Preparation method of optically active [1-(1-aminoethyl)cyclopropyl]methanol

Abstract

The invention discloses a method for preparing optically active [1-(1-aminoethyl)cyclopropyl]methanol, which comprises the following steps: compound 2 is subjected to cyclopropylation reaction, transamination reaction, amino protection reaction, reduction reaction, and amino deprotection reaction to prepare the optically active [1-(1-aminoethyl)cyclopropyl]methanol. The method has a novel and brief preparation route, efficient and convenient reaction and post-treatment, and readily available raw materials and reaction reagents, and does not require special equipment and operating conditions, so the method is suitable for industrialization. The purity of the obtained product is as high as 99.5% or more, and the ee value is as high as 99.5% or more, which meets the quality control requirements and improves the quality of the subsequent prepared raw materials and preparations.

Description

Technical Field

[0001] The present invention relates to a method for preparing optically active [1-(1-aminoethyl)cyclopropyl]methanol, in particular to a method for preparing optically active [1-(1-aminoethyl)cyclopropyl]methanol suitable for industrialization. Background Art

[0002] HIV-1 integrase inhibitors are a new type of HIV inhibitory drug with the advantage of high antiviral efficacy, becoming a first-line clinical treatment drug. The second-generation HIV-1 integrase inhibitors include dolutegravir sodium, which was approved by the FDA in 2013 by GlaxoSmithKline, Bituowei (a combination preparation containing bistegravir) launched by Gilead Sciences in 2018, and cartegravir sodium, which was launched by GlaxoSmithKline in 2021. The active molecular structures of each drug are as follows.

[0003]

[0004] As an important molecular building block, amino alcohol compounds are widely used in fine chemicals and pharmaceutical intermediates, and they also have broad application prospects in the synthesis of physiologically active anti-HIV drugs. Specifically, in the synthesis of the above three HIV-1 integrase inhibitor drugs, three optically active amino alcohol molecules as shown below were used respectively.

[0005]

[0006] Patent CN114230579 discloses the synthesis and application of a novel polycyclic aminoformyl pyridone derivative, which can be used as a drug molecule to effectively inhibit HIV-1 virus infection. In molecular structure-activity studies, it was found that amino alcohol compounds play an important role in activity, among which [1-(1-aminoethyl)cyclopropyl]methanol has significant biological properties.

[0007]

[0008] Generally, the preparation strategies of optically pure amino alcohols include chemical resolution, chemical induction, chiral raw material synthesis, bio-enzyme catalysis, etc. Patent CN114230579 uses chiral (R)-3-aminobutyric acid as a raw material and obtains optically pure amino alcohol derivatives through 6 steps of synthesis.

[0009]

[0010] In the above-mentioned preparation method of amino alcohol, harsh reaction conditions such as ultra-low temperature (-78°C), anhydrous and oxygen-free are used, chiral starting materials, expensive reagents such as LDA and LiHMDS, and each step of the product needs to be separated and purified by column chromatography, and the total yield is only 8.6%. In addition, there are process defects such as the risk of optical isomer impurities. Therefore, this preparation method is only suitable for laboratories and is difficult to achieve industrial scale-up preparation. Summary of the invention

[0011] Purpose of the invention: The present invention aims to provide a method for preparing optically active [1-(1-aminoethyl)cyclopropyl]methanol which is easy to industrialize.

[0012] Technical solution: The method for preparing optically active [1-(1-aminoethyl)cyclopropyl]methanol of the present invention comprises the following steps:

[0013]

[0014] Compound 2 is subjected to cyclopropylation reaction, transamination reaction, amino protection reaction, reduction reaction, and amino deprotection reaction to prepare the optically active [1-(1-aminoethyl)cyclopropyl]methanol;

[0015] Wherein the C* chiral carbon has R or S configuration;

[0016] R1 is selected from C1-C4 alkyl, benzyl or benzyl substituted by at least one halogen, cyano, nitro, C1-C4 alkyl or C1-C4 alkoxy; wherein C1-C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C1-C4 alkoxy is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy;

[0017] P is selected from benzyl (Bn-), benzyloxycarbonyl (Cbz-), tert-butyloxycarbonyl (Boc-), fluorenylmethyloxycarbonyl (Fmoc-), propyleneoxycarbonyl (Teoc-), acetyl (Ac-), trifluoroacetyl (CF3CO-).

