Preparation method of (4, 4-difluorotetrahydrofuran-3-yl) methanol

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of (4, 4-difluorotetrahydrofuran-3-yl) methanol. The invention provides the synthesis method of the (4, 4-difluorotetrahydrofuran-3-yl) methanol, the synthesis of the molecular block (4, 4-difluorotetrahydrofuran-3-yl) methanol is realized, the synthesis method only needs five-step reaction, the raw materials and reagents are low in price and safe, the operation is simple and convenient, and the yield and the purity are high. The synthesis method disclosed by the invention is expected to promote the development of related innovative drugs, and has a good application prospect in preparation of drugs taking substituted tetrahydrofuran as a molecular building block.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing (4,4-difluorotetrahydrofuran-3-yl)methanol. Background Art

[0002] Substituted tetrahydrofurans (THFs) are common structural fragments that are widely present in a variety of natural products and biologically relevant compounds. In addition, substituted tetrahydrofuran rings can also be found in many clinical drug candidates (e.g. Figure 1 As shown), such as the antiviral drug GS-6620, antitumor drugs, HIV protease inhibitors, GDC-6599, a molecule that exhibits TRPA1 (transient receptor potential A1) antagonism, and CDK2 (cyclin-dependent kinase 2 or cell division protein kinase 2) inhibitor compound T.

[0003] (4,4-difluorotetrahydrofuran-3-yl)methanol (such as Figure 2 Compound I-1) is a type of tetrahydrofuran molecular building block and an important intermediate in pharmaceutical synthesis. For example, in Novartis's published patent application WO2024 / 171094A1, compound T is a CDK2 inhibitor with a biochemical test IC50 value of 0.032μM. CDK2 is a core cell cycle regulator that is active from the late G1 phase throughout the S phase during cell division. The development of a targeted drug for CDK2 may bring potential benefits to patients with uterine carcinosarcoma, ovarian cancer, gastric cancer, esophageal cancer, endometrial cancer, and breast cancer. The synthetic route of compound T is relatively long, and the key fragment of intermediate B is the (4,4-difluorotetrahydrofuran-3-yl)methanol group (compound I-1). Therefore, it is of great significance to study the synthesis method of (4,4-difluorotetrahydrofuran-3-yl)methanol.

[0004] Therefore, constructing a synthesis method of (4,4-difluorotetrahydrofuran-3-yl)methanol suitable for industrial large-scale production is a problem faced in the field. Summary of the Invention

[0005] In view of the defects of the prior art, the present invention provides a method for preparing (4,4-difluorotetrahydrofuran-3-yl)methanol.

[0006] The present invention provides a method for preparing (4,4-difluorotetrahydrofuran-3-yl)methanol, which comprises the following steps:

[0007]

[0008] Compound VI is reacted to obtain.

[0009] Preferably, the reaction is carried out in the presence of a catalyst, and the catalyst is BF3·Et2O.

[0010] Preferably, the equivalent ratio of compound VI to the catalyst is 1:0.1-0.3.

[0011] Preferably, the method further comprises the following steps:

[0012]

[0013] Step 1, compound II reacts with a fluorine-substituted phosphine source to prepare compound III;

[0014] Step 2, compound III is reduced to generate compound IV;

[0015] Step 3, compound IV reacts with a fluorinating agent to obtain compound V;

[0016] Step 4: Compound V is reduced to generate Compound VI.

[0017] Preferably, in step 3, the reaction is carried out under the action of an organic base, and the organic base is selected from potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide; in step 3, the equivalent ratio of compound IV to the organic base is 1:1.5-1.8.

[0018] Preferably, in step 3, a metal ion additive is added to the reaction, and the metal ion additive is selected from ZnCl2, ZnSO4, FeCl2, FeSO4, and the equivalent ratio of the compound IV to the metal ion is 1:1.1-3.

[0019] Preferably, the fluorine-substituted phosphine source in step 1 is selected from at least one of triethyl 2-fluoro-2-phosphoryl acetate, trimethyl 2-fluoro-2-phosphoryl acetate, and triisopropyl 2-fluoro-2-phosphoryl acetate. An organic base is added to the reaction in step 1, and the organic base is selected from at least one of 1,8-diazabicycloundec-7-ene, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, N,N-diisopropylethylamine, triethylamine, and N-methylmorpholine. The equivalent ratio of compound II to the organic base is 1:1.2-3.

