Preparation method of (R)-2-((4-aminophenylethyl) amino)-1-phenylethyl-1-alcohol

Abstract

The invention discloses a preparation method of (R)-2-((4-aminophenylethyl) amino)-1-phenylethyl-1-alcohol, and belongs to the field of preparation of drug intermediates. (R)-2-((4-nitrophenyl ethyl) amino)-1-phenylethyl-1-alcohol is used as a raw material, an alkali metal borohydride and nickel chloride reduction system is used for reduction, and after-treatment and purification are carried out, a target product is obtained. Compared with the prior art, the method has the advantages that the raw materials are easy to obtain and convenient to store, the reaction process is high in safety, good in controllability, mild in reaction condition and low in toxicity, and the obtained product is high in yield, high in purity, good in quality, suitable for industrial production and the like.

Description

Technical Field

[0001] The invention relates to a method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol in the field of preparation of a drug mirabegron intermediate. Background Art

[0002] Overactive bladder (OAB) is a syndrome that describes bladder dysfunction, with related symptoms including urgency, frequency, nocturia, with or without urge incontinence, etc. According to epidemiological data, the incidence of OAB ranges from about 14% to 44%.

[0003] At present, the drugs used in clinical treatment of OAB are mainly selective muscarinic cholinergic receptor (M receptor) antagonists. The mechanism of action of this type of drug is to block the binding of acetylcholine to M3 receptors, inhibit the involuntary contraction of the bladder detrusor muscle, and thus delay urination. Although the efficacy is definite, this type of drug has a large individual selectivity and some related side effects, such as uncontrolled glaucoma, severe urinary retention, patients with a history of allergy to this type of drug, and toxic megacolon. In September 2018, Mirabegron sustained-release tablets were launched in China. It is the first and only β3 adrenergic receptor agonist. Compared with anticholinergic drugs such as solifenacin and tolterodine, it has the advantages of not affecting bladder emptying and not easily causing acute urinary retention. It can effectively improve the symptoms of patients with overactive urination, such as frequent urination, urgency at night, and urinary incontinence, and has few adverse reactions. Long-term treatment compliance is better than other M receptor antagonists. The launch of Mirabegron sustained-release tablets in China fills the gap in β3 receptor agonists in OAB treatment drugs.

[0004] According to MinEnet data, in 2022, OAB treatment drugs, including tolterodine, solifenacin, mirabegron, etc., had a total sales of 217 million yuan in public medical institutions, and the market size increased by 10% compared with the previous year. Mirabegron's sales have grown rapidly in recent years, from 140,000 yuan in 2018 to 55.83 million yuan in 2022. The sales in 2022 are 400 times that of 2018, and it has occupied a quarter of the market share of OAB treatment drugs, with considerable market prospects and huge market potential.

[0005] In the synthetic route of mirabegron API, (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is an important intermediate.

[0006] (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol, English chemical name (R)-2-((4-aminophenethyl)amino)-1-phenylethan-1-ol, structural formula see attached Figure 1 , molecular formula C16 H 20 N 2 O, with a molecular weight of 256.35, is a key intermediate in the industrial synthesis of mirabegron, and it is necessary to study its preparation method.

[0007] The compound molecule contains an amino group. The industrial synthesis and preparation of mirabegron is to reduce the nitro group of the intermediate in the previous step to an amino group. The classic method for reducing the nitro group to an amino group is to use hydrogen as a reducing agent to reduce the nitro group under the catalysis of palladium / carbon (Pd / C). The original patent for the preparation of mirabegron (patent CN1243740C) is to reduce the nitro group to an amino group under the catalysis of wet 10% Pd / C and methanol as a solvent. The methods of Chinese patents CN103896872A, CN104230840A, CN114539084B, and CN114539182B all use hydrogen to reduce the nitro group to an amino group under the catalysis of Pd / C and methanol as a solvent under normal pressure / pressurized conditions. Hydrogen is used as a reducing agent, which is flammable and explosive, has a large safety risk, and has high requirements for equipment, and is not suitable for large-scale industrial production. At the same time, metal catalysts such as Pd / C contain palladium and are relatively expensive. Therefore, various methods for replacing Pd / CH 2 reduction system.