[0018] Furthermore, the preparation method comprises the following steps:

[0019] (1) Compound 2 is reacted with a cyclopropylating agent in the presence of a phase transfer catalyst and a base to obtain compound 3;

[0020] (2) Compound 3 and an amino donor are reacted with a biological enzyme system to prepare compound 4;

[0021] (3) Compound 4 reacts with an amino protecting agent to prepare compound 5;

[0022] (4) Compound 5 reacts with a reducing agent to prepare compound 6;

[0023] (5) Compound 6 is treated with an amino deprotection reagent to obtain the optically active [1-(1-aminoethyl)cyclopropyl]methanol.

[0024] In step (1), the cyclopropylation reagent is selected from 1,2-dibromoethane, 1-bromo-2-iodoethane, 1-bromo-2-chloroethane, the phase transfer catalyst is selected from tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, the base is selected from potassium carbonate, sodium carbonate, sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, and the reaction solvent is selected from tetrahydrofuran, N,N-dimethylformamide, acetone, and acetonitrile.

[0025] The molar ratio of the cyclopropylating agent, the phase transfer catalyst, the base and the compound 2 is (1-2):(0.01-0.1):(1-5):1, preferably (1.15-1.5):(0.01-0.05):(2.2-3):1, more preferably (1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5):(0.01, 0.02, 0.03, 0.04, 0.05):(2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3):1, and can be specifically selected from 1.5:0.05:3:1, 1.15:0.05:2.2:1, 1.3:0.05:2.3:1, 1.5:0.05:3:1.

[0026] In step (2), the amino donor is selected from isopropylamine, the bioenzyme system comprises transaminase, coenzyme and buffer salt, wherein the transaminase is selected from A25, A31, A044, A161, A170, PA049, PA051, the coenzyme is selected from pyridoxal phosphate (PLP), and the buffer salt is selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, and aqueous hydrochloric acid solution.

[0027] When R1 is selected from ethyl, the conversion product of transaminase A161 and PA049 is R configuration, and the conversion product of transaminase A170 and PA051 is S configuration; when R1 is selected from methyl, the conversion product of transaminase A25 and A170 is S configuration, and the conversion product of transaminase A161 and A31 is R configuration; when R1 is selected from benzyl, the conversion product of transaminase A25 is S configuration, and the conversion product of transaminase A31 is R configuration.

[0028] The weight ratio of transaminase, coenzyme and compound 3 is (0.02-0.10): (0.0002-0.001): 1, preferably (0.03-0.05): (0.0007-0.001): 1, more preferably (0.03, 0.04, 0.05): (0.0007, 0.0008, 0.0009, 0.001): 1, specifically can be selected from 0.02: 0.0007: 1. The molar ratio of amino donor to compound 3 is (3-10): 1, preferably (3-7): 1, more preferably (3, 4, 5, 6, 7): 1, specifically 7: 1.

[0029] The pH value of the reaction system is 6 to 8, preferably 7 to 8, more preferably 7.5 to 8, and specifically can be selected from 7.8 to 7.9.

[0030] The reaction temperature is 15 to 45°C, preferably 25 to 35°C, more preferably 35 to 45°C, and can be specifically selected from 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, and 45°C. Each specific temperature point can also fluctuate within the temperature control fluctuation range of the equipment, that is, the temperature is controlled within the target value ± control accuracy value range. For example, when the temperature control accuracy is 0.5°C, it can also be specifically selected from 35°C ± 0.5°C, 36°C ± 0.5°C, 37°C ± 0.5°C, 38°C ± 0.5°C, 39°C ± 0.5°C, 40°C ± 0.5°C, 41°C ± 0.5°C, 42°C ± 0.5°C, 43°C ± 0.5°C, 44°C ± 0.5°C, and 45°C ± 0.5°C.

[0031] In step (3), the amino protecting agent is selected from benzyl bromide, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, fluorenylmethoxycarbonyl chloride, propyleneoxycarbonyl chloride, acetyl chloride, trifluoroacetyl chloride; the molar ratio of the amino protecting agent to compound 4 is (1-3):1, preferably (1-2):1, more preferably (1-1.3):1, and specifically can be selected from (1.05, 1.1, 1.15, 1.2, 1.25, 1.3):1.

