Sitafloxacin intermediate, its enzymatic preparation method and application
By synthesizing sitafloxacin intermediates enzymatically and using Arthrobacter sp. KNK168 transaminase to catalyze the preparation of compound 3 from compound 2, the problems of cumbersome synthesis process and low yield in the prior art were solved, and a highly efficient, low-cost, and stereoselective preparation was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HEFEI AOKE TIANCHEN BIOTECHNOLOGY CO LTD
- Filing Date
- 2026-02-28
- Publication Date
- 2026-06-26
Smart Images
Figure CN121779271B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis and bio-enzyme catalysis technology, and relates to a sitafloxacin intermediate and its enzymatic preparation method and application, especially to an enzymatic synthesis method of sitafloxacin intermediate (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester. Background Technology
[0002] Sitafloxacin belongs to the fourth-generation quinolone broad-spectrum antibacterial drug class and is approved for the treatment of various infectious diseases such as community-acquired pneumonia, urinary tract infections, bacterial prostatitis, and abdominal infections. Its antibacterial spectrum covers common pathogens. The amino substitution at the 5-position enhances antibacterial activity, the 2,4-difluorophenyl at the 7-position improves lipid solubility and tissue penetration, and the cyclopropyl group at the 1-position maintains broad-spectrum activity. The synergistic effect of these three substances solves the technical pain points of traditional quinolone drugs, such as insufficient activity against Gram-positive bacteria, ineffectiveness against anaerobic bacteria, and rapid drug resistance. However, the synthesis process of its chiral intermediate (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester has defects: the existing synthetic routes have problems such as cumbersome steps, harsh reaction conditions, difficulty in separating intermediates, and low yield. There is a lack of green and efficient chiral synthetic processes. Therefore, the industry urgently needs to develop a low-cost, highly stereoselective, and scale-up chiral synthesis method for the sitafloxacin intermediate (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester.
[0003] Currently, there are several methods for synthesizing (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester:
[0004] Method 1: First synthesize the racemic mixture, and then resolve it to obtain a single configuration compound. This method wastes more than half of the other chiral compound and requires multiple resolutions to achieve a high ee value.
[0005] Method 2 uses a catalyst to directly reduce chiral amines, but the reduction efficiency is not high, with an ee value of only 53% (JP2004099609A), and the difficulty of chiral separation still exists in the later stages.
[0006]
[0007] Where R1 represents a hydrogen atom or a protecting group of an amino group, and R2 is a protecting group of an amino group.
[0008] Method 3 uses carbonyl reductase (brewer's yeast) to reduce chiral alcohols, followed by a Mitsunobu reaction to obtain chiral amines. However, this method has low reduction volume efficiency and is difficult to scale up. Furthermore, the presence of large amounts of phosphonotrioxide not only complicates post-processing but also consumes more reducing reagents (Koji SATOH, et al. An Efficient Synthesis of a Key Intermediate of DU-6859a via Asymmetric Microbial Reduction, Chem. Pharm. Bull. 1998, 46, 587).
[0009]
[0010] The methods described above all have the problem of being difficult to scale up, so developing a route that is easy to scale up and environmentally friendly is particularly important. Summary of the Invention
[0011] To address the shortcomings of existing technologies, the present invention aims to provide a sitafloxacin intermediate, its enzymatic preparation method, and its application. In particular, it provides an enzymatic synthesis method for the sitafloxacin intermediate (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester. The preparation method provided by the present invention has a simple process operation, all steps use conventional reaction equipment, the raw materials are cheap and readily available, the yield is high, and the process obtains a product with high stereoselectivity by introducing bio-enzyme catalysis technology, which greatly reduces the cost.
