Method for synthesizing and decomposing chiral 3-hydroxy-4-fluoropiperidine derivatives

Abstract

This invention discloses a method for synthesizing and decomposing chiral 3-hydroxy-4-fluoropiperidine derivatives. Starting with piperidone, a compound, the α-position of the carbonyl group is fluorinated with a fluorine reagent under the catalytic action of an organic amine reagent to obtain a chiral fluorine compound. Next, a chiral hydroxy-fluorine compound is produced by reduction with a reducing agent. Four target products with single stereochemistrys, namely (3S,4R)-3-hydroxy-4-fluoropiperidine derivative, (3S,4S)-3-hydroxy-4-fluoropiperidine derivative, (3R,4S)-3-hydroxy-4-fluoropiperidine derivative, and (3R,4R)-3-hydroxy-4-fluoropiperidine derivative, are obtained by decomposition with a decomposing agent or by supercritical fluid chromatography. The above synthesis method has advantages such as a short number of steps, low cost, and ease of operation, making it suitable for industrial production, and can be used as a drug intermediate or in the study of potential drugs.

Description

[Technical Field]

[0001] The present invention relates to the technical field for the production of structures containing fluoropiperidine, and more particularly to methods for the synthesis and decomposition of chiral 3-hydroxy-4-fluoropiperidine derivatives. [Background technology]

[0002] The stereochemistry of organofluorine compounds exhibits a series of unique physical properties, which give them significant application value in scientific research and industry. Organofluorine compounds are widely used in the fields of pharmaceuticals, agrochemicals, and polymers. Fluorine is extremely important in life sciences; in drug chemistry, fluorine atoms can improve metabolic stability by blocking metabolically unstable sites, modulate the physicochemical properties of drug molecules, such as lipophilicity or basicity, and potentially have a substantial impact on the molecular conformation. Therefore, the introduction of fluorine atoms is an effective means of studying the physical and metabolic characteristics of candidate drugs in drug chemistry research.

[0003] The structure of piperidines plays a crucial role in the development of many drugs, serving as important intermediates in the research and development of new drugs. The introduction of fluorine atoms and fluorine-containing groups into piperidine molecules offers a new approach to drug design and synthesis, representing a promising policy for new drug research and development. This approach is expected to not only introduce specific biological activities but also improve the pharmacokinetic and pharmacokinetic properties of drugs, thereby promoting the development and improvement of new drugs.

[0004] Currently, there are several methods for synthesizing such fluorine-substituted piperidine derivatives, and a summary of the literature is as follows.

[0005] A typical synthesis method involves first epoxidizing an olefin, followed by ring-opening of the epoxy with hydrofluoric acid to produce a trans conformational product. Then, the trans conformation is converted to the cis conformation via the Mitsunobu reaction, and finally, the cis product is obtained through a hydrolysis step. However, this synthetic route requires relatively stringent operating conditions, resulting in the generation of large quantities of by-products, particularly the genotoxic triphenyloxyline. Furthermore, this method is atomically uneconomical, and the presence of some difficult-to-remove by-products increases the difficulty of product purification, making large-scale, efficient production extremely challenging. [ka]

[0006] Currently, only a few catalytic methods can asymmetrically link fluorine to the frame of piperidine derivatives. In 2011, MacMilan achieved highly enantioselective α-fluorination of ketones using an improved quinine catalyst. In 2013, Shaw improved MacMilan's method, demonstrating that the catalyst could be substituted with a commercially available primary amine, and successfully achieved the asymmetric synthesis of 3-hydroxy-4-fluoropiperidine derivatives. However, current methods are only applicable to symmetric piperidine derivatives. [ka]

[0007] Currently, there is a lack of methods for producing 3-hydroxy-4-fluoropiperidine derivatives, or all conventional methods have certain shortcomings. Therefore, developing novel synthesis methods and process improvements for chiral 3-hydroxy-4-fluoropiperidine derivatives has significant importance and application value. [Overview of the Initiative]

[0008] To overcome the problems of the prior art, the present invention aims to research and develop a method for synthesizing fluorine-substituted piperidine derivatives that has fewer steps, higher yield, better quality, and is easier to operate, specifically a method for synthesizing and decomposing chiral 3-hydroxy-4-fluoropiperidine derivatives.

[0009] To achieve the above objective, the present invention employs the following technical approach.

[0010] The synthesis route for the chiral 3-hydroxy-4-fluoropiperidine derivative of the present invention is shown below: [ka]

[0011] The above synthesis route starts with the compound of formula I (piperidone derivative) as the raw material, and uses the catalytic action of an organic amine reagent to fluorinate the carbonyl group at the α-position with a fluorine reagent to produce the chiral fluorine compound of formula II. Further reduction with a reducing agent produces the chiral hydroxy-fluorine compound of formula III, and the chiral hydroxy-fluorine compound of formula III is decomposed to produce the 3-hydroxy-4-fluoropiperidine derivative.

[0012] In the above synthetic route, the synthetic product is a chiral hydroxy-fluorine compound of formula III or a 3-hydroxy-4-fluoropiperidine derivative. The chiral hydroxy-fluorine compound of formula III is a mixture of (3S,4R)-3-hydroxy-4-fluoropiperidine derivatives, (3S,4S)-3-hydroxy-4-fluoropiperidine derivatives, (3R,4S)-3-hydroxy-4-fluoropiperidine derivatives, and (3R,4R)-3-hydroxy-4-fluoropiperidine derivatives. The 3-hydroxy-4-fluoropiperidine derivative is a (3S,4R)-3-hydroxy-4-fluoropiperidine derivative represented by formula IV, a (3R,4S)-3-hydroxy-4-fluoropiperidine derivative represented by formula V, a (3R,4R)-3-hydroxy-4-fluoropiperidine derivative represented by formula VI, or a (3S,4S)-3-hydroxy-4-fluoropiperidine derivative represented by formula VII.

[0013] In the above synthesis pathway, R 1 This is selected from hydrogen (H), tert-butoxycarbonyl group (Boc), benzyl group (Bn), benzyloxycarbonyl group (Cbz), aryl group, and C1-C9 alkyl group.

[0014] To achieve the above objective, the present invention employs the following technical approach.

