Chiral 3-hydroxy-4-fluoropiperidine derivative and synthesis method thereof
Through a new synthesis route, the synthesis of chiral 3-hydroxy-4-fluoperidine derivatives in the prior art was successfully solved using raw materials such as N-tert-butoxycarbonyl-4-piperidone and nitrosobene The problem of insufficient efficiency and selectivity of the method achieves efficient and selective synthesis, and the product has excellent optical purity and high yield.
Patent Information
- Application Number
- CN202411530216.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-30
- Publication Date
- 2025-02-14
AI Technical Summary
The prior art lacks efficient and highly selective synthetic methods to prepare chiral 3-hydroxy-4-fluoperidine derivatives, and the traditional methods have problems such as long reaction steps, many by-products, and low atomic economy.
Using N-tert-butoxycarbonyl-4-piperidone as the starting material, the carbonyl group is activated by tetrahydropyrrole compounds and reacted with nitrosobenzene, followed by reaction in sulfate, and then the compound is formed under the action of reducing agent. Finally, under the action of the alkali, react with the fluorine reagent and purify it through the resolving agent to obtain chiral 3-hydroxy-4-fluoperidine derivative.
The chiral 3-hydroxy-4-fluoperidine derivatives are synthesized with high selectivity and efficiency, overcoming the long reaction steps and multiple by-product problems in the traditional method, with excellent optical purity and high yield.
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Figure CN119431219A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of preparation of fluorine-containing piperidine structures, and in particular to a method for synthesizing chiral 3-hydroxy-4-fluoropiperidine derivatives. Background Art
[0002] Organofluorine compounds play an important role in drug design and development due to their unique stereostructure and physical properties. The introduction of fluorine atoms can significantly improve the efficacy and stability of drugs, mainly because fluorine atoms have high electronegativity and unique physicochemical properties, which can effectively block the action of metabolic enzymes, enhance the metabolic stability of drugs, and prolong their half-life in the body. In addition, the introduction of fluorine atoms can also regulate the physicochemical properties of drug molecules, such as increasing the lipid solubility of drugs and enhancing their ability to penetrate cell membranes, thereby improving the bioavailability of drugs. Therefore, organofluorine compounds occupy a key position in the design of a variety of drugs such as anticancer drugs, antiviral drugs, and antidepressants.
[0003] Piperidine compounds are an important type of skeleton structure in medicinal chemistry. They are widely used in drug design and synthesis due to their unique physicochemical properties and good biocompatibility. The piperidine ring structure exists in a variety of clinical drugs, such as antipsychotics, antidepressants, antihypertensives and anti-infectives, and can bind to receptors or enzymes, regulate their activity, and exert therapeutic effects. In addition, piperidine compounds are often used as key intermediates in the development of new drugs. They have diverse modification potential and can be used to synthesize candidate drug molecules with different biological activities. The introduction of the piperidine ring can also improve the pharmacokinetic properties of drugs, improve the solubility, stability, bioavailability and absorption distribution of drugs, and prolong their duration of action.
[0004] There are some methods for synthesizing such fluorine-substituted piperidine derivatives. The literature review is as follows:
[0005] The classic synthesis method includes the following steps: ① Epoxidation of olefins: First, a suitable olefin precursor is epoxidized to generate an epoxide intermediate. This step provides a good reactive site for subsequent fluorination. ② Fluorination ring-opening reaction: Under the action of hydrofluoric acid or a fluorinating agent, the epoxide undergoes a ring-opening reaction to obtain a piperidine skeleton containing a fluorine atom. This process usually generates an intermediate with a specific stereo configuration and affects the stereoselectivity of the final product. ③ Mitsunobu reaction or other stereochemical modification: In order to obtain a specific configuration, the Mitsunobu reaction or a similar stereochemical conversion method is usually used to convert the stereo configuration of the product from trans to cis or vice versa. This step is crucial to the stereoselectivity and yield of the final product. Traditional synthetic routes often involve harsh reaction conditions (such as strong acid, strong base or high temperature) and produce a large number of by-products, especially by-products that are difficult to separate, such as triphenylphosphine. In addition, the atom economy of the classic method is low, making it difficult to achieve green and efficient large-scale production. Therefore, in recent years, researchers have been committed to developing more efficient and selective synthetic routes to improve the preparation efficiency of fluorine-substituted piperidine derivatives.
[0006]
[0007] In 2022, Michael reported a selective deoxyfluorination reaction (Org. Process Res. Dev. 2022, 26, 551-559), which mainly includes the following steps: ① Deprotonation: Under alkaline conditions, the substrate (such as alcohol) is deprotonated to form the corresponding anionic intermediate. This process is usually catalyzed by a strong base (such as DBU). ② Fluorination reaction and stereoselectivity: The anionic intermediate reacts with the fluorination reagent to undergo a nucleophilic substitution reaction. The fluorine atom replaces the original leaving group through the SN2 mechanism, and the chirality is reversed to form a new fluorinated product. The regioselectivity of this reaction is mainly induced by the chiral fluorine at the ɑ position, which is easier to react with the trans hydroxyl group, but this method has not yet attempted the selective fluorination reaction of the hydroxyl group without chiral fluorine induction at the ɑ position, nor has the fluorination of piperidine compounds been attempted.
