CN115894503A - A kind of preparation method of azacyclopentane derivative - Google Patents

Abstract

A preparation method of an azacyclopentane derivative comprises the following steps: taking proline hydrochloride as a raw material, and esterifying the L-proline hydrochloride or the D-proline hydrochloride to obtain a compound shown in a formula 3; reacting the compound shown in the formula 3 with epoxy chloropropane to obtain a compound shown in a formula 4S or 4R, carrying out cyclization reaction on the compound shown in the formula 4S or 4R to obtain a compound shown in a formula 5R or 5S, carrying out fluorination reaction on the compound shown in the formula 5R or 5S to obtain a compound shown in a formula 6, and reducing the compound shown in the formula 6 to obtain the azacyclopentane derivative shown in the formula 1. The method is a synthetic route starting from L-proline hydrochloride, the improved route only comprises 5 or 6 steps of reaction, raw materials are cheap and easy to obtain, and fluorination and reduction reactions with relatively high cost are also in the later stage of the route, so that the route has high value.

Description

A kind of preparation method of azacyclopentane derivative

technical field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of azacyclopentane derivatives.

Background technique

In recent years, the compound ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol has the following structural formula 1:

KRASG12D is the most common KARS mutation, and it is expressed to varying degrees in various cancers such as pancreatic cancer, colorectal cancer, lung adenocarcinoma, and cholangiocarcinoma. The KARSG12D inhibitor MRTX1133, which can simultaneously bind to KRASG12D mutants in the inactive and active states. However, the compound of formula 1 is used as a raw material in the design and synthesis of some biologically active compounds, such as the tumor KRAS G12D inhibitor MRTX1133, and shows a more important role. 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:

Recently, another document【Organic Process Research&Development 2022,26(10),2839-2846.】reported an improved synthetic method of compound 1, but this synthetic route is also long and cumbersome to implement. The specific process is as follows Shown:

In order to solve the synthesis problem of compound 1, it is necessary to develop a new preparation method with simple process and low synthesis cost.

Contents of the invention

The purpose of the present invention is to provide a kind of preparation method of azocyclopentane derivatives.

Technical scheme of the present invention is as follows:

A preparation method of azacyclopentane derivatives, which comprises the following steps:

The structural formula of the azocyclopentane derivative is shown in formula 1:

S1. Using L-proline hydrochloride or D-proline hydrochloride as a raw material, esterify L-proline hydrochloride or D-proline hydrochloride to obtain a compound of formula 3 or its enantiomer,

In the formula, R is an alkyl group;

S2, reacting the compound of formula 3 with (S)-epichlorohydrin to obtain the compound of formula 4S, or preparing the enantiomer of the compound of formula 4S from the enantiomer of the compound of formula 3;

S3. The compound of formula 4S is cyclized to obtain the compound of formula 5R, or the enantiomer of the compound of formula 4S is cyclized to obtain the enantiomer of the compound of formula 5R,

S4, performing fluorination reaction on the compound of formula 5R to obtain the compound of formula 6, or performing fluorination reaction on the enantiomer of the compound of formula 5R to obtain the enantiomer of the compound of formula 6,

S5. Reducing the compound of formula 6 to obtain the compound of formula 1, or reducing the enantiomer of the compound of formula 6 to obtain the enantiomer of the compound of formula 1.

In a further scheme, 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 compound of formula 1 compound enantiomer,

In a further scheme, 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 compound of formula 4R. body:

The cyclization reaction of the compound of formula 4R to obtain the compound of formula 5S, or the enantiomeric cyclization reaction of the compound of formula 4R to obtain the enantiomer of the compound of formula 5S,

The compound of formula 5S is fluorinated by the above formula to obtain the compound of formula 6, or the enantiomer of the compound of formula 5S is fluorinated to obtain the enantiomer of the compound of formula 6.

In a further scheme, esterification in step S1 refers to dissolving L-proline hydrochloride or D-proline hydrochloride in methanol, and cooling down to 0°C, and then slowly adding thionyl chloride dropwise to reaction in the reaction solution.

In a further scheme, the reaction in step S2 refers to dissolving the compound of formula 3 in a protic solvent, cooling down to 0°C, adding a base and (S) or (R)-epichlorohydrin to react;

Described protic solvent comprises water, methanol, ethanol;

The base includes triethylamine, DBU, diisopropylethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate;

The epichlorohydrin includes R-epichlorohydrin and S-epichlorohydrin.