[0008] Patents WO2014132270A2, WO2015044965A1, and WO2015155664A1 report a method for reducing nitro groups. Under Raney nickel catalysis, methanol is used as a solvent and hydrogen is used to reduce nitro groups to amino groups. This method also uses hydrogen, which is flammable and explosive and has high safety risks, and needs to be pressurized to 4-5kg / cm 2 Or 60psi, which is equivalent to about 4 standard atmospheric pressures, and the safety risk is higher.

[0009] In patents CN109456277B, CN109651290B, and CN105481705A, the organic compound ammonium formate is used to replace hydrogen as a hydrogen donor, and the nitro group is reduced to an amino group under normal pressure conditions with methanol as a solvent under the catalysis of Pd / C. This method avoids the technical, equipment, and safety issues caused by the direct use of hydrogen, but the use of a hydrogen source such as ammonium formate for reduction will produce formylated impurities, which will participate in subsequent reactions and derive into finished products, and these impurities are difficult to remove, thereby affecting the quality of the API. At the same time, it still cannot avoid the use of metal catalysts such as Pd / C, which are more expensive.

[0010] Patents CN104876889B, WO2014132270A2, and WO2015155664A1 report the use of an iron powder / hydrochloric acid system to reduce nitro groups to amino groups. This method solves the shortcomings of metal-catalyzed hydrogenation reduction, avoiding the use of special high-pressure equipment and the use of flammable and explosive hydrogen, but the method uses a large amount of iron powder, produces a large amount of waste residue, and is not environmentally friendly. In addition, the iron powder has a large density and is easy to settle. The reaction process has high requirements for equipment stirring and mixing, and the process is difficult to scale up.

[0011] Patents CN113816864B and CN113880720A reported the use of hydrazine hydrate-ferric chloride hexahydrate-activated carbon system to reduce nitro groups to amino groups. Hydrazine hydrate is highly toxic and can cause toxic side effects on the liver, kidneys, blood and other systems. ICH M7 data shows that hydrazine hydrate is mutagenic and is usually controlled as a genotoxic impurity. Therefore, it is required that the residual amount of hydrazine hydrate in the drug must be below the acceptable limit. The most important feature of genotoxic impurities is that they can cause damage to human genetic material at extremely low concentrations, leading to gene mutations and promoting tumor occurrence. Because of its strong toxicity, it poses a strong threat to the safety of drugs. There have been many cases in the industry where marketed drugs have been forcibly recalled due to non-compliance with genotoxic impurity control. Therefore, today when individuals pay more attention to their own health and review agencies are more stringent in verifying the compliance of drug quality, such substances should be introduced with caution. Hydrazine hydrate compounds are relatively active and highly polar, and are poorly retained by conventional HPLC columns. They are usually difficult to detect directly by high performance liquid chromatography, so the liquid chromatography method for hydrazine hydrate requires the use of a derivatization method, which increases the difficulty and cost of the operation.

[0012] Therefore, it is a new issue to be solved urgently to find a method with high safety, simple operation, high yield, high purity, good product quality, mild reaction conditions, low cost and green environmental protection to reduce the nitro group of (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol to amino group and prepare (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol. Summary of the invention

[0013] The object of the present invention is to provide a method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol, which has high safety, simple operation, high yield, high purity, good product quality, mild reaction conditions, low cost and is green and environmentally friendly.

[0014] The object of the present invention is achieved by: a method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol, the method comprising the following steps:

[0015] (1) reacting (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or a salt thereof, nickel chloride, and an alkali metal borohydride in the presence of a first organic solvent and water;

[0016] (2) After the reaction is completed, the pH value of the reaction solution is adjusted to 1-5 with the first acid for acidification;

[0017] (3) adding a second organic solvent and a first base, adjusting the pH value to 8-12 for alkalization, extracting and stratifying to obtain a first organic layer and an aqueous layer;

[0018] (4) adding a second organic solvent to the aqueous layer, extracting for 0 to 10 times to obtain a second organic layer, combining the first organic layer and the second organic layer to obtain a combined organic layer; washing the combined organic layer with a salt aqueous solution and water, respectively, to obtain a washed organic layer;

[0019] (5) concentrating the washed organic layer to dryness under reduced pressure, adding a crystallization solvent, and performing thorough crystallization;

[0020] (6) (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is obtained.