[0008]
[0009] Since there is currently a lack of preparation methods for 3-hydroxy-4-fluoropiperidine derivatives or the existing methods all have certain defects, the development of new synthesis methods and process improvements for chiral 3-hydroxy-4-fluoropiperidine derivatives is of great significance and application value. Summary of the invention
[0010] In order to overcome the problems existing in the prior art, the present invention has developed a new 3-hydroxy-4-fluoropiperidine derivative with easily available raw materials, good quality and a synthetic method thereof.
[0011] In order to achieve the above object, the present invention adopts the following technical solutions:
[0012] The synthetic route of 3-hydroxy-4-fluoropiperidine derivatives in the present invention is as follows:
[0013]
[0014] The above synthetic route uses N-tert-butyloxycarbonyl-4-piperidone (compound 1) as the starting material, a tetrahydropyrrole compound first activates the carbonyl group, and then reacts with nitrosobenzene to obtain compound 2; compound 2 reacts in sulfate to obtain compound 3; compound 3 generates compound 4 under the action of a reducing agent; compound 4 is attacked by a fluorine reagent to generate compound 5, and compound 6 is obtained through post-treatment crystallization purification.
[0015] To achieve the above object, the present invention adopts the following technical solutions:
[0016] Step S1, in a first solvent, using compound 1 (N-tert-butyloxycarbonyl-4-piperidone) as a starting material, first activating the carbonyl group of a tetrahydropyrrole compound, and then reacting with nitrosobenzene to obtain compound 2;
[0017] Step S2, in a second solvent, compound 2 reacts in sulfate to obtain compound 3;
[0018] Step S3, in a third solvent, compound 3 generates compound 4 under the action of a reducing agent;
[0019] Step S4, under the action of a base, compound 4 is attacked by a fluorine reagent in a fourth solvent to generate compound 5;
[0020] Step S5: In a fifth solvent, compound 5 is purified by a resolving agent to obtain compound 6.
[0021] Furthermore, the specific operation steps of step S1 include: under the promotion of tetrahydropyrrole compounds, compound 1 (N-tert-butyloxycarbonyl-4-piperidone) (Formula I) and nitrosobenzene react in a first solvent, the reaction temperature is -20-100°C, the reaction time is 1 to 48 hours, and the reaction is concentrated to obtain a crude product of compound 2 (Formula II) after the reaction is completed.
[0022] Furthermore, in step S1, the tetrahydropyrrole compound is selected from any one or more of D-proline and 5-[(2S)-pyrrolidin-2-yl]-1H-1,2,3,4-tetrazole; preferably, the tetrahydropyrrole compound is D-proline.
[0023] Furthermore, in the step S1, the molar ratio of the compound 1, the tetrahydropyrrole compound and the nitrosobenzene is 1:0.01-5:0.5-5.
[0024] Further, in step S1, the first solvent is selected from any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, chloroform, 1,4-dioxane, tetrahydrofuran and dimethyl sulfoxide; preferably, the first solvent is any one or more of acetonitrile and dimethyl sulfoxide.
[0025] Furthermore, in the step S1, the reaction temperature is -20-100°C, and the reaction time is 1 to 48 hours; preferably, the reaction temperature is 20-30°C, and the reaction time is 6 hours.
[0026] Furthermore, the specific operation steps of step S2 include: reacting compound 2 and sulfate in a second solvent, the reaction temperature is -10-60°C, the reaction time is 1-24h, and post-treatment and purification are performed to obtain compound 3 (Formula III).
[0027] Furthermore, in step S2, the sulfate is selected from any one or more of copper sulfate, sodium sulfate, magnesium sulfate and iron sulfate; preferably, the sulfate is solid copper sulfate.
[0028] Furthermore, in step S2, the second solvent is selected from any one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and 1,4-dioxane; preferably, the second solvent is methanol.
[0029] Furthermore, in step S2, the molar ratio of compound 2 to sulfate is 1:0.1-5.0.
[0030] Furthermore, in step S2, the reaction temperature is -10-60°C, and the reaction time is 1-24h; preferably, the reaction temperature is 0°C, and the reaction time is 12h.
[0031] Furthermore, the specific operation steps of step S3 include: in a third solvent, compound 3 is reduced by a reducing agent to generate compound 4, the reaction temperature is -10-100°C, and compound 4 (IV) is obtained through post-treatment and purification.
[0032] Further, in step S3, the reducing agent is selected from any one or more of (S)-2-methyl-CBS-oxazaborolidine, sodium borohydride, potassium borohydride, lithium borohydride and lithium aluminum hydride; preferably, the reducing agent is (S)-2-methyl-CBS-oxazaborolidine.
[0033] Furthermore, in step S3, the third solvent is selected from any one or more of ethanol, isopropanol, methanol, tetrahydrofuran, acetonitrile and 1,4-dioxane; preferably, the third solvent is methanol.