In a further scheme, the cyclization reaction in step S3 refers to dissolving the compound of formula 4S or 4R in dry tetrahydrofuran, cooling down to -78°C, slowly adding alkali dropwise to the mixed solution, and maintaining the reaction below -50°C until the raw materials disappear; then Pour the reaction solution into an aqueous citric acid solution, adjust the pH to weakly alkaline with NaHCO ₃ , and finally extract the aqueous phase with DCM and MeOH at a volume ratio of 5:1, combine the organic phases, and concentrate the organic phases under reduced pressure to obtain the compound of formula 5R or 5S ;

The solvent includes tetrahydrofuran, tertiary methyl ether, 2-methyltetrahydrofuran, toluene, and methylene chloride; the base includes lithium diisopropylamide, LiHMDS, KHMDS, and isopropylmagnesium chloride.

In a further scheme, the fluorination reaction in step S4 refers to dissolving the compound of formula 5R or 5S in a solvent, and reducing the temperature of the reaction solution to 0°C; then adding a fluorination reagent to the reaction solution; the reaction solution naturally rises to room temperature to react;

The solvent includes tetrahydrofuran, methyl tertiary ether, 2-methyltetrahydrofuran, toluene, dichloromethane; the fluorinating reagent includes a combination of DAST, trifluoromethanesulfonic anhydride-HF pyridine solution, Combination of triethylamine solution and perfluorobutylsulfonyl fluoride.

In a further solution, the reduction in step S5 refers to dissolving the compound of formula 6 in a solvent, cooling the reaction solution to 0°C, adding a reducing agent to the reaction solution to stir the reaction, quenching the reaction with ice water after completion, filtering, concentrating, extracting, Purify to obtain the compound of formula 1;

The solvent includes tetrahydrofuran, methyl tertiary ether, 2-methyltetrahydrofuran, toluene;

The reducing agent includes lithium aluminum hydride, lithium borohydride, Red-Al.

In a further scheme, an aqueous NaOH solution with a mass concentration of 20% is added to the saponification reaction, 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.

The chemical reaction process of the present application is as follows:

That is, the present application proposes a synthetic route starting from L-proline hydrochloride, the improved route has only 5 or 6 steps of reaction, and the raw materials are all cheap and easy to obtain, and the fluorination and reduction reactions with relatively high cost are also all available. In the later stage of the route, so this route has a higher value.

The present invention can be carried out via the proline methyl ester route via intermediates (4aS) and (5aR).

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

The main advantages of the present invention include:

(a) the required reagents of the inventive method are comparatively cheap, and cost is low;

(b) the post-processing operation of the inventive method is simple;

(c) The method of the present invention has the advantages of short reaction time and easy industrial production.

Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrum figure of the compound 5aS prepared in embodiment 11;

Figure 2 is the H NMR spectrum of compound 6a prepared in Example 12.

Detailed ways

In order to make it easier for 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 in conjunction with specific embodiments of the specification.

The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

Example 1

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

Example 2

3a (5g, 0.03mol) was dissolved in methanol (16mL) and water (8mL), cooled to 0°C, 1,8-diazabicycloundec-7-ene (DBU) (8.0g, 0.06 mol) and S-epichlorohydrin (5.5g, 0.06mol) were added to the reaction solution. After reacting at room temperature for 6 h, TLC detected that the starting material disappeared, and ethyl acetate (25 mL, 5V) was added to the reaction solution, and the reaction solution was washed with saturated aqueous ammonium chloride solution (25 mL×5). The aqueous phase was extracted with ethyl acetate (25 mL), the combined organic phases were concentrated in vacuo to give 4aS (4.7 g, 70%). The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of M+H ⁺ was C9H17ClNO3+, the calculated value was 222.0891, and the measured value was 222.0899.

Example 3

3a (5g, 0.03mol) was dissolved in methanol (16mL) and water (8mL), cooled to 0 ° C, triethylamine (6.1g, 0.06mol) and S-epichlorohydrin (5.5g, 0.06mol) added to the reaction solution. After reacting at room temperature for 6 h, TLC detected that the raw materials disappeared, and tertiary methyl ether (25 mL, 5V) was added to the reaction solution, and the reaction solution was washed with saturated aqueous ammonium chloride solution (25 mL×5). The aqueous phase was extracted with tert-methyl ether (25 mL), the combined organic phases were concentrated in vacuo to give 4aS (5.3 g, 79%). The thin-layer chromatography of the product is consistent with the product in Example 2; the intermediate prepared in this example is subjected to high-resolution mass spectrometry HRMS detection and analysis: M+H ⁺ molecular formula is C9H17ClNO3+, calculated value 222.0891, measured value 222.0895.