[0020] And / or, in step 1, the equivalent ratio of compound II to the fluorine-substituted phosphine source is 1:0.8-1.2;

[0021] And / or, in step 1, the reaction is carried out under an inert atmosphere, and the organic solvent of the reaction is selected from at least one of tetrahydrofuran and diethyl ether.

[0022] Preferably, in step 2, the reducing agent used in the reduction is H2, the catalyst used in the reduction is selected from at least one of Pd / C and Pd(OH)2 / C, and the amount of the catalyst used in the reduction is 5-20% by mass of compound III;

[0023] And / or, in step 2, the reduction temperature is 20-30° C., the reduction time is 8-12 hours, the reduction solvent is selected from a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1-5:1, and the organic solvent is selected from at least one of tetrahydrofuran, methanol, and ethanol;

[0024] And / or, in step 3, the equivalent ratio of compound IV to the fluorination agent is 1:1.4-3;

[0025] And / or, the fluorination reagent in step 3 is selected from N-fluorobisbenzenesulfonamide;

[0026] And / or, in step 3, the reaction is carried out under an inert atmosphere, and the solvent of the reaction is selected from tetrahydrofuran;

[0027] And / or, the reaction temperature in step 3 is -70 to -80°C, and the reaction time is 40 to 80 minutes.

[0028] Preferably, the reducing agent used in the reduction in step 4 is selected from LiAlH4, NaBH4, DIBAL-H, LiAl(OC(CH3)3)3H, NaBH(OAc)3, and the equivalent ratio of compound V to the reducing agent is 1:0.5-1:1;

[0029] And / or, the reaction in step 4 is carried out under an inert atmosphere; and / or, in step 4, the reduction temperature is 0-30° C., the reduction time is 2-3 hours, the reduction solvent is selected from at least one of tetrahydrofuran and diethyl ether, and when the solvent is a mixed solvent of tetrahydrofuran and diethyl ether, the volume ratio of tetrahydrofuran to diethyl ether is 1:1-3.

[0030] Preferably, the reaction of compound VI is carried out under an inert atmosphere, the solvent of the reaction of compound VI is selected from diethyl ether, the temperature of the reaction of compound VI is 0-30° C., and the time of the reaction of compound VI is 0.5-6 h.

[0031] The present invention provides a method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol by screening synthetic routes, preparation methods, and conditions. This method requires only five reaction steps, utilizes inexpensive raw materials and reagents, is safe, and is easy to operate. Each step yields greater than 74%, for a total yield of 43.4%. The synthetic method of the present invention is expected to promote the development of related innovative drugs and has promising application prospects in the preparation of drugs using substituted tetrahydrofuran as molecular building blocks.

[0032] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0033] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 An example diagram of a clinical drug candidate containing a substituted tetrahydrofuran ring;

[0035] Figure 2 This is an example diagram of the (4,4-difluorotetrahydrofuran-3-yl)methanol group as an important intermediate in pharmaceutical synthesis;

[0036] Figure 3 is the H-NMR spectrum of compound III-1;

[0037] Figure 4 is the F-NMR spectrum of compound III-1;

[0038] Figure 5 is the H-NMR spectrum of compound IV-1;

[0039] Figure 6 is the F-NMR spectrum of compound IV-1;

[0040] Figure 7 is the H-NMR spectrum of compound V-1;

[0041] Figure 8 is the F-NMR spectrum of compound V-1;

[0042] Figure 9 is the H-NMR spectrum of compound VI-1;

[0043] Figure 10 is the F-NMR spectrum of compound VI-1;

[0044] Figure 11 is the H-NMR spectrum of compound I-1;

[0045] Figure 12 is the F-NMR spectrum of compound I-1;

[0046] Figure 13 This is the GCMS result of compound I-1. DETAILED DESCRIPTION

[0047] In the following examples and experimental examples, reagents and materials not otherwise specified are commercially available.