[0012] To achieve this objective, the present invention adopts the following technical solution:
[0013] On one hand, the present invention provides a sitafloxacin intermediate compound 3, which has the following structure:
[0014] ,
[0015] Wherein R is allyl, a straight-chain or branched alkyl group of C1-C8 (e.g., C1, C2, C3, C4, C5, C6, C7 or C8), a cycloalkyl group of C3-C7 (e.g., C3, C4, C5, C6 or C7), a heteroaryl group of C4-C8 (e.g., C4, C5, C6, C7 or C8), benzyl, or methoxybenzyl.
[0016] Preferably, R is methyl, ethyl, propyl, tert-butyl, or benzyl.
[0017] Compound 3 of the present invention is a 5-azaspiro[2.4]heptane derivative with a chiral structure and is a key chiral intermediate in the preparation of sitafloxacin. It is a key intermediate in the enzymatic synthesis of sitafloxacin intermediate (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester.
[0018] On the other hand, the present invention provides an enzymatic method for preparing sitafloxacin intermediate compound 3, the preparation method comprising the following steps:
[0019] (1) Compound 1 was reacted with an azide reagent to give compound 2;
[0020] (2) Compound 2 was catalyzed by transaminase to obtain compound 3;
[0021] The reaction route is as follows:
[0022] ,
[0023] Wherein R is allyl, C1-C8 straight-chain or branched alkyl, C3-C7 cycloalkyl, C4-C8 heteroaryl, benzyl, or methoxybenzyl.
[0024] Compound 3 of the present invention is prepared by transaminase derived from Arthrobacter sp. KNK168 from compound 2, exhibiting high stereoselectivity (ee≥99.5%). The preparation process of the present invention is simple, the raw materials are cheap and readily available, the stereoselectivity and yield are high, and all steps use conventional reaction equipment, which greatly reduces the cost.
[0025] Preferably, the azide reagent in step (1) includes any one or a combination of at least two of sodium azide, lithium azide, potassium azide or trimethylsilyl azide, with sodium azide being preferred.
[0026] Preferably, the molar ratio of compound 2 to the azide reagent in step (1) is 1:(0.9-1.5). For example, 1:0.9, 1:1.0, 1:1.1, 1:1.3, 1:1.4 or 1:1.5, etc., but not limited to the values listed above. Other unlisted values within the above range are also applicable.
[0027] Preferably, the reaction in step (1) is carried out in a solvent selected from any one or a combination of at least two of tetrahydrofuran (THF), acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or acetone.
[0028] Preferably, the reaction temperature in step (1) is 10-80℃, such as 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃ or 80℃, and the reaction time is 10-24 hours, such as 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours or 24 hours, but not limited to the values listed above. Other unlisted values within the above range are also applicable.
[0029] Preferably, the transaminase described in step (2) is derived from Arthrobacter sp. KNK168.
[0030] Preferably, the amount of transaminase used is 1 mg to 10 mg relative to 1 mL of the reaction solution in step (2), for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg or 10 mg.
[0031] Preferably, the catalytic reaction in step (2) is carried out in a buffer solution selected from phosphate buffer or Tris-HCl buffer.
[0032] Preferably, the catalytic reaction in step (2) is carried out in a co-solvent, which is selected from methanol or...
[0033] Dimethyl sulfoxide (DMSO)
[0034] Preferably, the temperature of the catalytic reaction in step (2) is 20-40℃, such as 20℃, 25℃, 30℃, 35℃, 40℃, etc., but not limited to the values listed above. Other unlisted values within the above range are also applicable.
[0035] Preferably, the catalytic reaction time in step (2) is 4-20 hours, such as 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 20 hours, but not limited to the values listed above. Other unlisted values within the above range are also applicable.
[0036] On the other hand, the present invention provides a method for preparing (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester using compound 3, characterized in that the method comprises the following steps:
[0037] (A) Compound 3 was reduced with a reducing agent and subjected to amino-ester exchange to obtain compound 4;
[0038] (B) Compound 4 reacts with Boc reagent to give compound 5;
[0039] (C) Compound 5 undergoes selective reduction to give compound TM, namely (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester;
[0040] The reaction route is as follows:
[0041]
[0042] Wherein R is allyl, C1-C8 straight-chain or branched alkyl, C3-C7 cycloalkyl, C4-C8 heteroaryl, benzyl, or methoxybenzyl.