Example 4

3a (5g, 0.03mol) was dissolved in ethanol (16mL) and water (8mL), cooled to 0 ° C, sodium bicarbonate (5.0g, 0.06mol) and S-epichlorohydrin (6.0g, 0.065mol) added to the reaction solution. After reacting at room temperature for 6 h, TLC detected that the starting material disappeared, and ethyl acetate (25 mL, 5V) was added to the reaction solution, and the reaction solution was washed with saturated aqueous ammonium chloride solution (25 mL×5). The aqueous phase was extracted with ethyl acetate (25 mL), the combined organic phases were concentrated in vacuo to give 4aS (4.1 g, 61%). The thin layer chromatography of product is consistent with the product of embodiment 2.

Example 5

4aS (76g, 0.38mol) was dissolved in dry tetrahydrofuran (380mL, 5V), cooled to -78°C, and 1M LiHMDS (800mL, 0.8mol) was slowly added dropwise to the reaction solution. Maintain the temperature below -50°C for 4 hours, TLC detects that the raw materials disappear, pour the reaction solution into aqueous citric acid (15%, 1L), adjust the pH to 8 with sodium carbonate, and use DCM:MeOH=5:1 (400mL×5 ) to extract the aqueous phase, combine the organic phases, and concentrate the organic phases under reduced pressure to obtain 5aR (54 g, 76%). The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of M+H ⁺ was C9H16NO3+, the calculated value was 186.1125, and the measured value was 186.1133.

Example 6

4aS (75.0 g, 0.38 mol) was dissolved in dry tetrahydrofuran (380 mL, 5V), cooled to -78°C, and a THF solution (0.65 mol) of lithium diisopropylamide was slowly added dropwise to the reaction solution. Maintain the reaction at below -50°C for 4h, TLC detects that the starting material disappears, pour the reaction solution into citric acid aqueous solution (15%, 1L), adjust the pH to 8 with potassium carbonate, and use DCM:MeOH=5:1 (400mL×5 ) to extract the aqueous phase, 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 the product in Example 5; the intermediate prepared in this example is subjected to high-resolution mass spectrometry HRMS detection and analysis: the M+H ⁺ molecular formula is C9H16NO3+, the calculated value is 186.1125, and the measured value is 186.1135.

Example 7

5aR (3g, 0.016mol) was dissolved in dichloromethane (15mL), the temperature of the reaction solution was lowered to -78°C, DAST (0.024mol) was added to the reaction solution, the reaction solution was naturally raised to room temperature for 12h, and detected by TLC The raw material disappeared, the reaction solution was poured into saturated ammonium chloride aqueous solution, the pH was adjusted to 8 with NaHCO ₃ , the aqueous phase was extracted with DCM (30mL×3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and passed through the column Purification gave 6a (1.2 g, 40%). The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of M+H ⁺ was C9H15FNO2+, the calculated value was 188.1081, and the measured value was 188.1088.

Example 8

Dissolve 5aR (3g, 0.016mol) in tetrahydrofuran (15mL), lower the temperature of the reaction solution to 0°C, add trifluoromethanesulfonic anhydride (0.02mol) to the reaction solution, stir at 0°C for 30min, then add HF Pyridine solution (0.08mol), the reaction solution was stirred at 0°C for 48h, then the reaction solution was poured into saturated ammonium chloride aqueous solution, the pH was adjusted to 8 with _NaHCO3 , and the aqueous phase was extracted with ethyl acetate (30mL×3), The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column to obtain 6a (1.4 g, 47%). The thin-layer chromatography of the product is consistent with the product of Example 7; the intermediate prepared in this example is subjected to high-resolution mass spectrometry HRMS detection and analysis: the M+H ⁺ molecular formula is C9H15FNO2+, the calculated value is 188.1081, and the measured value is 188.1088.

Example 9

Dissolve 6a (4g, 0.021mol) in tetrahydrofuran (20mL, 5V), cool the reaction solution to 0°C, add 1M LiAlH ₄ (32mL, 0.032mol) to the reaction solution and stir for 1h. The reaction was quenched, filtered, and the two-phase filtrate was concentrated, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, concentrated to dryness under reduced pressure, and purified by column to obtain 1 (2.5 g, 75%). The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of M+H ⁺ was C8H15FNO+, the calculated value was 160.1132, and the measured value was 160.1139.