[0032] In step (4), the reducing agent is selected from sodium dihydrogen bis(dimethoxyethoxy)aluminate (Red-Al), lithium aluminum tetrahydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium acetate borohydride, borane, boron trifluoride complex (BF3-Et2O, BF3-THF, BF3-CH3SCH3); the molar ratio of the reducing agent to compound 5 is (1-5):1, preferably (2-4):1, and more preferably (2.5, 3, 3.5, 4):1.

[0033] Among them, the acid is selected from hydrochloric acid, methanol solution of hydrogen chloride, ethanol solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, dioxane solution of hydrogen chloride, hydrobromic acid, sulfuric acid, trifluoroacetic acid, acetic acid, preferably hydrochloric acid; the base is selected from sodium hydroxide, potassium hydroxide, piperidine; the hydrogen donor-palladium carbon is selected from hydrogen-palladium carbon and formic acid-palladium carbon.

[0034] In step (5), the amino deprotecting agent is selected from an acid agent, a base agent, a hydrogen donor, and palladium on carbon; the molar ratio of the amino deprotecting agent to compound 6 is (0.5-3):1, preferably (1.0-2.5):1, and more preferably (1.5-2.5):1.

[0035] The intermediates (compounds 3 to 6) and the final product (compound 1) obtained from the above reactions are all purified and separated through steps including but not limited to extraction, concentration, recrystallization, crystallization, washing, beating, filtering, centrifugation and drying.

[0036] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0037] The preparation route is novel and brief, the reaction and post-treatment are efficient (the total yield reaches more than 35%) and convenient (no column chromatography is required for separation and purification), the raw materials and reaction reagents are easily available, no special equipment and operating conditions are required (the reaction conditions are mild), and it is suitable for industrialization; the product purity is as high as more than 99.5%, and the ee value is as high as more than 99.5%, which meets the quality control requirements of general organic impurities and isomer impurities of chemical drugs, and improves the quality of subsequent prepared raw materials and preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the H NMR spectrum of compound 3-2;

[0039] Figure 2 is the H NMR spectrum of compound 3-3;

[0040] Figure 3 is the H NMR spectrum of compound 4-2R;

[0041] Figure 4 is the GC chromatogram of compound 4-2R;

[0042] Figure 5 is the H NMR spectrum of compound 5;

[0043] Figure 6 is the GC chromatogram of compound 5;

[0044] Figure 7 is the H NMR spectrum of compound 6;

[0045] Figure 8 is the GC chromatogram of compound 6;

[0046] Fig. 9 is the H NMR spectrum of compound 1;

[0047] Fig.10 is the GC chromatogram of compound 1;

[0048] Fig.11 is the chiral HPLC chromatogram of compound 1;

[0049] Fig.12 is the H NMR spectrum of compound 9;

[0050] Fig.13 is the HPLC chromatogram of compound 9;

[0051] Fig.14 This is the chiral HPLC chromatogram of compound 9. DETAILED DESCRIPTION

[0052] The technical solution of the present invention is further described below in conjunction with embodiments.

[0053] Bioenzyme powders A25, A31, A044, A161, and A170 were provided by Shanghai Guoguang Biotechnology Co., Ltd. and Suzhou Hanzyme Biotechnology Co., Ltd., and bioenzyme powders PA049 and PA051 were provided by Nanjing Yaoshi Technology Co., Ltd.

[0054] Example 1: Synthesis of 1-acetylcyclopropane-1-carboxylic acid methyl ester (Compound 3-1)

[0055] Add 140 mL of acetonitrile, methyl acetoacetate (17.4 g, 15 mmol), potassium carbonate (49 g, 3 equiv.), tetrabutylammonium bromide (2.4 g, 0.05 equiv.) and 1,2-dibromoethane (42.3 g, 1.5 equiv.) to the reaction flask, and stir at 40-50 ° C for 48 hours. After the reaction is completed, filter, concentrate under reduced pressure to remove the solvent to obtain a yellow oil, and distill under reduced pressure to obtain compound 3-1, 10.8 g of oil.

[0056] Example 2: Synthesis of 1-acetylcyclopropane-1-carboxylic acid ethyl ester (Compound 3-2)

[0057] Add 12.5kg of tetrahydrofuran and 2kg of ethyl acetoacetate to the reactor in sequence, start stirring, add 4.67kg of potassium carbonate (2.2equiv.) and 0.25kg of tetrabutylammonium bromide (0.05equiv.), control the internal temperature not to exceed 35°C, add 1,2-dibromoethane (3.32kg, 1.15equiv.) dropwise, stir and react for a certain time. After monitoring the basic reaction of the raw materials, reduce the temperature to 20-25°C. Filter to remove the solid, distill under reduced pressure, collect the target fraction compound 3-2, 1.37kg of oil (yield 57.1%).

