A method for preparing an azacyclopentane derivative

Abstract

A method for preparing an azetidine derivative, comprising the following steps: using proline hydrochloride as a raw material, esterifying L-proline hydrochloride or D-proline hydrochloride to obtain a compound of formula 3; reacting the compound of formula 3 with epichlorohydrin to obtain a compound of formula 4S or 4R, subjecting the compound of formula 4S or 4R to a cyclization reaction to obtain a compound of formula 5R or 5S, performing a fluorination reaction on the compound of formula 5R or 5S to obtain a compound of formula 6, and reducing the compound of formula 6 to obtain the azetidine derivative of formula 1. This application is a synthetic route starting from L-proline hydrochloride. The improved route has only 5 or 6 reaction steps, and the raw materials are all cheap and easily available. The relatively costly fluorination and reduction reactions are also in the later stage of the route. Therefore, this route has high value.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of an azacyclopentane derivative. Background Art

[0002] In recent years, the compound ((2R,7aR)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol, whose structural formula is as follows in Formula 1:

[0003]

[0004] KRAS G12D is the most common KARS mutation, which is expressed to varying degrees in various cancer types such as pancreatic cancer, colorectal cancer, lung adenocarcinoma, and cholangiocarcinoma. Currently, a new selective non-covalent high-affinity KARS G12D inhibitor MRTX1133 has been discovered, which can bind to both the inactivated state and the activated state of the KRAS G12D mutant. The compound of Formula 1 plays an important role as a raw material in the design and synthesis of some bioactive compounds, such as the tumor KRAS G12D inhibitor MRTX1133. However, the synthesis of compound 1 is relatively difficult. Patent WO2022031678A1 reports a synthesis method that uses reagents such as ozone, dimethyl sulfide, DAST, and lithium aluminum hydride, which are not very friendly to process development. The synthesis process is as follows:

[0005]

[0006] Recently, another literature [Organic Process Research & Development 2022, 26(10), 2839 - 2846.] reported an improved synthesis method of compound 1, but this synthetic route is also long and the implementation is rather cumbersome. The specific process is as follows:

[0007]

[0008] To solve the synthesis problem of compound 1, it is necessary to develop a new preparation method with simple process and low synthesis cost. Summary of the Invention

[0009] The purpose of the present invention is to provide a preparation method of an azacyclopentane derivative.

[0010] The technical solution of the present invention is as follows:

[0011] A preparation method of an azacyclopentane derivative, which comprises the following steps:

[0012] The structural formula of the azacyclopentane derivative is as shown in Formula 1:

[0013]

[0014] S1. Using L - proline hydrochloride or D - proline hydrochloride as raw materials, esterify L - proline hydrochloride or D - proline hydrochloride to obtain the compound of formula 3 or its enantiomer,

[0015]

[0016] wherein R is an alkyl group;

[0017] S2. React the compound of formula 3 with (S) - epichlorohydrin to obtain the compound of formula 4S, or obtain the enantiomer of the compound of formula 4S from the enantiomer of the compound of formula 3;

[0018]

[0019] S3. Cyclize the compound of formula 4S to obtain the compound of formula 5R, or cyclize the enantiomer of the compound of formula 4S to obtain the enantiomer of the compound of formula 5R,

[0020]

[0021] S4. Fluorinate the compound of formula 5R to obtain the compound of formula 6, or fluorinate the enantiomer of the compound of formula 5R to obtain the enantiomer of the compound of formula 6,

[0022]

[0023] S5. Reduce the compound of formula 6 to obtain the compound of formula 1, or reduce the enantiomer of the compound of formula 6 to obtain the enantiomer of the compound of formula 1.

[0024] In a further embodiment, the compound of formula 6 in step S5 is saponified to obtain the compound of formula 7, and then reduced to obtain the compound of formula 1; or the enantiomer of the compound of formula 6 in step S5 is saponified to obtain the enantiomer of the compound of formula 7, and then reduced to obtain the enantiomer of the compound of formula 1.