Example 10

3a (60g, 0.362mol) was dissolved in methanol (192mL) and water (96mL), cooled to 0°C, triethylamine (73.1g, 0.724mol) and R-epichlorohydrin (66.98g, 0.724mol) added to the reaction solution. After reacting at room temperature for 6 h, TLC detected that the raw materials disappeared, and ethyl acetate (300 mL, 5V) was added to the reaction solution, and the reaction solution was washed with saturated aqueous ammonium chloride solution (300 mL×5). The aqueous phase was extracted with ethyl acetate (300 mL), the combined organic phases were concentrated in vacuo to give 60 g (80%) of 4aS. The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of M+H ⁺ was C9H17ClNO3+, the calculated value was 222.0891, and the measured value was 222.0895.

Example 11

4aR (58g, 0.28mol) was dissolved in dry tetrahydrofuran (290mL, 5V), cooled to -78°C, and a THF solution (0.35mol) of lithium diisopropylamide was slowly added dropwise to the reaction solution. Maintain the reaction below -50°C for 4 hours, TLC detects that the raw materials disappear, pour the reaction solution into aqueous citric acid (15%, 0.8L), adjust the Ph to 8 with sodium carbonate, and use DCM:MeOH=5:1 (290mL× 5) Extract the aqueous phase, combine the organic phases, and concentrate the organic phases under reduced pressure to obtain 5aS (27.8 g, 53%). The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of M+H ⁺ was C9H16NO3+, the calculated value was 186.1125, and the measured value was 186.1135. ^{The 1} H-NMR study was carried out on the intermediate prepared in this example, and the obtained spectrum is as shown in Figure 1, which is the hydrogen NMR spectrum of compound 5aS, to prove its structure.

Example 12

5aS (24g, 0.13mol) was dissolved in toluene (120mL, 5V), the temperature of the reaction solution was lowered to -78°C, and DAST (0.22mol) was added to the reaction solution. The reaction solution was naturally raised to room temperature and reacted for 12 hours. TLC detected that the raw materials disappeared. The reaction solution was poured into saturated ammonium chloride aqueous solution, and the pH was adjusted to 8 with aqueous sodium carbonate solution. The aqueous phase was extracted with DCM (200mL×3), and the organic phases were combined. It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column to obtain 6a (5.75 g, 24%). The thin-layer chromatography of the product is consistent with the product in Example 7; the intermediate prepared in this example is subjected to high-resolution mass spectrometry HRMS detection and analysis: the M+H ⁺ molecular formula is C9H15FNO2+, the calculated value is 188.1081, and the measured value is 188.1086. ¹ H-NMR study was carried out on the intermediate prepared in this example, and Fig. 2 is the H NMR spectrum of compound 6a to prove its structure.

Example 13

6a (0.10 mol) was dissolved in toluene (5 mL), the temperature of the reaction solution was lowered to 0°C, and Red-Al solution (0.15 mol) was added to the reaction solution. The reaction solution was stirred at room temperature for 10 h, TLC detected that the raw materials disappeared, the reaction solution was poured into saturated ammonium chloride aqueous solution, the organic phase was separated, concentrated under reduced pressure, and purified by column to obtain the compound of formula 1 (75%). The thin-layer chromatography of the product is consistent with the product in Example 9; the intermediate prepared in this example is subjected to high-resolution mass spectrometry HRMS detection and analysis: the M+H ⁺ molecular formula is C8H15FNO+, the calculated value is 160.1132, and the measured value is 160.1138.

Example 14

Dissolve 6a (0.10 mol) in methanol (2 mL), add 20% sodium hydroxide solution to this solution, and after TLC detects that the raw material disappears, adjust the pH of the reaction solution to 2-3 with 2M HCl, concentrate the reaction solution, and dilute the residue Column purification afforded 7 (80%). The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of ^MH- was C8H11FNO2-, the calculated value was 172.0779, and the measured value was 172.0783.

Example 15

7 (0.10 mol) was dissolved in THF (3 mL), the temperature of the reaction solution was lowered to 0° C., and a THF solution (0.2 mol) of borane was added to the reaction solution. The reaction solution was stirred at room temperature for 16 h, TLC detected that the raw material disappeared, the reaction solution was poured into saturated ammonium chloride aqueous solution, the organic phase was separated, concentrated under reduced pressure, and purified by column to obtain 1 (67%). The intermediate prepared in this example was detected and analyzed by high-resolution mass spectrometry HRMS: the molecular formula of M+H ⁺ was C8H15FNO+, the calculated value was 160.1132, and the measured value was 160.1138.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content 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 the present application.