[0015] A first aspect of the present invention is: Step S1 involves using the compound of formula I as a starting material and performing enantioselective fluorination of the α-position of the carbonyl group using a fluorine reagent under the catalytic action of an organic amine reagent to produce the chiral fluorine compound of formula II. The process includes step S2, which involves reducing a chiral fluorine compound of formula II with a reducing agent to produce a chiral hydroxy-fluorine compound of formula III, [ka] Here, the chiral fluorine compound of formula II includes both the S conformation and the R conformation. The chiral hydroxy-fluorine compound of formula III is a mixture of (3S,4R)-3-hydroxy-4-fluoropiperidine derivatives, (3S,4S)-3-hydroxy-4-fluoropiperidine derivatives, (3R,4S)-3-hydroxy-4-fluoropiperidine derivatives and (3R,4R)-3-hydroxy-4-fluoropiperidine derivatives, R 1 provides a method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative, where R is selected from the group consisting of hydrogen, a tert-butoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, an aryl group and a C1-C9 alkyl group.

[0016] Furthermore, the specific operation steps of step S1 include reacting the compound of formula I with a fluorine reagent in a first solvent under the promotion of a primary / secondary amine, an inorganic base, an organic acid and water, where the reaction temperature is -50 to 50 °C, to obtain a chiral fluorine compound of formula II or a solution thereof.

[0017] Furthermore, in step S1, the compound of formula I is N-R 1 -3-piperidone derivative, preferably, the compound of formula I is N-tert-butoxycarbonyl-3-piperidone.

[0018] Furthermore, in step S1, the primary / secondary amine is any one or more selected from S-1-phenylethylamine, R-1-phenylethylamine, L-proline, D-proline, chiral and racemized arylamines and C1-C9 alkylamines, preferably, the primary / secondary amine is any one or more selected from S-1-phenylethylamine, R-1-phenylethylamine, L-proline, D-proline, more preferably, the primary / secondary amine is S-1-phenylethylamine or R-1-phenylethylamine.

[0019] Furthermore, in the step S1, the inorganic base is any one or more selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and lithium carbonate. Preferably, the inorganic base is sodium carbonate.

[0020] Furthermore, in the step S1, the organic acid is any one or more selected from trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, and acetic acid. Preferably, the organic acid is any one or more selected from trifluoroacetic acid, trichloroacetic acid, and acetic acid. More preferably, the organic acid is trichloroacetic acid.

[0021] Furthermore, in the step S1, the fluorine reagent is any one or more selected from N-fluorobis(benzenesulfon)amide and a selective fluorine reagent. Preferably, the fluorine reagent is N-fluorobis(benzenesulfon)amide. Here, the selective fluorine reagent is any suitable reagent commonly used in the art, for example, Selectfluor, CAS: 140681-55-6.

[0022] Furthermore, in the step S1, the first solvent is any one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, and isopropanol. Preferably, the first solvent is tetrahydrofuran.

[0023] Furthermore, in the step S1, the molar ratio of the compound of formula I, primary / secondary amine, inorganic base, organic acid, water, and fluorine reagent is 1:0.01 - 5:0.5 - 10:0.01 - 5:0.01 - 10:0.5 - 10.

[0024] Furthermore, in the step S1, the reaction temperature is -25 to 25°C, and the reaction time is 20 to 24 h. Preferably, the reaction temperature is -20 to 10°C, and the reaction time is 24 h.

[0025] Furthermore, in step S1, the compound of formula I is N-tert-butoxycarbonyl-3-piperidone, the primary / secondary amine is S-1-phenylethylamine or R-1-phenylethylamine, the molar ratio of N-tert-butoxycarbonyl-3-piperidone to the primary / secondary amine is 1:0.01 to 2, preferably 1:0.01 to 0.5.

[0026] Furthermore, in step S1, the compound of formula I is N-tert-butoxycarbonyl-3-piperidone, the inorganic base is sodium carbonate, the molar ratio of N-tert-butoxycarbonyl-3-piperidone to the inorganic base is 1:1 to 5, preferably 1:1.2 to 2.

[0027] Furthermore, in step S1, the compound of formula I is N-tert-butoxycarbonyl-3-piperidone, the organic acid is trichloroacetic acid, the molar ratio of N-tert-butoxycarbonyl-3-piperidone to the organic acid is 1:0.01 to 2, and preferably 1:0.01 to 0.5.

[0028] Furthermore, in step S1, the compound of formula I is N-tert-butoxycarbonyl-3-piperidone, the fluorine reagent is N-fluorobisbenzenesulfonamide, the molar ratio of N-tert-butoxycarbonyl-3-piperidone to the fluorine reagent is 1:0.5 to 5, preferably 1:0.5 to 2.

[0029] Furthermore, the specific operational step of step S2 includes reacting the chiral fluorine compound of formula II with a reducing agent in a second solvent, with a reaction temperature of -10 to 100°C, to obtain the chiral hydroxy-fluorine compound of formula III.

[0030] Furthermore, in step S2, the chiral hydroxy-fluorine compound of formula III produced is a mixture mainly consisting of the chiral product (3S,4R)-3-hydroxy-4-fluoropiperidine derivative.

[0031] Furthermore, in step S2, the second solvent is one or more selected from alcohols, esters, or ethers, preferably the second solvent is tetrahydrofuran, methanol, or a mixture thereof, and more preferably the second solvent is a mixture of tetrahydrofuran and methanol.

[0032] Furthermore, in step S2, the reducing agent is one or more selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, and borane solution, preferably one or more selected from sodium borohydride, potassium borohydride, and lithium borohydride, and more preferably sodium borohydride.

[0033] Furthermore, in step S2, the molar ratio of the chiral fluorine compound of formula II to the reducing agent is 1:0.5 to 12, preferably 1:2 to 4.

[0034] Furthermore, in step S2, the reaction temperature is 0 to 50°C, the reaction time is 0.5 to 12 hours, and preferably the reaction temperature is 0 to 10°C and the reaction time is 0.5 hours.

