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, preferably hexamethyleneimine; and / or In S3, the organic template is added in the form of an aqueous solution.

3. A catalyst prepared by the preparation method according to claim 1 or 2.

4. A method for preparing a compound of formula (3), It includes the following reaction scheme: in, R is H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl); R1, R2, R3, R4 and R5 are each independently H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl), The following steps are involved: In the presence of the catalyst as claimed in claim 3, the substrate compound of formula (1) is subjected to a nitration reaction with ammonia and hydrogen peroxide at 30-80° C. to obtain a nitro-substituted intermediate compound of formula (2); the compound of formula (2) is subjected to a nucleophilic reaction with formaldehyde in the presence of ammonia to generate a target product compound of formula (3), Preferably, the compound of formula (3) is a compound of formula III: The method comprises the following reaction scheme: The following steps are involved: In the presence of the catalyst as claimed in claim 3, the compound of formula I is subjected to a nitration reaction with ammonia and hydrogen peroxide at 30-80° C. to obtain a nitro-substituted intermediate compound of formula II; the compound of formula II is subjected to a nucleophilic reaction with formaldehyde in the presence of ammonia to generate a target product compound of formula III, More preferably, Using a reaction solvent, wherein the reaction solvent is one or more selected from water, methanol, ethanol, isopropanol and tert-butanol, preferably ethanol; and / or The ammonia is ammonia gas or ammonia water.

5. A method for preparing a supported enzyme catalyst for preparing a chiral β-amino alcohol as shown in the following formula (4), in, R is H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl); R1, R2, R3, R4 and R5 are each independently H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl), Preferably, the compound of formula (4) is a compound of formula IV (L-phenylglycinol): The method comprises: A1, Preparation of β-cyclodextrin polymer Take N-methylpyrrolidone solution (concentration of 20-40g / L), β-cyclodextrin and silane coupling agent, stir and dissolve, then add NaHCO3 to obtain a prepared solution, wherein N-methylpyrrolidone accounts for 7-14wt%, β-cyclodextrin accounts for 20-40wt%, silane coupling agent accounts for 45-55wt%, NaHCO3 accounts for 1-5wt%, and then the prepared solution is continuously stirred at 40-80°C for 8-15 hours, the solution is yellow, after the reaction is completed and the solution is cooled, acetone is poured into it and stirred for 10-30min to produce a white precipitate, after reduced pressure filtration, it is repeatedly rinsed with acetone to form a cheese-like, and finally the sample is placed in a vacuum drying oven and dried at 30-50°C for 4-7 hours to obtain a white powder of β-cyclodextrin polymer, and then it is taken out and ground to obtain a β-cyclodextrin polymer; A2, Preparation of β-cyclodextrin-loaded enzyme catalyst The β-cyclodextrin polymer is prepared into a 30-50 g / L solution with deionized water, PBS is added to adjust the pH value to 4-7, the solution is stirred at 25-40°C for 10-30 hours, and then the enzyme (wherein the molar ratio of enzyme to β-cyclodextrin polymer is 8:1-2:1) is added, the solution is allowed to stand, centrifuged, the supernatant is removed, and the obtained white precipitate is washed to obtain a supported enzyme catalyst. Further preferably, wherein: In A1, the molar ratio of β-cyclodextrin to silane coupling agent is 1:3-1:8, for example, 1:4, 1:5, 1:6 or 1:7; and / or In A2, the enzyme is one selected from ammonia dehydrogenase, transaminase, amidase, and nitroreductase, preferably nitroreductase.

6. A supported enzyme catalyst prepared by the preparation method according to claim 5.

7. A method for preparing a chiral β-amino alcohol as shown in the following formula (4): in, R is H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl); R1, R2, R3, R4 and R5 are each independently H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl), It includes the following reaction scheme: The following steps are involved: At 30-70° C., in the presence of the supported enzyme catalyst as claimed in claim 6, reacting the substrate compound of formula (3) to generate a chiral β-amino alcohol as shown in formula (4); In particular, the chiral β-amino alcohol represented by formula (4) is a compound of formula IV (L-phenylglycinol): The method comprises the following reaction scheme: The following steps are involved: At 30-70° C., in the presence of the supported enzyme catalyst as claimed in claim 6, reacting the substrate compound of formula III to generate a chiral β-amino alcohol as shown in formula IV, Further preferably, wherein: A reaction solvent is used, and the reaction solvent is one or more selected from water, methanol, ethanol, isopropanol or tert-butanol, preferably ethanol.

8. A one-pot method for preparing a chiral β-amino alcohol as shown in formula (4), It includes the following reaction scheme: in, R is H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl); R1, R2, R3, R4 and R5 are each independently H or an alkyl group having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl), The following steps are involved: The catalyst as claimed in claim 3, the supported enzyme catalyst as claimed in claim 6, and the solvent are added to a reactor, mixed evenly, and then heated to 35-60° C. (for example, 40° C.), and the reaction substrate compound of formula (1), formaldehyde, ammonia, and hydrogen peroxide are added to the reactor, and the reaction is carried out for 30-55 hours to obtain a chiral β-amino alcohol as shown in formula (4).

9. The method according to claim 8, wherein: The compound of formula (1) is a compound of formula I, The method comprises the following reaction scheme: The following steps are involved: The catalyst as claimed in claim 3, the supported enzyme catalyst as claimed in claim 6, and the solvent are added to a reactor, mixed evenly, and then heated to 35-60° C. (for example, 40° C.), and the reaction substrate compound of formula (1), formaldehyde, ammonia, and hydrogen peroxide are added to the reactor, and the reaction is carried out for 30-55 hours to obtain a compound of formula IV.

10. The method according to claim 8 or 9, wherein: The molar ratio of the reaction substrate compound of formula (1), formaldehyde, ammonia and hydrogen peroxide is about 1:(1-1.5):(2-3):(1-2), especially, the molar ratio is about 1:1.2:2.5:1.5; and / or The mass feed ratio of the catalyst according to claim 3 to the reaction substrate is about 0.8:1-1.2:1; the mass feed ratio of the supported enzyme catalyst to the reaction substrate is about 0.8:5-1.2:5; the mass feed ratio of the solvent to the reaction substrate is about 2:1-1.5:1; and / or The ammonia is ammonia gas or ammonia water.

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