[0025]

[0026] In a further embodiment, in step S2, the compound of formula 3 is reacted with (R) - epichlorohydrin to obtain the compound of formula 4R, or the enantiomer of the compound of formula 3 is reacted with (S) - epichlorohydrin to obtain the enantiomer of the compound of formula 4R:

[0027]

[0028] Cyclize the above - mentioned compound of formula 4R to obtain the compound of formula 5S, or cyclize the enantiomer of the compound of formula 4R to obtain the enantiomer of the compound of formula 5S,

[0029]

[0030] The above formula is subjected to a fluorination reaction on the compound of formula 5S to obtain the compound of formula 6, or a fluorination reaction is carried out on the enantiomer of the compound of formula 5S to obtain the enantiomer of the compound of formula 6.

[0031] In a further embodiment, the esterification in step S1 means dissolving L-proline hydrochloride or D-proline hydrochloride in methanol, cooling the temperature to 0 °C, and then slowly dropping thionyl chloride into the reaction solution for reaction.

[0032] In a further embodiment, the reaction in step S2 means dissolving the compound of formula 3 in a protic solvent, cooling the temperature to 0 °C, and adding a base and (S)- or (R)-epichlorohydrin for reaction;

[0033] The protic solvent includes water, methanol, and ethanol;

[0034] The base includes triethylamine, DBU, diisopropylethylamine, sodium bicarbonate, sodium carbonate, and potassium carbonate;

[0035] The epichlorohydrin includes R-epichlorohydrin and S-epichlorohydrin.

[0036] In a further embodiment, the cyclization reaction in step S3 means dissolving the compound of formula 4S or 4R in dry tetrahydrofuran, cooling the temperature to -78 °C, slowly dropping a base into the mixture, maintaining the reaction at below -50 °C until the raw materials disappear; then pouring the reaction solution into an aqueous citric acid solution, adjusting the pH to weakly alkaline with NaHCO 3 Finally, the aqueous phase is extracted with DCM and MeOH in a volume ratio of 5:1, the organic phases are combined, and the organic phase is concentrated under reduced pressure to obtain the compound of formula 5R or 5S;

[0037] The solvent includes tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, toluene, and dichloromethane; the base includes lithium diisopropylamide, LiHMDS, KHMDS, and isopropylmagnesium chloride.

[0038] In a further embodiment, the fluorination reaction in step S4 means dissolving the compound of formula 5R or 5S in a solvent, and cooling the temperature of the reaction solution to 0 °C; then adding a fluorination reagent to the reaction solution respectively; the reaction solution is allowed to rise to room temperature naturally for reaction;

[0039] The solvent includes but tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, toluene, and dichloromethane; the fluorination reagent includes DAST, a combination of trifluoromethanesulfonic anhydride - HF pyridine solution, a combination of trifluoromethanesulfonic anhydride - HF triethylamine solution, and perfluorobutanesulfonyl fluoride.

[0040] In a further embodiment, the reduction in step S5 means dissolving the compound of formula 6 in a solvent, cooling the reaction solution to 0 °C, adding a reducing agent to the reaction solution and stirring for reaction, quenching the reaction with ice water after completion, filtering, concentrating, extracting, and purifying to obtain the compound of formula 1;

[0041] The solvent includes tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, and toluene;

[0042] The reducing agent includes lithium aluminum hydride, lithium borohydride, and Red-Al.

[0043] In a further embodiment, a 20% NaOH aqueous solution by mass concentration is added in the saponification reaction, and after the reaction is completed, the pH of the reaction solution is adjusted to 2-3 with an acid;

[0044] The reduction is to add a reducing agent, and the reducing agent is borane.

[0045] The chemical reaction process of this application is as follows:

[0046]

[0047] That is, this application proposes a synthetic route starting from L-proline hydrochloride. The improved route has only 5 or 6 reaction steps, and the raw materials are all cheap and easily available. The relatively costly fluorination and reduction reactions are also carried out in the later stage of the route. Therefore, this route has high value.