[0035] A second aspect of the present invention includes the step of chiralizing a chiral hydroxyfluorine compound of formula III with a decomposition agent to produce a compound of formula IV, formula V, formula VI, or formula VII, or separating a chiral hydroxyfluorine compound of formula III by supercritical fluid chromatography to produce a compound of formula IV, formula V, formula VI, or formula VII. [ka] Here, the chiral hydroxy-fluorine compound of formula III is a mixture of (3S,4R)-3-hydroxy-4-fluoropiperidine derivatives, (3S,4S)-3-hydroxy-4-fluoropiperidine derivatives, (3R,4S)-3-hydroxy-4-fluoropiperidine derivatives and (3R,4R)-3-hydroxy-4-fluoropiperidine derivatives, The compound of formula IV is a (3S,4R)-3-hydroxy-4-fluoropiperidine derivative, the compound of formula V is a (3R,4S)-3-hydroxy-4-fluoropiperidine derivative, the compound of formula VI is a (3R,4R)-3-hydroxy-4-fluoropiperidine derivative, and the compound of formula VII is a (3S,4S)-3-hydroxy-4-fluoropiperidine derivative. R 1 This invention provides a method for decomposing chiral 3-hydroxy-4-fluoropiperidine derivatives, selected from the group consisting of hydrogen, tert-butoxycarbonyl group, benzyl group, benzyloxycarbonyl group, aryl group, and C1-C9 alkyl group.

[0036] Furthermore, in the above decomposition method, the chiral hydroxy-fluorine compound of formula III is produced by the synthesis method described in any of the first aspects of the present invention.

[0037] Furthermore, chiral decomposition by a decomposing agent specifically involves reacting a chiral hydroxyfluorine compound of formula III with a decomposing agent in a third solvent at 0 to 80°C to obtain a compound of formula IV, a compound of formula V, a compound of formula VI, or a compound of formula VII.

[0038] Furthermore, the decomposing agent is one or more selected from D-dibenzoyl tartaric acid, L-dibenzoyl tartaric acid, D-tartaric acid, and L-tartaric acid, and preferably the decomposing agent is D-dibenzoyl tartaric acid.

[0039] Furthermore, the third solvent is one or more of the aromatic hydrocarbons, alcohols, and ethers, and preferably the third solvent is toluene.

[0040] Furthermore, the molar ratio of the chiral hydroxyfluorine compound of formula III to the decomposing agent is 1:0.5 to 12, preferably 1:0.5 to 2.

[0041] Furthermore, the reaction temperature for the decomposition is 40-60°C, the reaction time is 1-12 hours, and preferably the reaction temperature is 50-60°C and the reaction time is 1-12 hours.

[0042] Furthermore, the specific operational steps for separation by supercritical fluid chromatography include: column type: 3cm × 25cm, 5μm CHIRALPAK IG; mobile phase: CO2:MeOH = 80:20; flow rate: 80 mL / min; wavelength: UV 220 nm; temperature: 35°C.

[0043] Furthermore, in the above synthesis and decomposition methods, the products obtained from each reaction must undergo post-treatment.

[0044] A third aspect of the present invention provides a chiral 3-hydroxy-4-fluoropiperidine derivative represented by formula III, produced by the synthesis method described in any of the first aspects of the present invention, or provides compounds represented by formulas IV to VII, produced by the decomposition method described in any of the second aspects of the present invention.

[0045] A fourth aspect of the present invention provides an application in the production of drug intermediates of a chiral 3-hydroxy-4-fluoropiperidine derivative represented by formula III, or a compound represented by formulas IV to VII, produced by the synthesis method described in any of the first aspects of the present invention.

[0046] Compared to the prior art, the adoption of the above-described technology in the present invention has the following beneficial effects.

[0047] The method for synthesizing chiral 3-hydroxy-4-fluoropiperidine derivatives according to the present invention (1) allows for selective fluorination at the α-position of the carbonyl group and exhibits high chemoselectivity, (2) has fewer reaction steps and milder reaction conditions, overcoming the problems of conventional methods which have many reaction steps and many by-products, (3) allows for control of the chirality of the product by adjusting and controlling the chirality of the amine reagent, resulting in an excellent ee value, and (4) allows for the decomposition of the chiral product to a single stereochemistry by decomposition. [Modes for carrying out the invention]

[0048] The following describes the technical methods in the embodiments of the present invention clearly and completely, with reference to the embodiments of the present invention. Clearly, the embodiments described are only a selection of embodiments of the present invention, not all embodiments. All other embodiments obtained by those skilled in the art without creative work based on the embodiments of the present invention are all within the scope of protection of the present invention. Experimental methods in the following embodiments where specific conditions are not specified are usually measured according to national standards. Experimental materials in the following embodiments where the source is not specified are all commercially available raw materials. The apparatus used in each step in the following embodiments is all ordinary apparatus. If there is no applicable national standard, the procedure is carried out according to general international standards, usual conditions, or conditions suggested by the manufacturer. Unless otherwise specified, all parts are parts by weight, and all percentages are mass percentages. Unless otherwise defined or explained, all technical and scientific terms used in the present invention have the same meaning as those well known to those skilled in the art. Any methods and materials similar or equivalent to those described may be applied to the methods of the present invention.

[0049] Furthermore, the embodiments and features of the present invention can be combined with each other, as long as they do not contradict each other. The present invention will be further described below with reference to specific embodiments, but this is not intended to limit the present invention. [Examples]

[0050] [ka] Under a nitrogen atmosphere, add 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 120 mL of tetrahydrofuran to a reaction flask, cool to -20°C, and add 7.3 g of S-1-phenylethylamine (60.2 mmol, 0.2 equivalent) in a tetrahydrofuran solution (10 mL). The mixture was added dropwise, then 2.7 g of H2O (150.6 mmol, 0.5 equivalents) and 9.8 g of trichloroacetic acid (60.2 mmol, 0.2 equivalents) in a tetrahydrofuran (10 mL) solution were added dropwise, and finally 142.4 g of N-fluorobisbenzenesulfonamide (451.7 mmol, 1.5 equivalents) in a tetrahydrofuran (400 mL) solution was added dropwise, and the mixture was kept at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as 46.6 g (214.5 mmol) of a crude product of the chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture as a yellow liquid (yield: 71%, purity: 93%, ee: 92%).

[0051] A tetrahydrofuran-methanol solution (200-20 mL) containing 46.6 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (214.5 mmol) was cooled to 0°C. 17.01 g of sodium borohydride solid (451.6 mmol) was added in batches, and the reaction temperature was slowly raised to room temperature, with continuous stirring until the reaction was complete. 11.47 g of ammonium chloride solid (214.5 mmol) was added to the reaction mixture to quench it, and the mixture was filtered. The filtrate was evaporated under reduced pressure by rotation, and the concentrate was extracted with toluene (300 mL). The organic phase was dried and concentrated. Column chromatography yielded 42.33 g (194.9 mmol) of the chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product as a white solid (yield: 91%, purity: 95%, ee: 90%, dr: 3:1).