[0043] Preferably, the reducing agent in step (A) includes any one or a combination of at least two of triphenylphosphine, tributylphosphine, tritert-butylphosphine, or hydrogenation; preferably triphenylphosphine.
[0044] Preferably, the molar ratio of compound 3 to the reducing agent in step (A) is 1:(1.0-1.5). For example, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, etc., but not limited to the values listed above. Other unlisted values within the above range are also applicable.
[0045] Preferably, step (A) specifically involves reacting compound 3 with a reducing agent, then adding water to perform an amino-ester exchange reaction to obtain compound 4.
[0046] Preferably, the reaction of compound 3 with the reducing agent is carried out in an organic solvent selected from any one or a combination of at least two of tetrahydrofuran, acetonitrile, toluene, or dimethyl sulfoxide.
[0047] Preferably, the reaction temperature of compound 3 with the reducing agent is 10-40℃ (e.g., 10℃, 13℃, 16℃, 19℃, 22℃, 25℃, 28℃, 31℃, 34℃ or 40℃, etc.), and the reaction time is 4-20h (e.g., 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h or 20h, etc.).
[0048] Preferably, the temperature of the amine-ester exchange reaction is 50-120℃ (e.g., 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃ or 120℃, etc.), and the time is 2-15h (e.g., 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 12h or 15h, etc.).
[0049] Preferably, the Boc reagent in step (B) is di-tert-butyl carbonate ((Boc)2O).
[0050] Preferably, the molar ratio of compound 4 to Boc reagent in step (B) is 1:(1.0-1.2), such as 1:0.9, 1:1.0, 1:1.1 or 1:1.2, but not limited to the values listed above. Other unlisted values within the above range are also applicable.
[0051] Preferably, the reaction in step (B) is carried out in the presence of an alkaline reagent.
[0052] Preferably, the alkaline reagent is any one or a combination of at least two of potassium carbonate, sodium carbonate, or triethylamine.
[0053] Preferably, the reaction in step (B) is carried out in a solvent, which is any one or a combination of at least two of ethanol, methanol or tetrahydrofuran.
[0054] Preferably, the reaction temperature in step (B) is 10-40°C (e.g., 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, or 40°C, etc.), and the reaction time is 4-24 hours (e.g., 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, or 24 hours, etc.).
[0055] Preferably, the reducing agent in step (C) is any one or a combination of at least two of red aluminum, sodium borohydride, or Lewis acids;
[0056] Preferably, the Lewis acid is one or a combination of at least two of magnesium chloride, calcium chloride, or boron trifluoride ether.
[0057] Preferably, the molar ratio of compound 5 to reducing agent in step (C) is 1:(1.0-5.0), such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, but not limited to the values listed above. Other unlisted values within the above range are also applicable.
[0058] Preferably, the temperature of the reduction reaction in step (C) is 10-70℃ (e.g., 10℃, 12℃, 14℃, 16℃, 18℃, 20℃, 22℃, 24℃, 26℃, 30℃, 40℃, 50℃, 60℃, etc.), and the reaction time is 10-30h (e.g., 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, 26h, or 30h, etc.).
[0059] Preferably, the reduction reaction in step (C) is carried out in an organic solvent, which is selected from any one or a combination of at least two of tetrahydrofuran, toluene, acetonitrile, methanol, and ethanol.
[0060] Compared with the prior art, the present invention has the following beneficial effects:
[0061] The preparation process of this invention is simple to operate, the raw materials are cheap and readily available, and the yield is high. Furthermore, the introduction of bio-enzyme technology in this process allows for the highly selective acquisition of chiral intermediates (ee: 99.5%), which greatly reduces costs. Attached Figure Description
[0062] Figure 1 The image shows the 1H NMR spectrum of compound 2 prepared in Example 1.