[0058] The H NMR spectrum of compound 3-2 is shown in Figure 1 .

[0059] Example 3: Synthesis of 1-acetylcyclopropane-1-carboxylic acid ethyl ester (Compound 3-2)

[0060] Add 180mL N,N-dimethylformamide, ethyl acetoacetate (30g, 0.23mol) to the reaction flask in turn, start stirring, add potassium carbonate (63g, 0.57mol) and tetrabutylammonium bromide (3.7g, 0.05equiv.), control the internal temperature not to exceed 35°C, add 1,2-dibromoethane (56g, 1.3equiv.) dropwise, stir and react for a certain time. After monitoring the basic reaction of the raw materials, reduce the temperature to 20-25°C. Filter to remove the solid, distill under reduced pressure, collect the target fraction to obtain compound 3-2, 19g of oil.

[0061] Example 4: Synthesis of 1-acetylcyclopropane-1-carboxylic acid benzyl ester (Compound 3-3)

[0062] Acetone 115mL, benzyl acetoacetate (19.2g, 0.1mol), potassium carbonate (32.7g, 0.3mol), tetrabutylammonium bromide (1.61g, 5mmol) and 1,2-dibromoethane (28.2g, 0.15mol) were added to the reaction flask in sequence, and stirred at 50-60°C for 24h. After the reaction of the raw materials was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and then distilled under reduced pressure to obtain compound 3-3, 7.8g of oil.

[0063] The H NMR spectrum of compound 3-3 is shown in Figure 2 .

[0064] Example 5: Preparation of 1-[(1R)-1-aminoethyl]cyclopropane-1-carboxylic acid ethyl ester (Compound 4-2R)

[0065] Add 665 kg of water, 66.5 kg of isopropylamine and compound 3-2 (25 kg, 160 mol) into the reactor in sequence and start stirring. Add NaH2PO4.2H2O (4.68 g) and Na2HPO4.12H2O (16.13 kg) and then cool to 0-5°C; slowly add 103.75 kg of hydrochloric acid to adjust the pH of the reaction solution to 7.8-7.9, and control the temperature at 0-15°C; add 500 g of bioenzyme powder A161 and 18.5 g of coenzyme PLP; heat the reaction solution to 40-45°C, stir and react for 48-60 hours, and add an appropriate amount of isopropylamine at regular intervals to adjust the pH of the reaction solution to 7.8-7.9. After the reaction of the raw materials was completed, the solvent was removed by concentration under reduced pressure, the temperature was lowered to 0-10°C, an appropriate amount of 20% sodium hydroxide solution was added to adjust the pH to 9-10, an appropriate amount of diatomaceous earth was added and stirred for a certain period of time, the solid was removed by filtration, dichloromethane was added to the filtrate and stirred for separation, the aqueous layer was further extracted with dichloromethane once, and the combined organic layers were concentrated under reduced pressure to obtain compound 4-2R, 18.6 kg of brown liquid (yield 74%, GC purity 98.57%).

[0066] The H NMR spectrum of compound 4-2R is shown in Figure 3 , GC purity see Figure 4 and Table 1.

[0067] Table 1. GC purity of compound 4-2R

[0068]

[0069] Example 6: Optimization of biological enzymes

[0070]

[0071] Table 2. Optimization conditions and results of biological enzymes

[0072]

[0073] As can be seen from Table 2, different α-cyclopropyl ester compounds were selected and various transaminases were used for transamination reaction. The results showed that various transaminases had a high ee value catalytic effect, and the conversion rates at 48h and 120h were different.

[0074] Example 7: Synthesis of 1-[(1R)-1-aminoethyl]cyclopropane-1-carboxylic acid methyl ester (Compound 4-1R)

[0075] Compound 3-1R (1 g, 7 mmol), isopropylamine-hydrochloric acid buffer and A161 enzyme powder were added to the reaction flask in sequence, and the mixture was stirred at 35-40°C for 48 h. An appropriate amount of 10% sodium hydroxide solution was added to adjust the pH to 10. Dichloromethane was added to extract the reaction solution, and the organic phase was concentrated under reduced pressure to obtain compound 4-R.