[0048] In the present invention, it can be implemented via the proline methyl ester route through intermediates (4aS) and (5aR).

[0049]

[0050] In addition, using the route of epichlorohydrin enantiomers, the same compound of formula 1 can also be obtained via intermediates (4aR) and (5aS):

[0051]

[0052] The main advantages of the present invention include:

[0053] (a) The reagents required in the method of the present invention are relatively cheap and the cost is low;

[0054] (b) The post-treatment operation of the method of the present invention is simple;

[0055] (c) The reaction time of the method of the present invention is short, and it has advantages such as being easy to industrialize. Description of the Drawings

[0056] Figure 1 1H NMR spectrum of the compound 5aS prepared in Example 11;

[0057] Figure 21H NMR spectrum of compound 6a prepared in Example 12. Detailed implementation manners

[0058] To facilitate those skilled in the art to understand the technical solution of the present invention, the technical solution of the present invention will be further described below in conjunction with specific examples of the specification.

[0059] The present invention will be further described below in conjunction with specific implementations. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions indicated in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0060] Example 1

[0061]

[0062] Dissolve 2 (100 g, 0.77 mol) in methanol (500 mL), cool down to 0 °C, and slowly add thionyl chloride (101 g, 0.85 mol) dropwise to the reaction solution. React at room temperature for 5 h. When TLC detects that the raw materials disappear, concentrate the reaction solution under vacuum to obtain 3a (153.8 g) product. The intermediate prepared in this example was analyzed by high-resolution mass spectrometry HRMS: M+H + The molecular formula is C6H12NO2+, the calculated value is 130.0863, and the measured value is 130.0868.

[0063] Example 2

[0064]

[0065] Dissolve 3a (5 g, 0.03 mol) in methanol (16 mL) and water (8 mL), cool down to 0 °C, and add 1,8-diazabicycloundec-7-ene (DBU) (8.0 g, 0.06 mol) and S-epichlorohydrin (5.5 g, 0.06 mol) to the reaction solution. React at room temperature for 6 h. When TLC detects that the raw materials disappear, add ethyl acetate (25 mL, 5V) to the reaction solution, and wash the reaction solution with saturated ammonium chloride aqueous solution (25 mL × 5). Extract the aqueous phase with ethyl acetate (25 mL), combine the organic phases, and concentrate the organic phases under vacuum to obtain 4aS (4.7 g, 70%). The intermediate prepared in this example was analyzed by high-resolution mass spectrometry HRMS: M+H + The molecular formula is C9H17ClNO3+, the calculated value is 222.0891, and the measured value is 222.0899.

[0066] Example 3

[0067]

[0068] Dissolve 3a (5 g, 0.03 mol) in methanol (16 mL) and water (8 mL), cool down to 0 °C, and add triethylamine (6.1 g, 0.06 mol) and S-epichlorohydrin (5.5 g, 0.06 mol) to the reaction solution. React at room temperature for 6 h. When TLC detects that the raw materials have disappeared, add methyl tert-butyl ether (25 mL, 5V) to the reaction solution, and wash the reaction solution with saturated ammonium chloride aqueous solution (25 mL×5). Extract the aqueous phase with methyl tert-butyl ether (25 mL), combine the organic phases, and concentrate the organic phases under vacuum to obtain 4aS (5.3 g, 79%). The thin-layer chromatography of the product is consistent with that of the product in Example 2; perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C9H17ClNO3+, the calculated value is 222.0891, and the measured value is 222.0895.

[0069] Example 4

[0070]

[0071] Dissolve 3a (5 g, 0.03 mol) in ethanol (16 mL) and water (8 mL), cool down to 0 °C, and add sodium bicarbonate (5.0 g, 0.06 mol) and S-epichlorohydrin (6.0 g, 0.065 mol) to the reaction solution. React at room temperature for 6 h. When TLC detects that the raw materials have disappeared, add ethyl acetate (25 mL, 5V) to the reaction solution, and wash the reaction solution with saturated ammonium chloride aqueous solution (25 mL×5). Extract the aqueous phase with ethyl acetate (25 mL), combine the organic phases, and concentrate the organic phases under vacuum to obtain 4aS (4.1 g, 61%). The thin-layer chromatography of the product is consistent with that of the product in Example 2.