[0063] Figure 2 The image shows the 1H NMR spectrum of compound 3 prepared in Example 1.
[0064] Figure 3 The image shows the 1H NMR spectrum of compound 4 prepared in Example 1.
[0065] Figure 4 The image shows the 1H NMR spectrum of compound TM prepared in Example 1. Detailed Implementation
[0066] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.
[0067] Example 1
[0068] This embodiment provides a chiral synthetic method for (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester (TM), and the reaction route is as follows:
[0069]
[0070]
[0071] The preparation method is as follows:
[0072] (1) Add 46.2 g of compound 1, then add 462 mL of THF and start stirring. Add 14 g of sodium azide. After the addition is complete, react at 25 °C for 20 hours. After the reaction is complete, filter, concentrate, add 200 mL of water and 400 mL of EA, stir for 10 min, wash the organic phase once with 200 mL of sodium chloride solution, dry the organic phase with anhydrous sodium sulfate and separate by column chromatography to obtain 50 g of compound 2, purity: 95%, yield: 70% (its 1H NMR characterization is as follows). Figure 1 As shown, the NMR instrument was 400 MHz, and the deuterated reagent used to dissolve the sample was CDCl3.
[0073] (2) Add 4L of phosphate buffer, 237g of isopropylamine hydrochloride, and 40g of compound 2 dissolved in 360mL of DMSO and added to the reaction solution. Start stirring, control the internal temperature at 35-40℃, adjust the pH to about 8.0, add 40g of transaminase powder and 2.5g of PLP (pyridoxal phosphate) to start the reaction. After 48 hours, the reaction ends. Adjust the pH to 8-9, add 1L of dichloromethane, stir for 10min, centrifuge to separate the layers, and wash the organic phase once with saturated sodium chloride aqueous solution. Dry the organic phase with anhydrous sodium sulfate, concentrate it, and then perform column chromatography to obtain 16g of compound 3 with a purity of 98%, ee value of 99.6%, and yield of 40% (the 1H NMR characterization of compound 3 is as follows). Figure 2 As shown, the NMR instrument was 400 MHz, and the deuterated reagent used to dissolve the sample was CDCl3.
[0074] (3) Add 28g of compound 3, then add 280 mL of tetrahydrofuran, start stirring, add 40.88g of triphenylphosphine in portions at 25℃, react at 25℃ for 12 hours, then add 84 mL of water, and react at 100℃ for another 4 hours. After the reaction is complete, add 500 mL of EA, separate the liquid and liquid phases, dry the organic phase with sodium sulfate, concentrate and then perform column chromatography to obtain 16g of compound 4, purity: 95%, optical rotation: -96.6, yield: 89% (its 1H NMR characterization is as follows). Figure 3 As shown, the NMR instrument was 400 MHz, and the deuterated reagent used to dissolve the sample was CDCl3.
[0075] (4) Add 0.6 g of compound 4, then add 6 mL of dichloromethane and 0.53 g of triethylamine. Start stirring and add 1.1 g of (Boc)2O dropwise at 25 °C over 1 hour. After the addition is complete, react at 25 °C for 12 hours. After the reaction is complete, concentrate to remove the solvent, add 20 mL of saturated ammonium chloride aqueous solution, and extract with DCM (20 mL × 2). Separate the liquid and combine the organic phases, dry with sodium sulfate, and concentrate to obtain 1.0 g of compound 5 with a purity of 97% and a yield of 98%.