[0052] Add 15.4 g of D-dibenzoyl tartaric acid (42.9 mmol, 0.94 equivalents) and toluene (50 mL) to a reaction flask, raise the temperature to 50°C, add dropwise 50 mL of toluene solution of 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent), maintain the temperature at 50-70°C for 30 minutes, then cool to 0-45°C, slowly cool to -10-10°C, filter, dissolve the filtered cake in ethanol (10 mL), and add toluene (100 mL) dropwise to precipitate crystals. The solution was rotated and evaporated under reduced pressure to 50 mL, filtered, and the filtered cake was washed with 50 g of aqueous sodium carbonate solution (4.83 g, 45.6 mmol, 1.0 equivalent, dissolved in 45 mL of water), dried, and concentrated to obtain 7.74 g of the product (3S,4R)-4-fluoro-3-hydroxy-1-piperidine carboxylate tert-butyl ester as a white solid (yield: 77%, purity: 100%, ee: 100%).

[0053] The nuclear magnetic resonance data is as follows: 1H NMR(400MHz,Chloroform-d) δ 4.86-4.71(m,1H),3.76-3.53(m,3H),3.29-3.23(m,2H),2.46(s,1H),2.10-2.01(m,1H),1.79-1.66(m,1H),1.44(s,9H). [Examples]

[0054] [ka] Under a nitrogen atmosphere, add 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalents), and 120 mL of tetrahydrofuran to a reaction flask, cool to -20°C, and add 7.3 g of S-1-phenylethylamine (60.2 mmol, 0.2 equivalents) to tetrahydrofuran (10 mL). The solution was added dropwise, then 2.7 g of H2O (150.6 mmol, 0.5 equivalent) and 3.7 g of acetic acid (60.2 mmol, 0.2 equivalent) in tetrahydrofuran (10 mL) was added dropwise, and finally 94.9 g of N-fluorobisbenzenesulfonamide (301.1 mmol, 1.0 equivalent) in tetrahydrofuran (400 mL) was added dropwise, and the reaction was allowed to proceed for 48 hours at -15 to 10°C. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as a crude product of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture, in the form of a yellow liquid (yield: 70%, purity: 95%, ee: 80%).

[0055] A tetrahydrofuran-methanol solution (200-20 mL) containing 45.71 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (210.4 mmol) was cooled to 0°C, and 17.01 g of sodium borohydride solid (451.6 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred until the reaction was complete. 11.25 g of ammonium chloride solid (210.4 mmol) was added to the reaction mixture and quenched. The mixture was filtered, and the filtrate was evaporated under reduced pressure by rotation. Toluene (300 mL) was added to the concentrate and separated. The organic phase was dried and concentrated, and 42.02 g (191.7 mmol) of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained as a white solid (yield: 91%, purity: 91%, ee: 76%, dr: 3:1) by column chromatography.

[0056] 15.4 g of D-dibenzoyl tartaric acid (42.9 mmol, 0.90 equivalents) and toluene (50 mL) were added to a reaction flask, the temperature was raised to 50°C, and 50 mL of a toluene solution of 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) was added dropwise. The reaction was maintained at 50-70°C for 30 minutes, the temperature was slowly lowered to -10-10°C, the mixture was filtered, the filtered cake was dissolved in ethanol (10 mL), and toluene (100 mL) was added dropwise to precipitate the crystals. The solution was rotated and evaporated under reduced pressure to 50 mL, filtered, and the filtered cake was washed with 50 g of aqueous sodium carbonate solution (4.83 g, 45.6 mmol, 1.0 equivalent, dissolved in 45 mL of water), dried, and concentrated to obtain 7.85 g of (3S,4R)-4-fluoro-3-hydroxy-1-piperidine carboxylate tert-butyl ester as a white solid (yield: 79%, purity: 100%, ee: 100%).

[0057] The nuclear magnetic resonance data is as follows: 1H NMR(400MHz,Chloroform-d) δ 4.86-4.71(m,1H),3.76-3.53(m,3H),3.29-3.23(m,2H),2.46(s,1H),2.10-2.01(m,1H),1.79-1.66(m,1H),1.44(s,9H). [Examples]

[0058] [ka] Under a nitrogen atmosphere, add 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 120 mL of tetrahydrofuran to a reaction flask, cool to -20°C, and add 7.3 g of S-1-phenylethylamine (60.2 mmol, 0.2 equivalent) in a tetrahydrofuran solution (10 mL). The mixture was then added dropwise, followed by the addition of 2.7 g of H2O (150.6 mmol, 0.5 equivalent) and 9.8 g of trichloroacetic acid (60.2 mmol, 0.2 equivalent) in a tetrahydrofuran (10 mL) solution. Finally, 94.9 g of N-fluorobisbenzenesulfonamide (301.1 mmol, 1.0 equivalent) in a tetrahydrofuran (400 mL) solution was added dropwise, and the mixture was kept at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as 40.52 g (186.5 mmol) of a crude product of the chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture as a yellow liquid (yield: 62%, purity: 95%, ee: 90%).

[0059] A tetrahydrofuran-methanol solution (200-20 mL) containing 40.52 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (186.5 mmol) was cooled to 0°C, and 24.3 g of potassium borohydride solid (451.6 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred until the reaction was complete. 9.97 g of ammonium chloride solid (186.5 mmol) was added to the reaction mixture to quench it, and the mixture was evaporated under reduced pressure by rotation. Toluene (300 mL) was added to the concentrate, and the mixture was filtered. The filtrate was washed with hydrochloric acid (60 mL, 1 M), and the organic phase was washed with sodium hydroxide solution (30 mL, 1 N). The organic phase was dried and concentrated, and 37.22 g of the chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained by column chromatography as a white solid (yield: 91%, purity: 97%, ee: 87%, dr: 3:1).