[0048] Example 1 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0049] The structural formula of (4,4-difluorotetrahydrofuran-3-yl)methanol is shown below:

[0050]

[0051] The (4,4-difluorotetrahydrofuran-3-yl)methanol of this embodiment was prepared by the following method:

[0052]

[0053] Step 1, preparation of compound III-1:

[0054] Under nitrogen, compound II-1 (49 g, 1 eq), triethyl 2-fluoro-2-phosphorylacetate (164.67 g, 1 eq), and tetrahydrofuran (THF) (1 L) were added to a 2 L four-necked flask. The temperature was lowered to -10°C, and 1,8-diazabicycloundec-7-ene (DBU, 155.28 g, 1.5 eq) was slowly added dropwise at approximately -10°C. After addition, the mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride (2 L) for quenching, and then extracted with ether (3 x 1 L). The organic phase was dried and concentrated, and purified by column chromatography to obtain compound III-1 (103.7 g) as a yellow, transparent liquid in a yield of 95.2%. The H-NMR (300 M, CDCl3) spectrum of compound III-1 is shown below. Figure 3 As shown, the F-NMR (300M, CDCl3) spectrum of compound III-1 is as follows Figure 4 shown.

[0055] Step 2, preparation of compound IV-1:

[0056] Under nitrogen protection, compound III-1 (103.4 g, 1 eq), THF (600 mL), and H2O (200 mL) were added to a 2L four-necked flask. Aqueous Pd / C (10 g) was added. After hydrogen replacement, hydrogenation was performed using a hydrogen pack and the reaction was allowed to proceed overnight at room temperature. After monitoring the reaction completion with a plate, the catalyst was removed by filtration. The filtrate was added to saturated brine (1000 mL), extracted with ether (3 x 600 mL), dried, concentrated, and subjected to column chromatography to obtain compound IV-1 (93.1 g), a colorless, transparent liquid, in a yield of 89.2%. The H-NMR (300 M, CDCl3) spectrum of compound IV-1 is shown below. Figure 5 As shown, the F-NMR (300M, CDCl3) spectrum of compound IV-1 is as follows Figure 6 shown.

[0057] Step 3, preparation of compound V-1:

[0058] Under nitrogen protection, ZnCl2 (46.22 g, 2.2 eq) and THF (400 mL) were added to a 2L four-necked flask, and then a solution of compound Ⅳ-1 (25 g, 1 eq) in THF (400 mL) was added, the temperature was lowered to -78 ° C, potassium bis(trimethylsilyl)amide KHMDS (0.5 M toluene solution, 540 mL, 1.75 eq) was added, and N-fluorobisbenzenesulfonamide (N-Fluorobenzenesulfonamide) was added dropwise at -78 ° C. A solution of zenesulfonimide (NFSI, 68.06 g, 1.4 eq) in THF (400 mL) was reacted at -78°C for 1 hour and then at room temperature overnight. The reaction was confirmed to be complete by plate monitoring. The reaction solution was poured into a saturated aqueous NaHCO3 solution (2 L) for quenching. The mixture was then extracted with ethyl acetate (3 × 1 L), dried, concentrated, and filtered through a column to obtain a light yellow transparent liquid product, compound V-1 (22.1 g), with a yield of 79.6%. The H-NMR (300 M, CDCl3) spectrum of compound V-1 is shown below. Figure 7 As shown, the F-NMR (300M, CDCl3) spectrum of compound V-1 is as follows Figure 8 shown.

[0059] Step 4, preparation of compound VI-1:

[0060] Under nitrogen, THF (100 mL) and Et2O (150 mL) were added to a 500 mL three-necked flask, cooled to 0°C, and LiAlH4 (1.51 g, 0.5 eq) was added. After stirring for 15 minutes, a solution of compound V-1 (14.3 g, 1 eq) in Et2O (50 mL) was added dropwise. After the addition was complete, the reaction was allowed to react at room temperature for 3 hours. The reaction was confirmed to be complete by plate monitoring. The temperature was then lowered to 0°C and quenched by slowly adding 6 mL of ice water. After stirring for 1 hour, the mixture was filtered, the filtrate was collected, dried, concentrated, and filtered to obtain compound VI-1 (8.8 g) as a colorless, transparent oil with a yield of 74.4%. The H-NMR (300 M, CDCl3) spectrum of compound VI-1 is shown below. Figure 9 As shown, the F-NMR (300M, CDCl3) spectrum of compound VI-1 is as follows Figure 10 shown.