[0072] Example 5

[0073]

[0074] Dissolve 4aS (76 g, 0.38 mol) in dry tetrahydrofuran (380 mL, 5V), cool down to -78 °C, and slowly add 1M LiHMDS (800 mL, 0.8 mol) to the reaction solution. Maintain the reaction at below -50 °C for 4 h. When TLC detects that the raw materials have disappeared, pour the reaction solution into citric acid aqueous solution (15%, 1 L), adjust the pH to 8 with sodium carbonate, extract the aqueous phase with DCM:MeOH = 5:1 (400 mL×5), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain 5aR (54 g, 76%). Perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C9H16NO3+, the calculated value is 186.1125, and the measured value is 186.1133.

[0075] Example 6

[0076]

[0077] Dissolve 4aS (75.0 g, 0.38 mol) in dry tetrahydrofuran (380 mL, 5V), cool down to -78 °C, and slowly add dropwise the THF solution of lithium diisopropylamide (0.65 mol) to the reaction solution. Maintain the reaction at below -50 °C for 4 h. Detect by TLC that the raw materials disappear. Pour the reaction solution into the aqueous citric acid solution (15%, 1 L), adjust the pH to 8 with potassium carbonate, extract the aqueous phase with DCM:MeOH = 5:1 (400 mL × 5), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain 5aR (58 g, 81%). The thin-layer chromatography of the product is consistent with that of the product in Example 5; perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C9H16NO3+, the calculated value is 186.1125, and the measured value is 186.1135.

[0078] Example 7

[0079]

[0080] Dissolve 5aR (3 g, 0.016 mol) in dichloromethane (15 mL), cool down the temperature of the reaction solution to -78 °C, add DAST (0.024 mol) to the reaction solution, let the reaction solution rise to room temperature naturally and react for 12 h. Detect by TLC that the raw materials disappear. Pour the reaction solution into the saturated ammonium chloride aqueous solution, use NaHCO 3 to adjust the pH to 8, extract the aqueous phase with DCM (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 6a (1.2 g, 40%). Perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C9H15FNO2+, the calculated value is 188.1081, and the measured value is 188.1088.

[0081] Example 8

[0082]

[0083] Dissolve 5aR (3 g, 0.016 mol) in tetrahydrofuran (15 mL), cool down the temperature of the reaction solution to 0 °C, add trifluoromethanesulfonic anhydride (0.02 mol) to the reaction solution, stir at 0 °C for 30 min, then add the pyridine solution of HF (0.08 mol), stir the reaction solution at 0 °C for 48 h, and then pour the reaction solution into the saturated ammonium chloride aqueous solution, use NaHCO 3Adjust the pH to 8, extract the aqueous phase with ethyl acetate (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 6a (1.4 g, 47%). The thin-layer chromatography of the product is consistent with that of the product in Example 7; the intermediate prepared in this example was analyzed by high-resolution mass spectrometry HRMS: M+H + The molecular formula is C9H15FNO2+, the calculated value is 188.1081, and the measured value is 188.1088.

[0084] Example 9

[0085]

[0086] Dissolve 6a (4 g, 0.021 mol) in tetrahydrofuran (20 mL, 5V), cool the reaction solution to 0 °C, add 1M LiAlH 4 (32 mL, 0.032 mol) and stir for 1 h. Detect the disappearance of the raw materials by TLC, quench the reaction with ice water, filter, concentrate the two-phase filtrate, extract the aqueous phase with ethyl acetate (20 mL×3), combine the organic phases, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain 1 (2.5 g, 75%). The intermediate prepared in this example was analyzed by high-resolution mass spectrometry HRMS: M+H + The molecular formula is C8H15FNO+, the calculated value is 160.1132, and the measured value is 160.1139.