[0060] In a reaction flask, 15.4 g of D-dibenzoyl tartaric acid (42.9 mmol, 0.94 equivalents) and toluene (50 mL) were heated to 50°C. 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) in a toluene solution (50 mL) was added dropwise. The mixture was maintained at 50-70°C for 30 minutes, then slowly cooled to -10-10°C. The mixture was filtered, the filtered cake was dissolved in ethanol (10 mL), and toluene (100 mL) was added dropwise to precipitate the crystals. The solution was rotated and evaporated under reduced pressure to 50 mL, filtered, and the filtered cake was washed with 50 g of aqueous sodium carbonate solution (4.83 g, 45.6 mmol, 1.0 equivalent, dissolved in 45 mL of water), dried, and concentrated to obtain 6.59 g of (3S,4R)-4-fluoro-3-hydroxy-1-piperidine carboxylate tert-butyl ester as a white solid (yield: 66%, purity: 100%, ee: 100%).

[0061] The nuclear magnetic resonance data is as follows: 1H NMR(400MHz,Chloroform-d) δ 4.86-4.71(m,1H),3.76-3.53(m,3H),3.29-3.23(m,2H),2.46(s,1H),2.10-2.01(m,1H),1.79-1.66(m,1H),1.44(s,9H). [Examples]

[0062] [ka] Under a nitrogen atmosphere, add 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 300 mL of tetrahydrofuran to a reaction flask, cool to -20°C, and add 7.3 g of R-1-phenylethylamine (60.2 mmol, 0.2 equivalent) in a tetrahydrofuran (100 mL) solution. The mixture was added dropwise, then 5.4 g of H2O (301.1 mmol, 1.0 equivalent) and 9.8 g of trichloroacetic acid (60.2 mmol, 0.2 equivalents) in a tetrahydrofuran (100 mL) solution was added dropwise, and finally 142.4 g of N-fluorobisbenzenesulfonamide (451.7 mmol, 1.5 equivalents) in a tetrahydrofuran (700 mL) solution was added dropwise, and the mixture was kept at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as a crude product of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture, in the form of a yellow liquid (yield: 75%, purity: 94%, ee: 96%).

[0063] A tetrahydrofuran-methanol solution (200-20 mL) containing 49.23 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (226.6 mmol) was cooled to 0°C, and 9.83 g of lithium borohydride solid (451.6 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred until the reaction was complete. 12.12 g of ammonium chloride solid (226.6 mmol) was added to the reaction mixture to quench it, and the mixture was filtered. The filtrate was evaporated under reduced pressure by rotation, and toluene (300 mL) was added to the concentrate for liquid-liquid separation. The organic phase was dried and concentrated, and 42.2 g of the chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained as a white solid (yield: 85%, purity: 98%, ee: 93%, dr: 3:1) by column chromatography.

[0064] In a reaction flask, 19.6 g of L-dibenzoyl tartaric acid (54.7 mmol, 1.2 equivalents) and toluene (50 mL) were heated to 50°C. 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) in a toluene solution (50 mL) was added dropwise. The reaction was maintained at 50-55°C for 30 minutes, then slowly cooled to -10-10°C. The mixture was filtered, the filtered cake was dissolved in ethanol (10 mL), and toluene (100 mL) was added dropwise to precipitate the crystals. The solution was rotated and evaporated under reduced pressure to 50 mL, filtered, and the filtered cake was washed with 50 g of aqueous sodium carbonate solution (5.80 g, 65.6 mmol, 1.4 equivalents, dissolved in 42 g of water), dried, and concentrated to obtain 8.97 g of (3R,4S)-4-fluoro-3-hydroxy-1-piperidine carboxylate tert-butyl ester as a white solid (yield: 88%, purity: 100%, ee: 100%).

[0065] The nuclear magnetic resonance data is as follows: 1H NMR(400MHz,Chloroform-d) δ 4.85-4.71(m,1H),3.76-3.54(m,3H),3.28-3.21(m,2H),2.64(s,1H),2.10-2.01(m,1H),1.78-1.62(m,1H),1.43(s,9H). [Examples]

[0066] [ka] Under a nitrogen atmosphere, add 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 300 mL of tetrahydrofuran to a reaction flask, cool to -20°C, and add 7.3 g of R-1-phenylethylamine (60.2 mmol, 0.2 equivalent) in a tetrahydrofuran (100 mL) solution. The mixture was added dropwise, then 2.7 g of H2O (150.6 mmol, 0.5 equivalents) and 6.4 g of trifluoroacetic acid (60.2 mmol, 0.2 equivalents) in a tetrahydrofuran (100 mL) solution were added dropwise, and finally 142.4 g of N-fluorobisbenzenesulfonamide (451.7 mmol, 1.5 equivalents) in a tetrahydrofuran (700 mL) solution was added dropwise, and the mixture was kept at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as a crude product of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture, in the form of a yellow liquid (yield: 76%, purity: 96%, ee: 76%).

[0067] A solution of 49.67 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (228.6 mmol) in tetrahydrofuran-methanol (200 - 20 mL) was cooled to 0 °C, and 17.01 g of solid sodium borohydride (451.6 mmol) was added in one batch. The reaction temperature was slowly raised to room temperature, and stirring was continued until the reaction was complete. The reaction temperature was slowly raised to room temperature, and stirring was continued until the reaction was complete. 12.22 g of solid ammonium chloride (300 mL) was added to the reaction solution to quench it, and it was filtered. The filtrate was rotary evaporated under reduced pressure, toluene (300 mL) was added to the concentrated solution for liquid separation, the organic phase was dried and concentrated, and 45.69 g of a chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained as a white solid (yield: 92%, purity: 98%, e.e.: 78%, d.r.: 3:1) by column chromatography.

[0068] 24.5 g of L-dibenzoyl tartaric acid (68.5 mmol, 1.5 equivalents) and toluene (50 mL) were heated to 50 °C in a reaction flask, and a toluene solution (50 mL) of 10.0 g of a chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) was added dropwise. The temperature was maintained at 50 - 55 °C for 30 min for reaction, then cooled to 40 - 45 °C, and slowly cooled to -10 - 10 °C. It was filtered, the filter cake was dissolved in ethanol (10 mL), and toluene (100 mL) was added dropwise to precipitate crystals. It was rotary evaporated to 50 mL under reduced pressure, filtered, the filter cake was washed with 50 g of an aqueous sodium carbonate solution (8.71 g, 82.2 mmol, 1.8 equivalents, dissolved in 42 g of water) and dried, and concentrated to obtain 8.61 g of (3R,4S)-4-fluoro-3-hydroxy-1-piperidinecarboxylic acid tert-butyl ester as a white solid (yield: 86%, purity: 100%, e.e.: 100%).