[0061] Step 5, preparation of compound I-1:

[0062] Under nitrogen, compound VI-1 (6.5 g, 1 eq) and Et2O (65 mL) were added to a 250 mL three-necked flask, cooled to 5°C, and BF3·Et2O (1.3 g, 0.2 eq) was added dropwise. The mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by F-NMR. Saturated aqueous NaHCO3 solution (5 mL) was slowly added dropwise to quench the reaction solution. The mixture was dried over anhydrous sodium sulfate, concentrated, and filtered to obtain a colorless, transparent liquid compound I-1 (5.6 g) with a purity of 98.6% and a yield of 86.2%. The H-NMR (300 M, CDCl3) spectrum of compound I-1 is shown below. Figure 11 As shown, the F-NMR (300M, CDCl3) spectrum of compound Ⅰ-1 is as follows Figure 12 As shown, the GCMS results of compound Ⅰ-1 are as follows Figure 13 shown.

[0063] Example 2 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0064] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that: in step 3, ZnCl2 was not added; 1.75eq of KHMDS was replaced by 1.5eq of sodium bis(trimethylsilyl)amide NaHMDS; and the equivalent of NFSI was adjusted to 1.5eq.

[0065] Example 3 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0066] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that: in step 3, ZnCl2 was not added; 1.75eq of KHMDS was replaced by 1.5eq of lithium bis(trimethylsilyl)amide LiHMDS; and the equivalent of NFSI was adjusted to 1.5eq.

[0067] Example 4 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0068] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that: in step 3, ZnCl2 was not added; 1.75eq of KHMDS was replaced by 1.5eq of lithium diisopropylamide LDA; and the equivalent of NFSI was adjusted to 1.5eq.

[0069] Example 5 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0070] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that: in step 3, ZnCl2 was not added; 1.75eq of KHMDS was replaced by 1.5eq of KHMDS; and the equivalent of NFSI was adjusted to 1.5eq.

[0071] Example 6 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0072] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that in step 3, 1.75 eq of KHMDS was replaced with 1.5 eq of LiHMDS; and the equivalent of NFSI was adjusted to 1.5 eq.

[0073] Example 7 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0074] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that the equivalent of the catalyst BF3·Et2O in step 5 was adjusted to 0.1 eq.

[0075] Example 8 A method for synthesizing (4,4-difluorotetrahydrofuran-3-yl)methanol

[0076] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that the equivalent of the catalyst BF3·Et2O in step 5 was adjusted to 0.3 eq.

[0077] Comparative Example 1

[0078] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that the catalyst in step 5 (0.1 eq of BF3·Et2O) was adjusted to 0.3 eq of ZnCl2.

[0079] Comparative Example 2

[0080] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that the catalyst in step 5 (0.1 eq of BF 3 ·Et 2 O) was adjusted to 0.3 eq of LiCl.

[0081] Comparative Example 3

[0082] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that the catalyst in step 5 (0.1 eq of BF3·Et2O) was adjusted to 0.3 eq of LiI.

[0083] Comparative Example 4

[0084] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that the catalyst in step 5 (0.1 eq of BF3·Et2O) was adjusted to 0.3 eq of HCl, wherein the HCl was dissolved in tert-butyl methyl ether (MTBE).

[0085] Comparative Example 5

[0086] (4,4-Difluorotetrahydrofuran-3-yl)methanol was prepared according to the method of Example 1, except that the catalyst in step 5 (0.1 eq of BF3·Et2O) was adjusted to 0.3 eq of CF3COOH.

[0087] The technical solution of the present invention is further illustrated by experiments below.

[0088] Screening experiment of reaction conditions in step 3 of experimental example 1

[0089] In order to optimize the preparation efficiency of the target product, Examples 2-6 explored the effects of the reaction conditions in step 3 on the product yield, and the reaction results are shown in Table 1.