[0087] Example 10

[0088]

[0089] Dissolve 3a (60 g, 0.362 mol) in methanol (192 mL) and water (96 mL), cool to 0 °C, and add triethylamine (73.1 g, 0.724 mol) and R-epichlorohydrin (66.98 g, 0.724 mol) to the reaction solution. React at room temperature for 6 h. Detect the disappearance of the raw materials by TLC, add ethyl acetate (300 mL, 5V) to the reaction solution, and wash the reaction solution with saturated ammonium chloride aqueous solution (300 mL×5). Extract the aqueous phase with ethyl acetate (300 mL), combine the organic phases, and concentrate the organic phase under vacuum to obtain 4aS 60 g (80%). The intermediate prepared in this example was analyzed by high-resolution mass spectrometry HRMS: M+H + The molecular formula is C9H17ClNO3+, the calculated value is 222.0891, and the measured value is 222.0895.

[0090] Example 11

[0091]

[0092] Dissolve 4aR (58 g, 0.28 mol) in dry tetrahydrofuran (290 mL, 5V), cool the temperature to -78 °C, and slowly add dropwise a THF solution of lithium diisopropylamide (0.35 mol) to the reaction solution. Maintain the reaction at below -50 °C for 4 h. When the raw materials disappear as detected by TLC, pour the reaction solution into a citric acid aqueous solution (15%, 0.8 L), adjust the pH to 8 with sodium carbonate, extract the aqueous phase with DCM:MeOH = 5:1 (290 mL × 5), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain 5aS (27.8 g, 53%). Perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C9H16NO3+, the calculated value is 186.1125, and the measured value is 186.1135. Perform 1 1H-NMR study on the intermediate prepared in this example, and the obtained spectrum is as shown in Figure 1 the 1H nuclear magnetic resonance spectrum of compound 5aS to prove its structure.

[0093] Example 12

[0094]

[0095] Dissolve 5aS (24 g, 0.13 mol) in toluene (120 mL, 5V), cool the temperature of the reaction solution to -78 °C, and add DAST (0.22 mol) to the reaction solution. Let the reaction solution naturally rise to room temperature and react for 12 h. When the raw materials disappear as detected by TLC, pour the reaction solution into a saturated ammonium chloride aqueous solution, adjust the pH to 8 with an aqueous sodium carbonate solution, extract the aqueous phase with DCM (200 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 6a (5.75 g, 24%). The thin-layer chromatography of the product is consistent with that of the product in Example 7; perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C9H15FNO2+, the calculated value is 188.1081, and the measured value is 188.1086. Perform 1 1H-NMR study on the intermediate prepared in this example, Figure 2 which is the 1H nuclear magnetic resonance spectrum of compound 6a to prove its structure.

[0096] Example 13

[0097]

[0098] Dissolve 6a (0.10 mol) in toluene (5 mL), cool the temperature of the reaction solution to 0 °C, and add Red-Al solution (0.15 mol) to the reaction solution. Stir the reaction solution at room temperature for 10 h. When the raw materials disappear detected by TLC, pour the reaction solution into saturated ammonium chloride aqueous solution, separate the organic phase, concentrate under reduced pressure, and purify by column chromatography to obtain the compound of formula 1 (75%). The thin-layer chromatography of the product is consistent with that of the product in Example 9; perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C8H15FNO+, the calculated value is 160.1132, and the measured value is 160.1138.

[0099] Example 14

[0100]

[0101] Dissolve 6a (0.10 mol) in methanol (2 mL), add 20% sodium hydroxide solution to this solution. After the raw materials disappear detected by TLC, adjust the pH of the reaction solution to 2 - 3 with 2M HCl, concentrate the reaction solution, and purify the residue by column chromatography to obtain 7 (80%). Perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M-H - The molecular formula is C8H11FNO2-, the calculated value is 172.0779, and the measured value is 172.0783.