[0076] (5) Add 1g of compound 5, then add 10mL of toluene, raise the system temperature to 70℃, and at this temperature add the toluene solution of red aluminum (5.0g, 70% in toluene) dropwise to the system. After the addition is complete, keep the reaction at 70℃ for 5 hours. After the reaction of the raw materials is complete, add 4mL of 15% sodium hydroxide aqueous solution for quenching, add 20mL of water for dilution, extract with 20mL of DCM, wash successively with 10mL of saturated sodium bicarbonate and 10mL of saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, concentrate and column chromatography to obtain compound TM (0.5g, white solid), yield 53% (its 1H NMR characterization is as follows). Figure 4 As shown, 1 H NMR (400 MHz, CDCl3)).
[0077] Example 2
[0078] This embodiment provides a chiral synthesis method for (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester (TM), comprising the following steps:
[0079] Add 4.6 g of compound 1, followed by 46 mL of DMSO, and start stirring. Add 1.4 g of sodium azide, and after the addition is complete, react at 25 °C for 20 hours. After the reaction is complete, add 200 mL of water and 400 mL of EA to the reaction mixture, stir for 10 min, wash the organic phase once with 200 mL of sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain 5 g of compound 2, purity: 90%, yield: 65%.
[0080] (2) Add 40 mL of Tris-HCl buffer to a three-necked flask, start stirring, add 0.4 g of KNK168, dissolve 0.4 g of compound 2 in 4 mL of DMSO and add it to the above reaction solution, control the internal temperature in the range of 35-40℃ and react for 48 hours. After the reaction is completed, adjust the pH to 8-9, add 1 L of dichloromethane, stir for 10 min, centrifuge to separate the layers, and wash the organic phase once with saturated sodium chloride aqueous solution. Dry the organic phase with anhydrous sodium sulfate, concentrate and then perform column chromatography to obtain 0.2 g of compound 3, purity: 95%, ee value: 99.6%, yield: 50%.
[0081] (3) Add 3g of compound 3 to a 100mL three-necked flask, then add 30mL of toluene, start stirring, add 5g of triphenylphosphine in portions at 25℃, react at 25℃ for 12 hours, then add 10mL of water, and react at 100℃ for another 4 hours. After the reaction is complete, separate the liquid and liquid phases, dry the organic phase with sodium sulfate, concentrate and then perform column chromatography to obtain 1.6g of compound 4, purity: 92%, yield: 85%.
[0082] (4) Add 1g of compound 4 to a 50 mL three-necked flask, then add 10 mL of methanol and 0.97g of triethylamine. Start stirring and add 1.5g of (Boc)2O dropwise at 25°C over 1 hour. After the addition is complete, react at 25°C for 2 hours. After the reaction is complete, concentrate to remove the solvent, dissolve in 10 mL of LCM, and wash twice with 10 mL of saturated NaHCO3. Separate the liquid and combine the organic phases, dry with sodium sulfate, and concentrate to obtain 1.6g of compound 5 with a purity of 97% and a yield of 95%.
[0083] (5) Add 2g of compound 5, then add 30mL of THF, add sodium borohydride at 25℃, and then add MgCl2 in batches to the system. Stir for 1h, and then heat to 40℃ and react for 20h. Then heat to 60℃ and add 1eq of sodium borohydride dropwise. After the addition is complete, keep the reaction at 70℃ for 5h. After the raw materials have reacted, add 4mL of 15% sodium hydroxide aqueous solution for quenching, remove the solvent by evaporation, extract with DCM (20mL×2) with 10mL of saturated sodium bicarbonate, wash with 10mL of saturated NaCl aqueous solution, dry with anhydrous sodium sulfate, concentrate and then column chromatography to obtain compound TM (0.625g, white solid), yield 34%.
[0084] The applicant declares that the present invention is illustrated by the above embodiments, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.
Claims
1. A method for preparing a sitafloxacin intermediate compound 3, characterized in that, The preparation method includes the following steps: (1) Compound 1 was reacted with an azide reagent to give compound 2; (2) Compound 2 was catalyzed by transaminase to obtain compound 3; The reaction route is as follows: ； Where R is methyl, ethyl, propyl, tert-butyl, or benzyl; The transaminase mentioned in step (2) is derived from Arthrobacter sp. KNK168.