[0021] In step (1), the first organic solvent is selected from an ether solvent, and the ether solvent is selected from one or more of isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and ethylene glycol dimethyl ether; in step (1), the salt is selected from one or more of hydrochloride, sulfate, and phosphate; the nickel chloride is selected from one or more of anhydrous nickel chloride, nickel chloride dihydrate, nickel chloride tetrahydrate, and nickel chloride hexahydrate; the alkali metal borohydride is selected from one or more of sodium borohydride, potassium borohydride, and lithium borohydride; the reaction temperature is 35 to 50°C, preferably 38 to 50°C, and more preferably The reaction temperature is 40-47° C.; the reaction time is 20 min-600 min, preferably, the reaction time is 25 min-300 min, more preferably, the reaction time is 25 min-120 min; the molar ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to nickel chloride is 1:0.05-0.5, preferably, the molar ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to nickel chloride is 1:0.06-0.2, more preferably, The molar ratio of the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to nickel chloride is 1:0.06-0.16; the molar ratio of the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to alkali metal borohydride is 1:3-9. Preferably, the molar ratio of the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to alkali metal borohydride is 1:5-8. More preferably, the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to alkali metal borohydride is 1:5-8. The molar ratio of its salt to the alkali metal borohydride is 1:6-8; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the first organic solvent is 1:3-10, preferably, the volume ratio is 1:5-9, the unit of the weight is kg, and the unit of the volume is L; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to water is 5:80-200, preferably, the volume ratio is 5:100-160, the unit of the weight is kg, and the unit of the volume is L.

[0022] In step (2), the first acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and tartaric acid; the pH value of the reaction solution is adjusted to 1-4 by the first acid, and preferably the pH value of the reaction solution is adjusted to 2-3 by the first acid; the acidification temperature is 50-60°C, and preferably, the acidification temperature is 52-58°C; the acidification time is 10-300min, and preferably, the acidification time is 20-150min, and more preferably, the acidification time is 20-120min; after the acidification, the step of cooling the temperature to 10-40°C is also included, and preferably, the step of cooling the temperature to 20-30°C is also included after the acidification.

[0023] In step (3), the second organic solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, ether, isopropyl acetate, n-hexane, and n-pentane; the first alkali is selected from one of ammonia water or a combination of ammonia water and a second alkali aqueous solution; the second alkali is selected from alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates; the alkali metal hydroxide is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; the alkali metal carbonate is selected from one or more of sodium carbonate, potassium carbonate, and lithium carbonate; the alkali metal bicarbonate is selected from one or more of sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate; the concentration of the ammonia water is 1-30%, preferably, The concentration is 5-20%; the pH value is adjusted to 8-11 for alkalization, preferably, the pH value is adjusted to 9-10 for alkalization; the alkalization time is 0.4h-2h, preferably, the alkalization time is 0.4h-1h; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the second organic solvent in step (3) is 5:70-300, preferably, the ratio is 5:50-300, more preferably, the ratio is 5:70-210, the unit of the weight is kg, and the unit of the volume is L; the combination of the ammonia water and the second alkaline aqueous solution is added in a manner of first adding the ammonia water and then adding the second alkaline aqueous solution.

[0024] In step (4), the extraction is performed 0-5 times, preferably 0-3 times; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the second organic solvent in step (4) is 5:30-300, preferably 5:50-210; the salt aqueous solution is selected from one or more of a reducing salt aqueous solution and a saline solution; the saline solution is selected from a 10%-saturated saline solution; the reducing salt aqueous solution is selected from a 1%-30% reducing salt aqueous solution; the washing of the combined organic layer with the salt aqueous solution and water is specifically washing with a reducing salt aqueous solution, water, and a saline solution in sequence; the reducing salt aqueous solution is selected from one or more of a sodium thiosulfate aqueous solution, a sodium sulfite aqueous solution, a ferrous sulfate aqueous solution, a sodium sulfide aqueous solution, and a sodium oxalate aqueous solution.