[0069] The nuclear magnetic resonance data are as follows. 1H NMR(400MHz,Chloroform-d) δ 4.85-4.71(m,1H),3.76-3.54(m,3H),3.28-3.21(m,2H),2.64(s,1H),2.10-2.01(m,1H),1.78-1.62(m,1H),1.43(s,9H). [Examples]

[0070] [ka] Under a nitrogen atmosphere, add 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 300 mL of tetrahydrofuran to a reaction flask, cool to -20°C, and add 7.3 g of R-1-phenylethylamine (60.2 mmol, 0.2 equivalent) in a tetrahydrofuran (100 mL) solution. The mixture was added dropwise, then 2.7 g of H2O (150.6 mmol, 0.5 equivalents) and 9.8 g of trichloroacetic acid (60.2 mmol, 0.2 equivalents) in a tetrahydrofuran (100 mL) solution were added dropwise, and finally 142.4 g of N-fluorobisbenzenesulfonamide (451.7 mmol, 1.5 equivalents) in a tetrahydrofuran (700 mL) solution was added dropwise, and the mixture was kept at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as a 45.09 g (207.6 mmol) crude product of the chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture as a yellow liquid (yield: 69%, purity: 96%, ee: 95%).

[0071] A tetrahydrofuran-methanol solution (200-20 mL) containing 45.09 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (207.6 mmol) was cooled to 0°C, and 17.01 g of sodium borohydride solid (451.6 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred continuously until the reaction was complete. 11.10 g of ammonium chloride solid (207.6 mmol) was added to the reaction mixture and quenched. The mixture was filtered, and the filtrate was evaporated under reduced pressure by rotation. Toluene (300 mL) was added to the concentrate and separated. The organic phase was dried and concentrated, and 38.69 g of a chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained as a white solid (yield: 85%, purity: 98%, ee: 96%, dr: 3:1) by column chromatography.

[0072] In a reaction flask, combine 17.17 g of L-dibenzoyl tartaric acid (42.9 mmol, 1.05 equivalents) and toluene (50 mL). Heat to 50°C, then dropwise add 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) in a toluene solution (50 mL). Maintain the temperature at 50-55°C for 30 minutes, then slowly cool to -10-10°C. Filter the mixture and add the filtered cake to ethanol (10 mL). The mixture was dissolved in toluene (100 mL), toluene (100 mL) was added dropwise to precipitate the crystals, and the mixture was evaporated under reduced pressure by rotation to 50 mL. The mixture was filtered, and the filtered cake was washed with 50 g of aqueous sodium carbonate solution (5.45 g, 51.4 mmol, 1.1 equivalents, dissolved in 45 g of water), dried, and concentrated to obtain 9.44 g of (3R,4S)-4-fluoro-3-hydroxy-1-piperidinecarboxylic acid tert-butyl ester as a white solid (yield: 94%, purity: 100%, ee: 100%).

[0073] The nuclear magnetic resonance data is as follows: 1H NMR(400MHz,Chloroform-d) δ 4.85-4.71(m,1H),3.76-3.54(m,3H),3.28-3.21(m,2H),2.64(s,1H),2.10-2.01(m,1H),1.78-1.62(m,1H),1.43(s,9H). [Examples]

[0074] [ka] Under a nitrogen atmosphere, 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 120 mL of tetrahydrofuran were added to a reaction flask. The temperature was lowered to -20°C, 6.9 g of D-proline (60.2 mmol, 0.2 equivalent) was added, then 2.7 g of H2O (150.6 mmol, 0.5 equivalent) and 3.7 g of acetic acid (60.2 mmol, 0.2 equivalent) were added dropwise in a tetrahydrofuran (10 mL) solution, and finally 94.9 g of N-fluorobisbenzenesulfonamide (301.1 mmol, 1.0 equivalent) was added dropwise in a tetrahydrofuran (400 mL) solution. The reaction was maintained at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as a crude product of the chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture, 45.71 g (210.4 mmol), as a yellow liquid (yield: 70%, purity: 95%, ee: 60%).

[0075] A tetrahydrofuran-methanol solution (200-20 mL) containing 45.71 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (210.4 mmol) was cooled to 0°C, and 17.01 g of sodium borohydride solid (451.6 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred until the reaction was complete. 11.25 g of ammonium chloride solid (210.4 mmol) was added to the reaction mixture to quench it, and the mixture was filtered. The filtrate was evaporated under reduced pressure by rotation, and toluene (300 mL) was added to the concentrate for liquid-liquid separation. After drying the organic phase, the mixture was concentrated, and 6.9 g of the chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained as a white solid (yield: 15%, purity: 95%, ee: 58%, dr: 4:1) by column chromatography.

[0076] In a reaction flask, 6.88 g of D-tartaric acid (45.6 mmol, 1.0 equivalent) and toluene (50 mL) were heated to 50°C. 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) in a toluene solution (50 mL) was added dropwise, and the reaction was maintained at 50-55°C for 30 minutes. The temperature was then slowly lowered to -10-10°C, the mixture was filtered, and the filtered cake was dissolved in ethanol (5 mL). Toluene (50 mL) was added dropwise to precipitate the crystals, and the mixture was evaporated by rotation under reduced pressure to 25 mL. The mixture was filtered, and the filtered cake was washed with 25 g of aqueous sodium carbonate solution (2.90 g, 27.3 mmol, 0.6 equivalents, dissolved in 22 g of water), dried, and concentrated to obtain 4.65 g of (3R,4R)-4-fluoro-3-hydroxy-1-piperidine carboxylate tert-butyl ester as a white solid (yield: 46%, purity: 100%, ee: 100%). [Examples]

[0077] [ka] Under a nitrogen atmosphere, 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 120 mL of tetrahydrofuran were added to a reaction flask. The temperature was lowered to -20°C, and 6.9 g of D-proline (60.2 mmol, 0.2 equivalent) was added. Next, a solution of 2.7 g of H2O (150.6 mmol, 0.5 equivalent) and 9.8 g of trichloroacetic acid (60.2 mmol, 0.2 equivalent) in tetrahydrofuran (10 mL) was added dropwise. Finally, a solution of 94.9 g of N-fluorobisbenzenesulfonamide (301.1 mmol, 1.0 equivalent) in tetrahydrofuran (400 mL) was added dropwise, and the reaction was carried out at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, and column chromatography directly yielded 45.71 g (210.4 mmol) of the crude chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture as a yellow liquid (yield: 70%, purity: 95%, ee: 55%).