[0090] Table 1: Effects of different reaction conditions on step 3

[0091] Example NFSI equivalent Different bases (equivalent) additive Yield 1 1.4 KHMDS(1.75) <![CDATA[ZnCl2]]> 79.6％ 2 1.5 NaHMDS (1.5) / 20.3％ 3 1.5 LiHMDS(1.5) / 51.6％ 4 1.5 LDA (1.5) / 10.8％ 5 1.5 KHMDS(1.5) / 56.5％ 6 1.5 KHMDS(1.5) <![CDATA[ZnCl2]]> 60.36％

[0092] From the experimental results in Table 1, it can be seen that in the absence of additives, when comparing the yields obtained with different bases (KHMDS, NaHMDS, LiHMDS, LDA), KHMDS has the best effect (Examples 2 to 5); using KHMDS as the base and adding the additive ZnCl2, the yield can be improved (Examples 5 and 6); further optimization of the equivalent weight yielded an optimal yield of 79.6% under the method of Example 1 (Examples 1 and 6).

[0093] In addition, the present invention also screens the dosage of the additive ZnCl2. When the equivalent of ZnCl2 is 1.1-1.3eq, the reaction can occur, but the yield is low and the reaction is not sufficient. When the equivalent of ZnCl2 reaches 2.2eq, the yield reaches the highest and the reaction is fully complete. When the equivalent of ZnCl2 is greater than 2.2eq, the reaction yield will not be further improved.

[0094] According to the reaction conditions in step 3, the preferred base is KHMDS, the preferred fluorination agent is 1.4 eq of NFSI, and the preferred additive is 2.2 eq of ZnCl2.

[0095] Screening experiment of reaction conditions in step 5 of experimental example 2

[0096] This experimental example optimized step 5 and explored the effect of different reaction conditions on the yield of step 5. The reaction conditions and methods were based on the methods of Examples 1, 7, 8 and Comparative Examples 1-5. The optimization results are shown in Table 2.

[0097] Table 2: Effects of different reaction conditions on step 5

[0098] catalyst Catalyst equivalent Reaction results Yield Example 1 <![CDATA[BF3·Et2O]]> 0.2 No raw materials 86.2％ Example 7 <![CDATA[BF3·Et2O]]> 0.1 No raw materials 65.4％ Example 8 <![CDATA[BF3·Et2O]]> 0.3 No raw materials 73.1％ Comparative Example 1 <![CDATA[ZnCl2]]> 0.3 No product / Comparative Example 2 LiCl 0.3 No product / Comparative Example 3 LiI 0.3 No product / Comparative Example 4 HCl in MTBE 0.3 No product / Comparative Example 5 <![CDATA[CF3COOH]]> 0.3 No product /

[0099] From the experimental results in Table 2, it can be seen that in the selection of the catalyst in step 5, the reaction will proceed only when BF3·Et2O is used as the catalyst (Example 8, Comparative Examples 1-5); in particular, among the different equivalents of BF3·Et2O, 0.2eq has the best effect (Examples 1, 7, and 8).

[0100] Through screening experiments on the preparation process and reaction conditions, the present invention has demonstrated a simpler synthesis route for (4,4-difluorotetrahydrofuran-3-yl)methanol, with significantly improved yield and purity. Compared to the method in patent CN2024112676324, which requires six steps to synthesize (4,4-difluorotetrahydrofuran-3-yl)methanol with a total yield of 36% and low purity, the present invention only requires five steps to synthesize (4,4-difluorotetrahydrofuran-3-yl)methanol, achieving a total yield of 43% and a purity of 98.6%.

[0101] As demonstrated in the aforementioned examples and experimental work, the present invention achieves the synthesis of the molecular building block (4,4-difluorotetrahydrofuran-3-yl)methanol in a simple, five-step process with a 43.4% overall yield. As a potential building block for cyclin-dependent kinase (CDK2) inhibitors, this novel building block provides a novel structural unit and tool for drug development for CDK2-related diseases, potentially promoting the development of related innovative drugs and potentially bringing new therapeutic options and drug options to the medical field.