[0025] In step (5), the crystallization solvent is selected from a mixed solvent of the second organic solvent and the first alcohol solvent; the first alcohol solvent is selected from one or more of methanol, ethanol, propanol, and isopropanol; in step (5), after the full crystallization, the steps of filtering, washing, and drying are also included; the washing adopts the first alcohol solvent; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the crystallization solvent is 5:20 -50, preferably, the volume ratio of the weight of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the crystallization solvent is 5:25-40, the unit of the weight is kg, and the unit of the volume is L; in step (5), the volume ratio of the second organic solvent to the first alcohol solvent is 10-45:0.1-10, preferably, the volume ratio is 20-40:0.1-5, and more preferably, the volume ratio is 25-35:0.5-2.

[0026] In step (5), after adding the crystallization solvent and before fully crystallizing, the step of adding a second acid to adjust the pH to 1-4 is also included. Preferably, the step of adding a second acid to adjust the pH to 1.5-3 is also included; the second acid is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, and tartaric acid; the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is selected from (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol hydrochloride, (R)-2-((4-aminophenethyl)amino)-1-phenylethyl -1-ol sulfate, (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol phosphate, (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol tartrate; the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol hydrochloride is selected from (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride; the crystallization time is 1-4 hours, preferably, the crystallization time is 1.5-3 hours.

[0027] The purity of the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is greater than 90%, preferably greater than 95%, and more preferably greater than 99%. The purity of the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is greater than 99.5%.

[0028] The gist of the present invention is to provide a method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol. The pharmaceutical principle is as follows: (1) using an "alkali metal borohydride + nickel chloride" reduction system for reduction can achieve very good reaction results, and the target product obtained has high yield, high purity, mild reaction conditions, high safety, and does not require the use of hydrogen; (2) the product yield can be better improved by optimizing the type of organic solvent in the reaction; (3) a good reaction effect can be obtained by optimizing reaction conditions such as reaction temperature and reaction time; (4) by selecting the molar ratio of (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol to sodium borohydride or potassium borohydride and nickel chloride hexahydrate in the reaction; , the degree of reaction can be precisely controlled, the yield and quality of the product can be better improved, and the occurrence of side reactions can be reduced; (5) the organic layer is washed with a salt aqueous solution (a salt aqueous solution with reducing properties, a salt water solution) and water respectively, which can effectively remove peroxide impurities, water-soluble salts, alkaline substances, etc. in the organic layer and facilitate stratification, thereby improving the yield and purity of the product; (6) by selecting the crystallization solvent and the amount used, a better product yield and purity can be obtained; (7) the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol obtained by the present invention has high purity, does not require recrystallization, and reduces the number of operating steps.

[0029] Compared with the prior art, the preparation method of (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol has the advantages of easy availability of raw materials and convenient storage, high safety and controllability of the reaction process, mild reaction conditions, low toxicity, high yield, high purity and good quality of the obtained product, and is suitable for industrial production. The method will be widely used in the field of preparation of intermediates of the compound mirabegron. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The present invention is described in detail below with reference to the accompanying drawings and embodiments.

[0031] Figure 1 The structural formula of (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is shown.

[0032] Figure 2 This is the structural formula of (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol.

[0033] Figure 3 The present invention is a schematic diagram of a synthetic route for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol.

[0034] Figure 4 1 is a structural diagram of the dehydroxylated impurity of the present invention. DETAILED DESCRIPTION

[0035] The following examples will help to understand the present invention, but these examples are only for illustrating the present invention, and the present invention is not limited to these contents.

[0036] Terminology Note:

[0037] (R)-2-((4-Nitrophenylethyl)amino)-1-phenylethyl-1-ol, structural formula is attached Figure 2 , referred to as raw material A.

[0038] Its English chemical name is:

[0039] (R)-2-((4-nitrophenethyl)amino)-1-phenylethan-1-ol, molecular formula C 16 H 18 N 2 O 3 , molecular weight 286.33. The more stable hydrochloride is often used in the reaction.

[0040] Embodiment 1

[0041] Effect of different first organic solvents on reaction yield:

[0042] A first organic solvent (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), and potassium borohydride (5.5 g) were added to a 1000 mL reaction bottle, and the temperature was raised to 42-44° C. after the addition, and the reaction was carried out for 0.5 h. The selection of the different first organic solvents is shown in Table 1.

[0043] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0044] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0045] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0046] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0047] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0048] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0049] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0050] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0051] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0052] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 1, and the appearance is an off-white solid.