[0078] A tetrahydrofuran-methanol solution (200-20 mL) containing 45.71 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (210.4 mmol) was cooled to 0°C, and 24.3 g of potassium borohydride solid (451.6 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred until the reaction was complete. 11.25 g of ammonium chloride solid (210.4 mmol) was added to the reaction mixture to quench it, and the mixture was filtered. The filtrate was evaporated under reduced pressure by rotation, and toluene was added to the concentrate for liquid-liquid separation. After drying the organic phase, the mixture was concentrated, and 7.3 g of the chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained as a white solid (yield: 16%, purity: 95%, ee: 52%, dr: 3:1) by column chromatography.

[0079] In a reaction flask, 6.88 g of D-tartaric acid (45.6 mmol, 1.0 equivalent) and toluene (50 mL) were heated to 50°C. 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) in a toluene solution (50 mL) was added dropwise. The mixture was maintained at 50-55°C for 30 minutes, then slowly cooled to -10-10°C. The mixture was filtered, the filtered cake was dissolved in ethanol (2 mL), and toluene (20 mL) was added dropwise to precipitate the crystals. The solution was rotated and evaporated under reduced pressure to 10 mL, filtered, and the filtered cake was washed with 10 g of aqueous sodium carbonate solution (1.16 g, 10.9 mmol, 0.2 equivalents, dissolved in 8.8 g of water), dried, and concentrated to obtain 1.39 g of (3R,4R)-4-fluoro-3-hydroxy-1-piperidine carboxylate tert-butyl ester as a white solid (yield: 14%, purity: 100%, ee: 100%). [Examples]

[0080] [ka] Under a nitrogen atmosphere, 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 120 mL of tetrahydrofuran were added to a reaction flask. The temperature was lowered to -20°C, 6.9 g of L-proline (60.2 mmol, 0.2 equivalent) was added, then 2.7 g of H2O (150.6 mmol, 0.5 equivalent) and 9.8 g of trichloroacetic acid (60.2 mmol, 0.2 equivalent) were added dropwise in a tetrahydrofuran (10 mL) solution, and finally 94.9 g of N-fluorobisbenzenesulfonamide (301.1 mmol, 1.0 equivalent) was added dropwise in a tetrahydrofuran (400 mL) solution. The reaction was maintained at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered, concentrated, and directly obtained by column chromatography as a crude product of the chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture, 45.71 g (210.4 mmol), as a yellow liquid (yield: 70%, purity: 95%, ee: 56%).

[0081] A tetrahydrofuran-methanol solution (200-20 mL) containing 45.71 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (210.4 mmol) was cooled to 0°C, and 17.01 g of sodium borohydride solid (451.6 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred until the reaction was complete. 11.25 g of ammonium chloride solid (210.4 mmol) was added to the reaction mixture to quench it, and the mixture was filtered. The filtrate was evaporated under reduced pressure by rotation, and toluene (300 mL) was added to the concentrate for liquid-liquid separation. After drying the organic phase, the mixture was concentrated, and 7.2 g of the chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained as a white solid (yield: 17%, purity: 93%, ee: 50%) by column chromatography.

[0082] In a reaction flask, 6.88 g of L-tartaric acid (45.6 mmol, 1.0 equivalent) and toluene (50 mL) were heated to 50°C. 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (45.6 mmol, 1.0 equivalent) in a toluene solution (50 mL) was added dropwise. The mixture was maintained at 50-55°C for 30 minutes, then slowly cooled to -10-10°C. The mixture was filtered, the filtered cake was dissolved in ethanol (2 mL), and toluene (20 mL) was added dropwise to precipitate the crystals. The solution was rotated and evaporated under reduced pressure to 10 mL, filtered, and the filtered cake was washed with 10 g of aqueous sodium carbonate solution (1.16 g, 10.9 mmol, 0.2 equivalents, dissolved in 8.8 g of water), dried, and concentrated to obtain 1.02 g of (3S,4R)-4-fluoro-3-hydroxy-1-piperidine carboxylate tert-butyl ester as a white solid (yield: 10%, purity: 100%, ee: 100%). [Examples]

[0083] [ka] Under a nitrogen atmosphere, add 60.0 g of N-tert-butoxycarbonyl-3-piperidone (301.1 mmol, 1.0 equivalent), 47.9 g of Na2CO3 (451.7 mmol, 1.5 equivalent), and 120 mL of tetrahydrofuran to a reaction flask, cool to -20°C, and add 7.3 g of S-1-phenylethylamine (60.2 mmol, 0.2 equivalent) in a tetrahydrofuran solution (10 mL). The mixture was then added dropwise, followed by the addition of 2.7 g of H2O (150.6 mmol, 0.5 equivalent) and 9.8 g of trichloroacetic acid (60.2 mmol, 0.2 equivalent) in tetrahydrofuran (10 mL) solution. Finally, 94.9 g of N-fluorobisbenzenesulfonamide (301.1 mmol, 1.0 equivalent) in tetrahydrofuran (400 mL) solution was added dropwise, and the mixture was kept at -15 to 10°C for 48 hours. After the reaction was complete, the mixture was filtered and concentrated, and 40.52 g (186.5 mmol) of the crude chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone mixture was directly obtained by column chromatography as a yellow liquid (yield: 62%, purity: 95%, dr: 3:1).

[0084] A tetrahydrofuran-methanol solution (200-20 mL) containing 40.52 g of chiral N-tert-butoxycarbonyl-4-fluoro-3-piperidone (186.5 mmol) was cooled to 0°C, and 17.4 g of sodium borohydride solid (186.5 mmol) was added in batches. The reaction temperature was slowly raised to room temperature, and the mixture was stirred until the reaction was complete. 9.97 g of ammonium chloride solid (210.4 mmol) was added to the reaction mixture to quench it, and the mixture was filtered. The filtrate was evaporated under reduced pressure by rotation, and toluene (300 mL) was added to the concentrate for liquid-liquid separation. The organic phase was dried and concentrated, and the chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture product was obtained by column chromatography.