[0102] Example 15

[0103]

[0104] Dissolve 7 (0.10 mol) in THF (3 mL), cool the temperature of the reaction solution to 0 °C, and add THF solution of borane (0.2 mol) to the reaction solution. Stir the reaction solution at room temperature for 16 h. When the raw materials disappear detected by TLC, pour the reaction solution into saturated ammonium chloride aqueous solution, separate the organic phase, concentrate under reduced pressure, and purify by column chromatography to obtain 1 (67%). Perform high-resolution mass spectrometry HRMS detection and analysis on the intermediate prepared in this example: M+H + The molecular formula is C8H15FNO+, the calculated value is 160.1132, and the measured value is 160.1138.

[0105] All documents mentioned in the present invention are cited in this application as references, just as each document is cited separately as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A method for preparing an azetidine derivative, characterized in that: It includes the following steps: The structural formula of the azetidine derivative is shown in Formula 1: ； S1. Using L-proline hydrochloride or D-proline hydrochloride as raw materials, esterifying L-proline hydrochloride or D-proline hydrochloride to obtain a compound of Formula 3, wherein R is an alkyl group; S2. Reacting the compound of Formula 3 with (S)-epichlorohydrin to obtain a compound of Formula 4S; The reaction means dissolving the compound of Formula 3 in a protic solvent, cooling to 0 °C, adding a base and epichlorohydrin for reaction; wherein the protic solvent is water, methanol or ethanol; The base is triethylamine, DBU, diisopropylethylamine, sodium bicarbonate, sodium carbonate or potassium carbonate; S3. Subjecting the compound of Formula 4S to a cyclization reaction to obtain a compound of Formula 5R, The cyclization reaction refers to dissolving the compound of Formula 4S in a dry solvent, cooling the temperature to -78 °C, slowly dropping an alkali into the mixture, maintaining the reaction at a temperature below -50 °C until the raw materials disappear; then pouring the reaction solution into an aqueous citric acid solution, adjusting the pH to weakly alkaline with NaHCO 3 to a weakly alkaline pH, and finally extracting the aqueous phase with DCM and MeOH in a volume ratio of 5:1, combining the organic phases, and concentrating the organic phases under reduced pressure to obtain the compound of Formula 5R; The solvent is tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, toluene or dichloromethane; wherein the base is lithium diisopropylamide, LiHMDS, KHMDS or isopropylmagnesium chloride; S4. Performing a fluorination reaction on the compound of Formula 5R to obtain a compound of Formula 6, The fluorination reaction means dissolving the compound of Formula 5R in a solvent and cooling the reaction solution to 0 °C; then adding a fluorination reagent to the reaction solution respectively; the reaction solution is allowed to rise to room temperature naturally for reaction; The solvent is tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, toluene or dichloromethane; the fluorination reagent is DAST, a combination of trifluoromethanesulfonic anhydride - HF pyridine solution, a combination of trifluoromethanesulfonic anhydride - HF triethylamine solution or perfluorobutanesulfonyl fluoride; S5. Reducing the compound of Formula 6 to obtain the compound of Formula 1; The reduction means dissolving the compound of Formula 6 in a solvent, cooling the reaction solution to 0 °C, adding a reducing agent to the reaction solution and stirring for reaction, quenching the reaction with ice water after completion, filtering, concentrating, extracting and purifying to obtain the compound of Formula 1; The solvent is tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran or toluene; The reducing agent is lithium aluminum hydride, lithium borohydride or Red-Al.

2. The preparation method according to claim 1, characterized in that: In step S5, the compound of Formula 6 is subjected to a saponification reaction to obtain a compound of Formula 7, and then reduced to obtain the compound of Formula 1; 。 3. The preparation method according to claim 1, characterized in that: The esterification in step S1 means dissolving L-proline hydrochloride or D-proline hydrochloride in methanol, cooling to 0 °C, and then slowly dropping thionyl chloride into the reaction solution for reaction.

4. The preparation method according to claim 2, characterized in that: In the saponification reaction, an aqueous NaOH solution with a mass concentration of 20% is added, and after the reaction is completed, the pH of the reaction solution is adjusted to 2 - 3 with an acid; The reduction is to add a reducing agent, and the reducing agent is borane.

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