[0053] Table 1: Selection of the first organic solvent and the amount and yield of the product

[0054] Serial number The first organic solvent Gain g Molar yield% 1 Isopropyl ether 4.63 90.8 2 Tetrahydrofuran 4.88 95.9 3 2-Methyltetrahydrofuran 4.94 96.9 4 Ethylene glycol dimethyl ether 4.58 89.8

[0055] Different first organic solvents have little effect on the purity of the product, so they are not listed. Comprehensively comparing the yield and cost, tetrahydrofuran is the preferred first organic solvent.

[0056] Embodiment 2

[0057] Effect of using different alkali metal borohydrides on reaction yield and purity:

[0058] Tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), and alkali metal borohydride were added to a 1000 mL reaction bottle, and the temperature was raised to 42-44° C. after the addition, and the reaction was carried out for 0.5 h. The selection of the different alkali metal borohydrides is shown in Table 2.

[0059] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0060] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0061] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0062] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0063] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0064] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0065] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0066] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0067] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0068] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 2, and the appearance is an off-white solid.

[0069] Table 2: Selection of different alkali metal borohydrides and the yield, yield, purity and main impurities of the products

[0070]

[0071] Embodiment 3

[0072] Effect of different addition amounts of potassium borohydride on reaction yield and purity:

[0073] Tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), and potassium borohydride were added to a 1000 mL reaction bottle, and the temperature was raised to 42-44° C. after the addition, and the reaction was carried out for 0.5 h. The selection of different addition amounts of potassium borohydride is shown in Table 3.

[0074] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0075] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0076] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0077] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0078] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0079] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0080] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0081] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0082] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0083] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 3, and the appearance is an off-white solid.

[0084] Table 3: Selection of different dosages of potassium borohydride and the amount, yield and purity of the product

[0085]

[0086] Embodiment 4

[0087] Effect of different addition amounts of nickel chloride hexahydrate on reaction yield and purity:

[0088] Tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate, and potassium borohydride (5.5 g) were added to a 1000 mL reaction bottle. After the addition, the temperature was raised to 42-44° C. and the reaction was carried out for 0.5 h. The selection of different addition amounts of the nickel chloride hexahydrate is shown in Table 4.

[0089] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0090] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0091] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0092] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0093] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0094] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0095] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0096] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0097] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0098] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 4, and the appearance is an off-white solid.

[0099] Table 4: Selection of different dosages of nickel chloride hexahydrate and the amount, yield and purity of the product

[0100]

[0101] Embodiment 5

[0102] Effect of different reaction temperatures on reaction yield and purity:

[0103] Tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), potassium borohydride (5.5 g) were added to a 1000 mL reaction bottle, and the temperature was raised to a certain temperature after the addition, and the reaction was carried out for 0.5 h. The selection of the reaction temperature of the reaction is shown in Table 5.

[0104] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0105] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0106] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0107] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0108] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0109] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0110] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0111] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0112] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0113] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 5, and the appearance is an off-white solid.

[0114] Table 5: Selection of reaction temperature and yield, yield and purity of product

[0115] Serial number Reaction temperature℃ Gain g Molar yield% purity% 1 35～37 4.56 89.41 93.50 2 38～39 4.60 90.20 98.07 3 40～41 4.76 93.33 99.50 4 42～44 4.89 95.88 99.73 5 45～47 4.71 92.35 99.64 6 48～50 4.68 91.76 98.65

[0116] Embodiment 6

[0117] Effect of different reaction times on reaction yield and purity:

[0118] Tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), and potassium borohydride (5.5 g) were added to a 1000 mL reaction bottle. After the addition, the temperature was raised to 42-44° C. to react. The reaction time selection of the reaction is shown in Table 6.

[0119] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0120] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0121] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0122] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0123] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0124] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0125] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0126] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0127] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0128] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 6, and the appearance is an off-white solid.

[0129] Table 6: Reaction time selection and product yield, yield and purity

[0130] Serial number Reaction time min Gain g Molar yield% purity% 1 20 4.52 88.63 92.80 2 25 4.75 93.14 97.72 3 30 4.89 95.88 99.73 4 40 4.91 96.27 99.70 5 60 4.78 93.73 99.56 6 90 4.75 93.14 99.47 7 120 4.65 91.18 98.78

[0131] Embodiment 7

[0132] To a 1000 mL reaction bottle, add tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), and potassium borohydride (5.5 g). After the addition, raise the temperature to 42-44 ° C and react for 0.5 h.