Claims

1. A method for preparing (4,4-difluorotetrahydrofuran-3-yl)methanol, characterized in that: It includes the following steps: Compound VI is reacted to obtain.

2. The preparation method according to claim 1, characterized in that: The reaction is carried out in the presence of a catalyst, which is BF3·Et2O.

3. The preparation method according to claim 2, characterized in that: The equivalent ratio of compound VI to the catalyst is 1:0.1-0.

3.

4. The preparation method according to claim 1, characterized in that The following steps are also included: Step 1, compound II reacts with a fluorine-substituted phosphine source to prepare compound III; Step 2, compound III is reduced to generate compound IV; Step 3, compound IV reacts with a fluorinating agent to obtain compound V; Step 4: Compound V is reduced to generate Compound VI.

5. The preparation method according to claim 4, characterized in that: In step 3, the reaction is carried out under the action of an organic base, and the organic base is selected from potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide; in step 3, the equivalent ratio of compound IV to the organic base is 1:1.5-1.

8.

6. The preparation method according to claim 4, characterized in that: In step 3, a metal ion additive is added to the reaction, wherein the metal ion additive is selected from ZnCl2, ZnSO4, FeCl2, and FeSO4, and the equivalent ratio of the compound IV to the metal ion is 1:1.1-3.

7. The preparation method according to claim 4, characterized in that: The fluorine-substituted phosphine source in step 1 is selected from at least one of triethyl 2-fluoro-2-phosphoryl acetate, trimethyl 2-fluoro-2-phosphoryl acetate, and triisopropyl 2-fluoro-2-phosphoryl acetate. An organic base is added to the reaction in step 1, and the organic base is selected from at least one of 1,8-diazabicycloundec-7-ene, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, N,N-diisopropylethylamine, triethylamine, and N-methylmorpholine. The equivalent ratio of compound II to the organic base is 1:1.2-3. And / or, in step 1, the equivalent ratio of compound II to the fluorine-substituted phosphine source is 1:0.8-1.2; And / or, in step 1, the reaction is carried out under an inert atmosphere, and the organic solvent of the reaction is selected from at least one of tetrahydrofuran and diethyl ether.

8. The preparation method according to claim 4, characterized in that: In step 2, the reducing agent used in the reduction is H2, the catalyst used in the reduction is selected from at least one of Pd / C and Pd(OH)2 / C, and the amount of the catalyst used in the reduction is 5-20% by mass of compound III; And / or, in step 2, the reduction temperature is 20-30° C., the reduction time is 8-12 hours, the reduction solvent is selected from a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1-5:1, and the organic solvent is selected from at least one of tetrahydrofuran, methanol, and ethanol; And / or, in step 3, the equivalent ratio of compound IV to the fluorination agent is 1:1.4-3; And / or, the fluorination reagent in step 3 is selected from N-fluorobisbenzenesulfonamide; And / or, in step 3, the reaction is carried out under an inert atmosphere, and the solvent of the reaction is selected from tetrahydrofuran; And / or, the reaction temperature in step 3 is -70 to -80°C, and the reaction time is 40 to 80 minutes.

9. The preparation method according to claim 4, characterized in that: The reducing agent used in the reduction in step 4 is selected from LiAlH4, NaBH4, DIBAL-H, LiAl(OC(CH3)3)3H, NaBH(OAc)3, and the equivalent ratio of compound V to the reducing agent is 1:0.5-1:1; And / or, the reaction in step 4 is carried out under an inert atmosphere; and / or, in step 4, the reduction temperature is 0-30° C., the reduction time is 2-3 hours, the reduction solvent is selected from at least one of tetrahydrofuran and diethyl ether, and when the solvent is a mixed solvent of tetrahydrofuran and diethyl ether, the volume ratio of tetrahydrofuran to diethyl ether is 1:1-3.

10. The preparation method according to claim 1, characterized in that: The reaction of compound VI is carried out under an inert atmosphere, the solvent of the reaction of compound VI is selected from diethyl ether, and the temperature of the reaction of compound VI is 0-30°C.

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