[0076] Example 8: Synthesis of methyl 1-[(1S)-1-aminoethyl]cyclopropane-1-carboxylate (Compound 4-1S)

[0077] Compound 3-1S (1 g, 7 mmol), isopropylamine-hydrochloric acid buffer and A170 enzyme powder were added to the reaction flask in sequence, and the mixture was stirred at 35-40°C for 48 h. An appropriate amount of 10% sodium hydroxide solution was added to adjust the pH to 10. Dichloromethane was added to extract the reaction solution, and the organic phase was concentrated under reduced pressure to obtain compound 4-S.

[0078] Example 9: Synthesis of 1-[(1R)-1-aminoethyl]cyclopropane-1-carboxylic acid benzyl ester (Compound 4-3R)

[0079] Compound 3-3R (1 g, 7 mmol), isopropylamine-hydrochloric acid solution and A31 enzyme powder were added to the reaction flask in sequence, and the mixture was stirred at 35-40 °C for 72 h. An appropriate amount of 10% sodium hydroxide solution was added to adjust the pH to 10. Dichloromethane was added to extract the reaction solution, and the organic phase was concentrated under reduced pressure to obtain compound 4-3R.

[0080] Example 10: Synthesis of 1-[(1S)-1-aminoethyl]cyclopropane-1-carboxylic acid benzyl ester (Compound 4-3S)

[0081] Compound 3-3S (1 g, 7 mmol), isopropylamine-hydrochloric acid buffer and A25 enzyme powder were added to the reaction flask in sequence, and the mixture was stirred at 35-40°C for 72 h. An appropriate amount of 10% sodium hydroxide solution was added to adjust the pH to 10. Dichloromethane was added to extract the reaction solution, and the organic phase was concentrated under reduced pressure to obtain compound 4-3S.

[0082] Example 11: Preparation of 2-methylpropan-2-yl {[(1R)-1-[(ethoxycarbonyl)cyclopropyl]ethyl]amino}methane ester (Compound 5)

[0083] Add 78.6 kg of methyl tert-butyl ether, compound 4-2R (18.6 kg), 71 kg of water and 15 kg of sodium bicarbonate to the reactor, start stirring, cool to 0-10 ° C, add a mixture of di-tert-butyl dicarbonate (27.1 kg) and 13.6 kg of methyl tert-butyl ether, control 0-10 ° C, and control 10-25 ° C after adding and stirring for 16 hours. After the reaction of the raw materials is completed, stand and separate, add an appropriate amount of methyl tert-butyl ether to the water layer for extraction twice, combine the organic layers, wash with water to obtain the organic layer, and add an appropriate amount of n-heptane to stir and precipitate the solid after vacuum concentration. Filter and dry to obtain compound 5, a light yellow solid of 29.2 kg (yield 96.1%, GC purity 95.5%).

[0084] The H NMR spectrum of compound 5 is shown in Figure 5 , GC purity see Figure 6 and Table 3.

[0085] Table 3. GC purity of compound 5

[0086]

[0087] Example 12: Preparation of 2-methylpropan-2-yl {[(1R)-1-[(hydroxymethyl)cyclopropyl]ethyl]amino}methane ester (Compound 6)

[0088] Under nitrogen protection, 24 L tetrahydrofuran and compound 5 (3.07 kg, 19.5 mol) were added to the reactor, the temperature was lowered to 0-10°C, 70% Red-Al (6.827 kg, 23.876 mol) was added dropwise, the temperature was controlled at 0-10°C, and after the addition, the reaction was stirred at 25-30°C for 16 h.

[0089] After the reaction is completed, the temperature is lowered to 0-10°C, and a 10% sodium hydroxide solution is added to adjust the pH to 9-10; an appropriate amount of methyl tert-butyl ether is added, stirred and separated, the aqueous layer is extracted twice with methyl tert-butyl ether, the organic layers are combined, and appropriate amounts of 15% ammonium chloride solution and 15% sodium chloride solution are added in sequence to wash the organic layer, which is concentrated under reduced pressure, and an appropriate amount of n-heptane is added to continue distillation until there is no fraction to obtain compound 6, 2.52 kg of light yellow oil (yield 98.3%, GC purity 99.8%).

[0090] The H NMR spectrum of compound 6 is shown in Figure 7 , GC purity see Figure 8 and Table 4.