[0133] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0134] Add dichloromethane (140 ml), add alkaline aqueous solution, adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers. The selection of the alkaline aqueous solution is shown in Table 7.

[0135] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0136] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0137] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0138] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0139] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0140] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0141] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0142] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 7, and the appearance is an off-white solid.

[0143] Table 7: Selection of alkaline aqueous solution and the amount, yield and purity of the product

[0144]

[0145]

[0146] Embodiment 8

[0147] To a 1000 mL reaction bottle, add tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), and potassium borohydride (5.5 g). After the addition, raise the temperature to 42-44 ° C and react for 0.5 h.

[0148] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0149] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0150] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0151] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0152] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0153] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0154] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0155] Add dichloromethane and isopropanol, stir and dissolve. Slowly drop concentrated hydrochloric acid (about 14 g), adjust the pH value to 2, and stir and crystallize for 2 hours. The selection of the amount of dichloromethane and isopropanol is shown in Table 8.

[0156] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0157] The filter cake was moved to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and it was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride. The product yield is shown in Table 8, and the appearance is an off-white solid.

[0158] Table 8: The selection of the amount of dichloromethane and isopropanol and the amount, yield and purity of the product

[0159]

[0160] Embodiment 9

[0161] To a 1000 mL reaction bottle, add tetrahydrofuran (35 ml), water (130 ml), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 g), nickel chloride hexahydrate (0.3 g), and potassium borohydride (5.5 g). After the addition, raise the temperature to 42-44 ° C and react for 0.5 h.

[0162] After the reaction, hydrochloric acid (about 50 ml) was added dropwise to the reaction bottle to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 h, and the temperature was lowered to 20-30°C.

[0163] Add dichloromethane (140 ml), first add 10% ammonia water (10 ml), then add 5% NaOH solution (50 ml) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0164] Dichloromethane (100 ml) was added to the aqueous layer and stirred for 5 minutes. The mixture was allowed to stand for about 20 minutes and the layers were separated.

[0165] The organic layers were combined, and a 10% aqueous sodium thiosulfate solution (10 g of sodium thiosulfate, 90 ml of water) was added to the organic layers, stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0166] Water (100 ml) was added to the organic layer, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0167] To the organic layer was added saline (30 g of sodium chloride, 100 ml of water), stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0168] The washed organic layer was concentrated under reduced pressure with dichloromethane (external temperature was controlled to be ≤70°C and the final vacuum degree was ≥0.085MPa) to dryness.

[0169] Add dichloromethane (30 ml) and isopropanol (1.25 ml), stir to dissolve, slowly add concentrated hydrochloric acid (about 14 g) dropwise, adjust the pH value to 2, and stir to crystallize for 2 hours.

[0170] The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 ml).

[0171] The filter cake was transferred to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and the mixture was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride, which was an off-white solid. The yield of the product was 4.89 g, the yield was 95.88%, the HPLC purity was 99.73%, and the dehydroxylated impurity (see the attached structural formula) was Figure 4 )0.19%, impurity raw material A (structural formula see attached Figure 2 ):0.04%.

[0172] Embodiment 10

[0173] To a 1000 L reaction tank, add tetrahydrofuran (35 L), water (130 L), (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol hydrochloride (5.0 kg), nickel chloride hexahydrate (0.3 kg), and potassium borohydride (5.5 kg). After the addition, raise the temperature to 42-44 ° C and react for 0.5 h.

[0174] After the reaction, hydrochloric acid (about 50 L) was added dropwise to the reaction tank to adjust the pH value to 2-3, the temperature was raised to 56°C for acidification for 0.5 hours, and the temperature was lowered to 20-30°C.

[0175] Add dichloromethane (140 L), first add 10% ammonia water (10 L), then add 5% NaOH solution (50 L) to adjust the pH value to 9-10, alkalize for 0.5 h, and separate the layers.

[0176] The organic layer was transferred into a 1000 L separation tank, and dichloromethane (100 L) was added into the reaction tank (water layer), stirred for 5 minutes, allowed to stand for about 20 minutes, and separated into layers.