[0085] 10.0 g of chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture (46.0 mmol) was taken and separated by supercritical fluid chromatography to obtain four single-conjugation products, with yields of (3S,4R): 75%, (3R,4S): 13%, (3R,4R): 8%, and (3S,4S): 4%, respectively.

[0086] Although specific embodiments of the present invention have been described in detail above, these are merely illustrative, and the present invention is not limited to the above-described embodiments. Any equivalent modifications and substitutions made to the present invention will be within the scope of the invention for those skilled in the art. Accordingly, any equivalent transformations and modifications made without departing from the spirit and scope of the invention should be included within the scope of the invention.

Claims

1. Step S1 involves using the compound of formula I as a starting material and fluorinating the α-position of the carbonyl group with a fluorine reagent under the catalytic action of an organic amine reagent to produce the chiral fluorine compound of formula II. The method includes step S2, which involves reducing a chiral fluorine compound of formula II with a reducing agent to produce a chiral hydroxy-fluorine compound of formula III, 【Chemistry 16】 Here, the chiral fluorine compound of formula II includes both the S conformation and the R conformation. The chiral hydroxy-fluorine compound of formula III is a mixture of (3S,4R)-3-hydroxy-4-fluoropiperidine derivatives, (3S,4S)-3-hydroxy-4-fluoropiperidine derivatives, (3R,4S)-3-hydroxy-4-fluoropiperidine derivatives, and (3R,4R)-3-hydroxy-4-fluoropiperidine derivatives. R １ A method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative, characterized in that the group is selected from hydrogen, a tert-butoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, an aryl group, and a C1-C9 alkyl group.

2. The specific operational step of step S1 includes reacting a compound of formula I with a fluorine reagent in a first solvent with the accelerating of a primary / secondary amine, an inorganic base, an organic acid, and water, at a reaction temperature of -50 to 50°C, to obtain a chiral fluorine compound of formula II or a solution thereof. The synthesis method according to claim 1, characterized in that the specific operational step of step S2 includes reacting a chiral fluorine compound of formula II with a reducing agent in a second solvent, the reaction temperature being -10 to 100°C, to obtain a chiral hydroxy-fluorine compound of formula III.

3. In step S1, The compound of formula I is N-R １ It is a -3-piperidone derivative, and / or, the primary / secondary amine is one or more selected from S-1-phenylethylamine, R-1-phenylethylamine, L-proline, D-proline, chiral and racemized arylamines, and C1-C9 alkylamines. and / or, the inorganic base is one or more selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and lithium carbonate. and / or, the organic acid is one or more selected from trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, and acetic acid. and / or, the fluorine reagent is one or more selected from N-fluorobisbenzenesulfonamide and selective fluorine reagents. and / or, the first solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, and isopropanol. and / or, the molar ratio of the compound of formula I, primary / secondary amine, inorganic base, organic acid, water and fluorine reagent is 1:0.01 to 5:0.5 to 10:0.01 to 5:0.01 to 10:0.5 to 10. The synthesis method according to claim 2, characterized in that the reaction temperature is -25 to 25°C and the reaction time is 20 to 24 hours.

4. In step S2, The second solvent is one or more selected from alcohols, esters, or ethers. and / or, the reducing agent is one or more selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, and borane solution. And / or, the molar ratio of the chiral fluorine compound of formula II to the reducing agent is 1:0.5 to 12. The synthesis method according to claim 2, characterized in that the reaction temperature is 0 to 50°C and the reaction time is 0.5 to 12 hours.

5. The process includes the steps of: decomposing a chiral hydroxyfluorine compound of formula III into a chiral form using a decomposition agent to produce a compound of formula IV, formula V, formula VI, or formula VII; or separating a chiral hydroxyfluorine compound of formula III by supercritical fluid chromatography to produce a compound of formula IV, formula V, formula VI, or formula VII. 【Chemistry 17】 Here, the chiral hydroxy-fluorine compound of formula III is a mixture of (3S,4R)-3-hydroxy-4-fluoropiperidine derivatives, (3S,4S)-3-hydroxy-4-fluoropiperidine derivatives, (3R,4S)-3-hydroxy-4-fluoropiperidine derivatives and (3R,4R)-3-hydroxy-4-fluoropiperidine derivatives, The compound of formula IV is a (3S,4R)-3-hydroxy-4-fluoropiperidine derivative, the compound of formula V is a (3R,4S)-3-hydroxy-4-fluoropiperidine derivative, the compound of formula VI is a (3R,4R)-3-hydroxy-4-fluoropiperidine derivative, and the compound of formula VII is a (3S,4S)-3-hydroxy-4-fluoropiperidine derivative. R １ A method for decomposing a chiral 3-hydroxy-4-fluoropiperidine derivative, characterized in that the group is selected from hydrogen, a tert-butoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, an aryl group, and a C1-C9 alkyl group.

6. The decomposition method according to claim 5, characterized in that the chiral hydroxyfluorine compound of formula III is produced by the synthesis method described in any one of claims 1 to 4.

7. The decomposition method according to claim 5, characterized in that the specific operational steps of chiral decomposition with a decomposition agent include reacting a chiral hydroxyfluorine compound of formula III with a decomposition agent in a third solvent at 0 to 80°C to obtain a compound of formula IV, a compound of formula V, a compound of formula VI, or a compound of formula VII.

8. The aforementioned decomposing agent is one or more selected from D-dibenzoyl tartaric acid, L-dibenzoyl tartaric acid, D-tartaric acid, and L-tartaric acid. and / or the third solvent is one or more of the aromatic hydrocarbon, alcohol, or ether solvents. And / or, the molar ratio of the chiral hydroxyfluorine compound of formula III to the decomposition agent is 1:0.5 to 12. The decomposition method according to claim 7, characterized in that the reaction temperature for the decomposition is 40 to 60°C and the reaction time is 1 to 12 hours.

9. The specific steps for separation by supercritical fluid chromatography are as follows: Column type: 3 cm × 25 cm, 5 μm CHIRALPAK IG, Mobile phase: CO2 ２ The decomposition method according to claim 5, characterized by comprising: MeOH = 80:20, flow rate: 80 mL / min, wavelength: UV 220 nm, and temperature: 35°C.

10. The synthesis method described in any one of claims 1 to 4, or the application of a chiral 3-hydroxy-4-fluoropiperidine derivative produced thereby, in the production of a drug intermediate.

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