[0091] Table 4. GC purity of compound 6

[0092]

[0093] Example 13: Preparation of 2-methylpropan-2-yl {[(1R)-1-[(hydroxymethyl)cyclopropyl]ethyl]amino}methane ester (Compound 6)

[0094] Under nitrogen protection, 24 L of tetrahydrofuran was added to the reaction kettle, compound 5 (5.14 g, 20 mmol) was cooled to 0-10°C, lithium aluminum tetrahydride (1.04 g, 50 mmol) and lithium chloride (2.12 g, 50 mmol) were added, and the temperature was controlled at 0-10°C. After the addition, the reaction was stirred at 25-30°C.

[0095] After the reaction is completed, the temperature is lowered to 0-10°C, dilute hydrochloric acid is added to quench the reaction solution, 10% sodium hydroxide solution is added to adjust to neutrality, ethyl acetate is added to extract the aqueous layer, the liquid is allowed to stand, and the organic phase is concentrated under reduced pressure to obtain compound 6 as a light yellow liquid.

[0096] Example 14: Preparation of {[(1R)-1-aminoethyl]cyclopropyl}methanol hydrochloride (Compound 1)

[0097] 30L of methyl tert-butyl ether, 1.5L of tetrahydrofuran and compound 5-1 (4.64kg, 21.5mol) were added to the reactor, and the temperature was reduced to 0-5°C. Hydrochloric acid gas was introduced into the reaction solution until saturated, and the reaction was stirred at 10-20°C for 16h to precipitate a large amount of solid; after the reaction of the raw materials was completed, the temperature was reduced to 0-10°C and stirred for 2h, the reaction solution was filtered, the filter cake was washed with methyl tert-butyl ether, and the compound 1 hydrochloride was obtained after vacuum drying at 40-50°C, 2.86kg of white solid (yield 87.4%, GC purity 99.7%, ee value 99.53%).

[0098] The H NMR spectrum of compound 1 is shown in Fig. 9 , GC purity see Fig.10 and Table 5, chiral purity see Fig.11 and Table 6.

[0099] Table 5. GC purity of compound 1

[0100]

[0101] Table 6. Chiral purity of compound 1

[0102]

[0103] Example 15: Application of high-purity optical amino alcohol derivatives

[0104]

[0105] A 50L reactor was protected by nitrogen, and acetonitrile (26.3kg), compound 7 (3.3kg, 8.0mol, 1.0eq), compound 1 (1.1kg, 8.8mol, 1.1eq), acetic acid (2.4kg, 40.0mol, 5.0eq), potassium acetate (0.79kg, 8.0mol, 1.0eq) were added, stirring was started, and the reaction system was heated to 70-75°C and kept warm for 16 hours. After the reaction was monitored, acetonitrile was removed by vacuum distillation, ethyl acetate and sodium bicarbonate solution were added, and the pH of the aqueous phase was adjusted to 6-7. After stirring, the liquid was allowed to stand for separation, the water layer was separated, and the organic layer was concentrated under reduced pressure. n-heptane was added to stir to precipitate solids, centrifuged, and the solids were washed with ethyl acetate / n-heptane mixed solution, and vacuum dried to obtain compound 8 (3.65kg, yield 96.1%).

[0106] A 50L reactor was protected by nitrogen, and compound 8 (3.35kg, 7.29mol, 1.0eq) and tetrahydrofuran (14.7kg) were added. The reaction solution was stirred until it became clear, and the temperature was controlled at 20-45°C. Lithium bromide (2.53kg, 29.0mol, 4.0eq) was added in batches. After the addition, the reaction was continued for 2-4 hours. The reaction was monitored to be finished, and the temperature was lowered to 25-35°C. The solvent was removed by concentration under reduced pressure, and ethanol, glacial acetic acid and water were added. The mixture was stirred, and an off-white solid was precipitated. The off-white solid was centrifuged, washed with water, and dried to obtain an off-white solid compound 9 (2.97kg, yield 91.3%, purity 99.61%, ee value 99.96%).

[0107] The H NMR spectrum of compound 9 is shown in Fig.12 , HPLC purity see Fig.13 and Table 7, chiral purity see Fig.14 and Table 8.