[0177] The organic layers were combined, and a 10% sodium thiosulfate aqueous solution (10 kg of sodium thiosulfate, 90 L of water) was added to the separation tank (organic layer), stirred for 5 minutes, and allowed to stand for about 20 minutes to separate the layers.

[0178] The organic layer was transferred to a reaction tank, water (100 L) was added, stirred for 5 minutes, allowed to stand for about 20 minutes, and the layers were separated.

[0179] The organic layer was transferred to a separation tank, and saline (30 kg of sodium chloride, 100 L of water) was added, stirred for 5 minutes, allowed to stand for about 20 minutes, and separated into layers.

[0180] The organic layer was transferred into a 250L distillation tank, the external temperature was controlled to be ≤70°C, the final vacuum degree was ≥0.085MPa, and the dichloromethane was concentrated to dryness under reduced pressure.

[0181] Add dichloromethane (30 L) and isopropanol (1.25 L) to the distillation tank and stir to dissolve. Slowly add concentrated hydrochloric acid (about 14 kg) dropwise to adjust the pH value to 2 and stir to crystallize for 2 hours.

[0182] The reaction solution was placed in a centrifuge, centrifuged and filtered, and the filter cake was washed with isopropanol (10 L).

[0183] The filter cake was transferred to a vacuum drying oven, the temperature was controlled at 50-60°C, the vacuum degree was ≥0.85MPa, and the mixture was dried for 3 hours to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol, which was an off-white solid. The product yield was 4.91kg, the yield was 96.27%, HPLC 99.75%, and the dehydroxylated impurity (see the attached structural formula) was Figure 4 )0.19%, impurity raw material A (structural formula see attached Figure 2 ):0.04%.

Claims

1. A method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol, the method comprising the following steps: (1) reacting (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or a salt thereof, nickel chloride, and an alkali metal borohydride in the presence of a first organic solvent and water; (2) After the reaction is completed, the pH value of the reaction solution is adjusted to 1-5 with the first acid for acidification; (3) adding a second organic solvent and a first base, adjusting the pH value to 8-12 for alkalization, extracting and stratifying to obtain a first organic layer and an aqueous layer; (4) adding a second organic solvent to the aqueous layer, extracting for 0 to 10 times to obtain a second organic layer, combining the first organic layer and the second organic layer to obtain a combined organic layer; washing the combined organic layer with a salt aqueous solution and water, respectively, to obtain a washed organic layer; (5) concentrating the washed organic layer to dryness under reduced pressure, adding a crystallization solvent, and performing thorough crystallization; (6) (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is obtained.

2. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 1, characterized in that: In step (1), the first organic solvent is selected from an ether solvent, and the ether solvent is selected from one or more of isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and ethylene glycol dimethyl ether; in step (1), the salt is selected from one or more of hydrochloride, sulfate, and phosphate; the nickel chloride is selected from one or more of anhydrous nickel chloride, nickel chloride dihydrate, nickel chloride tetrahydrate, and nickel chloride hexahydrate; the alkali metal borohydride is selected from one or more of sodium borohydride, potassium borohydride, and lithium borohydride; the reaction temperature is 35 to 50°C, preferably 38 to 50°C, and more preferably The reaction temperature is 40-47° C.; the reaction time is 20 min-600 min, preferably, the reaction time is 25 min-300 min, more preferably, the reaction time is 25 min-120 min; the molar ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to nickel chloride is 1:0.05-0.5, preferably, the molar ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to nickel chloride is 1:0.06-0.2, more preferably, The molar ratio of the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to nickel chloride is 1:0.06-0.16; the molar ratio of the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to alkali metal borohydride is 1:3-9. Preferably, the molar ratio of the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to alkali metal borohydride is 1:5-8. More preferably, the (R)-2-((4-nitrophenethyl)amino)-1-phenylethyl-1-ol or its salt to alkali metal borohydride is 1:5-8. The molar ratio of its salt to the alkali metal borohydride is 1:6-8; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the first organic solvent is 1:3-10, preferably, the volume ratio is 1:5-9, the unit of the weight is kg, and the unit of the volume is L; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to water is 5:80-200, preferably, the volume ratio is 5:100-160, the unit of the weight is kg, and the unit of the volume is L.

3. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 1, characterized in that: In step (2), the first acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and tartaric acid; the pH value of the reaction solution is adjusted to 1-4 by the first acid, and preferably the pH value of the reaction solution is adjusted to 2-3 by the first acid; the acidification temperature is 50-60°C, and preferably, the acidification temperature is 52-58°C; the acidification time is 10-300min, and preferably, the acidification time is 20-150min, and more preferably, the acidification time is 20-120min; after the acidification, the step of cooling the temperature to 10-40°C is also included, and preferably, the step of cooling the temperature to 20-30°C is also included after the acidification.

4. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 1, characterized in that: In step (3), the second organic solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, ether, isopropyl acetate, n-hexane, and n-pentane; the first alkali is selected from one of ammonia water or a combination of ammonia water and a second alkali aqueous solution; the second alkali is selected from alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates; the alkali metal hydroxide is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; the alkali metal carbonate is selected from one or more of sodium carbonate, potassium carbonate, and lithium carbonate; the alkali metal bicarbonate is selected from one or more of sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate; the concentration of the ammonia water is 1-30%, preferably, The concentration is 5-20%; the pH value is adjusted to 8-11 for alkalization, preferably, the pH value is adjusted to 9-10 for alkalization; the alkalization time is 0.4h-2h, preferably, the alkalization time is 0.4h-1h; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the second organic solvent in step (3) is 5:70-300, preferably, the ratio is 5:50-300, more preferably, the ratio is 5:70-210, the unit of the weight is kg, and the unit of the volume is L; the combination of the ammonia water and the second alkaline aqueous solution is added in a manner of first adding the ammonia water and then adding the second alkaline aqueous solution.

5. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 1, characterized in that: In step (4), the extraction is performed 0-5 times, preferably 0-3 times; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the second organic solvent in step (4) is 5:30-300, preferably 5:50-210; the salt aqueous solution is selected from one or more of a reducing salt aqueous solution and a saline solution; the saline solution is selected from a 10%-saturated saline solution; the reducing salt aqueous solution is selected from a 1%-30% reducing salt aqueous solution; the washing of the combined organic layer with the salt aqueous solution and water is specifically washing with a reducing salt aqueous solution, water, and a saline solution in sequence; the reducing salt aqueous solution is selected from one or more of a sodium thiosulfate aqueous solution, a sodium sulfite aqueous solution, a ferrous sulfate aqueous solution, a sodium sulfide aqueous solution, and a sodium oxalate aqueous solution.

6. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 1, characterized in that: In step (5), the crystallization solvent is selected from a mixed solvent of the second organic solvent and the first alcohol solvent; the first alcohol solvent is selected from one or more of methanol, ethanol, propanol, and isopropanol; in step (5), after the full crystallization, the steps of filtering, washing, and drying are also included; the washing adopts the first alcohol solvent; the weight ratio of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the volume ratio of the crystallization solvent is 5:20 -50, preferably, the volume ratio of the weight of the (R)-2-((4-nitrophenylethyl)amino)-1-phenylethyl-1-ol or its salt to the crystallization solvent is 5:25-40, the unit of the weight is kg, and the unit of the volume is L; in step (5), the volume ratio of the second organic solvent to the first alcohol solvent is 10-45:0.1-10, preferably, the volume ratio is 20-40:0.1-5, and more preferably, the volume ratio is 25-35:0.5-2.

7. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 1, characterized in that: In step (5), after adding the crystallization solvent and before fully crystallizing, the step of adding a second acid to adjust the pH to 1-4 is also included. Preferably, the step of adding a second acid to adjust the pH to 1.5-3 is also included; the second acid is selected from one of hydrochloric acid, sulfuric acid, phosphoric acid, and tartaric acid; the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is selected from (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol hydrochloride, (R)-2-((4-aminophenethyl)amino)-1-phenylethyl -1-ol sulfate, (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol phosphate, (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol tartrate; the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol hydrochloride is selected from (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol dihydrochloride; the crystallization time is 1-4 hours, preferably, the crystallization time is 1.5-3 hours.

8. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 1, characterized in that: The purity of the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is greater than 90%, preferably greater than 95%, and more preferably greater than 99%.

9. The method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol according to claim 8, characterized in that: The purity of the (R)-2-((4-aminophenethyl)amino)-1-phenylethyl-1-ol is greater than 99.5%.

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