2. The preparation method according to claim 1, characterized in that, The azide reagent mentioned in step (1) includes any one or a combination of at least two of sodium azide, lithium azide, potassium azide or trimethylsilyl azide; The molar ratio of compound 2 to the azide reagent in step (1) is 1:(0.9-1.5); The reaction in step (1) is carried out in a solvent selected from any one or a combination of at least two of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or acetone; The reaction temperature in step (1) is 10-80℃ and the reaction time is 10-24 hours.
3. The preparation method according to claim 1, characterized in that, The amount of transaminase used is 1 mg to 10 mg relative to 1 mL of the reaction solution in step (2); The catalytic reaction in step (2) is carried out in a buffer solution, which is selected from phosphate buffer or Tris-HCl buffer. The catalytic reaction in step (2) is carried out in a co-solvent, which is selected from methanol or dimethyl sulfoxide; The temperature of the catalytic reaction in step (2) is 20-40℃; the reaction time is 4-20h.
4. A method for preparing (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester, characterized in that, The method includes the following steps: (1) Compound 1 was reacted with an azide reagent to give compound 2; (2) Compound 2 was catalyzed by transaminase to obtain compound 3; (A) Compound 3 was reduced with a reducing agent and subjected to amino-ester exchange to obtain compound 4; (B) Compound 4 reacts with Boc reagent to give compound 5; (C) Compound 5 undergoes selective reduction to give compound TM, namely (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate tert-butyl ester; The reaction route is as follows: ； Where R is methyl, ethyl, propyl, tert-butyl, or benzyl; The transaminase mentioned in step (2) is derived from Arthrobacter sp. KNK168.
5. The method according to claim 4, characterized in that, The reducing agent mentioned in step (A) includes any one or a combination of at least two of triphenylphosphine, tributylphosphine, or tritert-butylphosphine; The molar ratio of compound 3 to the reducing agent in step (A) is 1:(1.0-1.5); Step (A) involves reacting compound 3 with a reducing agent, then adding water to perform an amino-ester exchange reaction to obtain compound 4. The reaction of compound 3 with the reducing agent is carried out in an organic solvent selected from any one or a combination of at least two of tetrahydrofuran, acetonitrile, toluene or dimethyl sulfoxide. The reaction temperature of compound 3 with the reducing agent is 10-40℃, and the reaction time is 4-20h; The temperature for the amine-ester exchange reaction is 50-120℃, and the time is 2-15h.
6. The method according to claim 4, characterized in that, The Boc reagent mentioned in step (B) is di-tert-butyl carbonate anhydride; The molar ratio of compound 4 to Boc reagent in step (B) is 1:(1.0-1.2); The reaction described in step (B) is carried out in the presence of a basic reagent; The alkaline reagent is any one or a combination of at least two of potassium carbonate, sodium carbonate, or triethylamine; The reaction in step (B) is carried out in a solvent, which is any one or a combination of at least two of ethanol, methanol or tetrahydrofuran; The reaction temperature in step (B) is 10-40℃, and the reaction time is 4-24h.
7. The method according to claim 4, characterized in that, The reducing agent used in the reaction described in step (C) includes any one or a combination of at least two of aluminum hydroxide, sodium borohydride, or Lewis acids; The Lewis acid is one or a combination of at least two of magnesium chloride, calcium chloride, or boron trifluoride ether.
8. The method according to claim 4, characterized in that, The molar ratio of compound 5 to the reducing agent in step (C) is 1:(1.0-5.0); The reduction reaction in step (C) is carried out at a temperature of 10-70℃ for a time of 10-30 hours. The reduction reaction in step (C) is carried out in an organic solvent selected from any one or a combination of at least two of tetrahydrofuran, toluene, acetonitrile, methanol or ethanol.