[0108] Table 7. HPLC purity of compound 9

[0109] RT Area %Area Height 1 6.983 16854 0.10 1433 2 15.278 16580709 99.61 846073 3 16.988 48706 0.29 1939

[0110] Table 8. Chiral purity of compound 9

[0111] RT Area %Area Height 1 14.432 3522 0.02 181 2 17.158 16488391 99.98 513155

Claims

1. A method for preparing optically active [1-(1-aminoethyl)cyclopropyl]methanol, characterized in that: The following steps are involved: (1) Compound 2 is reacted with a cyclopropylating agent in the presence of a phase transfer catalyst and a base to obtain compound 3; (2) Compound 3 and an amino donor are reacted with a biological enzyme system to prepare compound 4, wherein the biological enzyme system comprises a transaminase, a coenzyme and a buffer salt, wherein the transaminase is selected from A25, A31, A161, A170, PA049 and PA051; (3) Compound 4 reacts with an amino protecting agent to prepare compound 5; (4) Compound 5 reacts with a reducing agent to prepare compound 6; (5) Compound 6 is treated with an amino deprotection reagent to obtain the optically active [1-(1-aminoethyl)cyclopropyl]methanol; Wherein the C* chiral carbon has R or S configuration; R1 is selected from C1-C4 alkyl, benzyl or benzyl substituted by at least one halogen, cyano, nitro, C1-C4 alkyl or C1-C4 alkoxy group; P is selected from benzyl, benzyloxycarbonyl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, propyleneoxycarbonyl, acetyl and trifluoroacetyl.

2. The preparation method according to claim 1, characterized in that: In step (1), the cyclopropylation reagent is selected from 1,2-dibromoethane, 1-bromo-2-iodoethane, 1-bromo-2-chloroethane, the phase transfer catalyst is selected from tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, the base is selected from potassium carbonate, sodium carbonate, sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, and the reaction solvent is selected from tetrahydrofuran, N,N-dimethylformamide, acetone, acetonitrile; the molar ratio of the cyclopropylation reagent, the phase transfer catalyst, the base and the compound 2 is (1-2):(0.01-0.1):(1-5):

1.

3. The preparation method according to claim 1, characterized in that: In step (2), the amino donor is selected from isopropylamine, the coenzyme is selected from pyridoxal phosphate, and the buffer salt is selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, and hydrochloric acid aqueous solution; the weight ratio of transaminase, coenzyme and compound 3 is (0.02-0.10):(0.0002-0.001):1, and the molar ratio of amino donor to compound 3 is (3-10):

1.

4. The preparation method according to claim 3, characterized in that: In step (2), the weight ratio of transaminase, coenzyme and compound 3 is (0.03-0.05):(0.0007-0.001):1, and the molar ratio of amino donor and compound 3 is (3-7):

1.

5. The preparation method according to claim 3, characterized in that: In step (2), the pH value of the reaction system is 6 to 8, and the reaction temperature is 15 to 45°C.

6. The preparation method according to claim 1, characterized in that: In step (3), the amino protecting agent is selected from benzyl bromide, benzyl chloride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, fluorenylmethoxycarbonyl chloride, propyleneoxycarbonyl chloride, acetyl chloride, trifluoroacetyl chloride; the molar ratio of the amino protecting agent to compound 4 is (1-3):

1.

7. The preparation method according to claim 1, characterized in that: In step (4), the reducing agent is selected from sodium dihydrogen bis(dimethoxyethoxy)aluminate, lithium aluminum tetrahydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium acetate borohydride, borane, and boron trifluoride complex; the molar ratio of the reducing agent to compound 5 is (1-5):

1.

8. The preparation method according to claim 1, characterized in that: In step (5), the amino deprotecting agent is selected from an acid, a base, and a hydrogen donor-palladium carbon; the molar ratio of the amino deprotecting agent to compound 6 is (0.5-3):

1.

9. The preparation method according to claim 8, characterized in that: The acid is selected from hydrochloric acid, methanol solution of hydrogen chloride, ethanol solution of hydrogen chloride, ethyl acetate solution of hydrogen chloride, dioxane solution of hydrogen chloride, hydrobromic acid, sulfuric acid, trifluoroacetic acid, and acetic acid; the base is selected from sodium hydroxide, potassium hydroxide, and piperidine; and the hydrogen donor-palladium carbon is selected from hydrogen-palladium carbon and formic acid-palladium carbon.

10. The preparation method according to claim 1, characterized in that: Each step of the reaction also includes purification and separation procedures.

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