Claims (9)

1. a preparation method of azacyclopentane derivatives, characterized in that: comprise the following steps: The structural formula of the azocyclopentane derivative is shown in formula 1:

S1. Using L-proline hydrochloride or D-proline hydrochloride as a raw material, esterify L-proline hydrochloride or D-proline hydrochloride to obtain a compound of formula 3 or its enantiomer,

In the formula, R is an alkyl group; S2, reacting the compound of formula 3 with (S)-epichlorohydrin to obtain the compound of formula 4S, or preparing the enantiomer of the compound of formula 4S from the enantiomer of the compound of formula 3;

S3. The compound of formula 4S is cyclized to obtain the compound of formula 5R, or the enantiomer of the compound of formula 4S is cyclized to obtain the enantiomer of the compound of formula 5R,

S4, performing fluorination reaction on the compound of formula 5R to obtain the compound of formula 6, or performing fluorination reaction on the enantiomer of the compound of formula 5R to obtain the enantiomer of the compound of formula 6,

S5. Reducing the compound of formula 6 to obtain the compound of formula 1, or reducing the enantiomer of the compound of formula 6 to obtain the enantiomer of the compound of formula 1. 2. The preparation method according to claim 1, characterized in that: 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 Afterwards, the compound enantiomer of formula 7 is obtained, and then reduced to obtain the enantiomer of compound of formula 1,

3. The preparation method according to claim 1, characterized in that: 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 reaction makes formula 4R compound enantiomer:

The cyclization reaction of the compound of formula 4R to obtain the compound of formula 5S, or the enantiomeric cyclization reaction of the compound of formula 4R to obtain the enantiomer of the compound of formula 5S,

The compound of formula 5S is fluorinated by the above formula to obtain the compound of formula 6, or the enantiomer of the compound of formula 5S is fluorinated to obtain the enantiomer of the compound of formula 6. 4. The preparation method according to claim 1, characterized in that: in step S1, esterification refers to dissolving L-proline hydrochloride or D-proline hydrochloride in methanol, and cooling to 0°C, and then slowly drop thionyl chloride into the reaction liquid to react. 5. The preparation method according to claim 1, characterized in that: the reaction in step S2 refers to dissolving the compound of formula 3 in a protic solvent, cooling to 0°C, adding alkali and epichlorohydrin to react; Described protic solvent comprises water, methanol, ethanol; The base includes triethylamine, DBU, diisopropylethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate; The epichlorohydrin includes R-epichlorohydrin and S-epichlorohydrin. 6. The preparation method according to claim 1, characterized in that: the cyclization reaction in step S3 refers to dissolving the compound of formula 4S in dry tetrahydrofuran, cooling down to -78°C, slowly adding alkali dropwise to the mixture, and maintaining it at React below -50°C until the raw materials disappear; then pour the reaction solution into an aqueous citric acid solution, adjust the pH to weakly alkaline with NaHCO ₃ , and finally extract the aqueous phase with DCM and MeOH at a volume ratio of 5:1, and combine the organic phases. Concentrate the organic phase under reduced pressure to obtain the compound of formula 5R; The solvent includes tetrahydrofuran, tertiary methyl ether, 2-methyltetrahydrofuran, toluene, and methylene chloride; the base includes lithium diisopropylamide, LiHMDS, KHMDS, and isopropylmagnesium chloride. 7. The preparation method according to claim 1, characterized in that: the fluorination reaction in step S4 refers to dissolving the compound of formula 5R in a solvent, and reducing the temperature of the reaction solution to 0°C; Add the fluorinating reagent; the reaction solution naturally rises to room temperature for reaction; The solvent includes tetrahydrofuran, methyl tertiary ether, 2-methyltetrahydrofuran, toluene, dichloromethane; the fluorinating reagent includes a combination of DAST, trifluoromethanesulfonic anhydride-HF pyridine solution, Combination of triethylamine solution and perfluorobutylsulfonyl fluoride. 8. The preparation method according to claim 1, characterized in that: the reduction in step S5 refers to 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 the reaction. Quench the reaction with ice water, filter, concentrate, extract, and purify to obtain the compound of formula 1; The solvent includes tetrahydrofuran, methyl tertiary ether, 2-methyltetrahydrofuran, toluene; The reducing agent includes lithium aluminum hydride, lithium borohydride, Red-Al. 9. The preparation method according to claim 2, characterized in that: adding a mass concentration of 20% NaOH aqueous solution in the saponification reaction, and adjusting the pH of the reaction solution with an acid after the reaction is finished is 2-3; The reduction is to add a reducing agent, and the reducing agent is borane.

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