[0034] Furthermore, in the step S3, the molar ratio of the compound 3 to the reducing agent is 1:1.0-5.0.
[0035] Furthermore, in step S3, the reaction temperature is -10-100°C, and the reaction time is 1-24h; preferably, the reaction temperature is 0°C, and the reaction time is 6h.
[0036] Furthermore, the specific operation steps of step S4 include: under the action of a base, compound 4 is attacked by a fluorine reagent in a fourth solvent to generate compound 5, the reaction temperature is -30-100°C, and the crude product of compound 5 (Formula V) is obtained by concentration under reduced pressure.
[0037] Furthermore, in step S4, the fluorine reagent is selected from any one or more of N-fluorobisbenzenesulfonamide, a selective fluorine reagent, KF, perfluorobutylsulfonyl fluoride and CsF; preferably, the fluorine reagent is perfluorobutylsulfonyl fluoride.
[0038] Furthermore, in step S4, the base is any one or more of 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), triethylamine, pyridine and diisopropylamine; preferably, the base is DBU.
[0039] Furthermore, in step S4, the fourth solvent is selected from any one or more of ethylene glycol dimethyl ether (DME), tetrahydrofuran, acetonitrile and 1,4-dioxane; preferably, the fourth solvent is DME.
[0040] Furthermore, in step S4, the molar ratio of compound 4, fluorine reagent and base is 1:1.0-5.0:1.0-3.0.
[0041] Furthermore, in step S4, the reaction is carried out at -30-100°C for 1-48 hours; preferably, the reaction temperature is 0°C and the reaction time is 24 hours.
[0042] Furthermore, the specific operation steps of step S5 include: in a fifth solvent, compound 5 is purified by a resolving agent at a reaction temperature of 0-80° C. to obtain compound 6 (Formula VI).
[0043] Furthermore, in step S5, the resolving agent is selected from any one or more of L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-tartaric acid, and D-tartaric acid; preferably, the resolving agent is D-dibenzoyltartaric acid.
[0044] Furthermore, the fifth solvent is any one or more of toluene, methanol, n-heptane, tetrahydrofuran and acetonitrile; preferably, the fifth solvent is toluene.
[0045] Furthermore, in the step S5, the molar ratio of the compound 5 to the resolving agent is 1:1.0-5.0.
[0046] Furthermore, in step S5, the reaction temperature is 0-80°C, and the reaction time is 0.5-12h; preferably, the reaction temperature is 80°C, and the reaction time is 1h.
[0047] The present invention also provides a chiral 3-hydroxy-4-fluoropiperidine derivative, which is synthesized according to the above-mentioned method for synthesizing the chiral 3-hydroxy-4-fluoropiperidine derivative.
[0048] The synthesis method of the chiral 3-hydroxy-4-fluoropiperidine derivative provided by the present invention has the following beneficial effects:
[0049] (1) The carbonyl group is first activated by a hydropyrrole compound, and then reacted with nitrosobenzene to generate a chiral nitrogen oxide compound with high reaction selectivity;
[0050] (2) The reaction steps are few and the reaction conditions are mild, overcoming the problems of the traditional method with long reaction steps and many by-products;
[0051] (3) By regulating the chirality of the chiral reducing agent, the chirality of the product can be controlled, with excellent ee value;
[0052] (4) Chiral products can be separated into a single configuration by resolution. BRIEF DESCRIPTION OF THE DRAWINGS
[0053] Figure 1 is the hydrogen spectrum of compound 3 of Example 1 of the present invention;
[0054] Figure 2 is the hydrogen spectrum of compound 4 of Example 3 of the present invention;
[0055] Figure 3 This is the hydrogen spectrum of compound 6 in Example 5 of the present invention. DETAILED DESCRIPTION
[0056] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work belong to the scope of protection of the present invention. The experimental methods without specific conditions in the following embodiments are usually measured according to national standards. The experimental materials without the source in the following embodiments are all commercially available raw materials. The equipment used in each step in the following embodiments is conventional equipment. If there is no corresponding national standard, it is carried out according to the general international standards, conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, all parts are weight parts and all percentages are mass percentages. Unless otherwise defined or specified, all professional and scientific terms used in the present invention have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equal to the recorded content can be applied to the method of the present invention.
[0057] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other. The present invention is further described below in conjunction with specific embodiments, but is not intended to be a limitation of the present invention.
[0058] The synthetic route of the present invention is to use N-tert-butyloxycarbonyl-4-piperidone (compound 1) as a starting material, first activate the carbonyl group of a tetrahydropyrrole compound, and then react with nitrosobenzene to obtain compound 2; compound 2 reacts in sulfate to obtain compound 3; compound 3 generates compound 4 under the action of a reducing agent; compound 4 is attacked by a fluorine reagent to generate compound 5, and compound 6 is obtained through post-treatment crystallization purification.
[0059] First, step S1: in a first solvent, using compound 1 (N-tert-butyloxycarbonyl-4-piperidone) as a starting material, a tetrahydropyrrole compound is first used to activate the carbonyl group, and then reacts with nitrosobenzene to obtain compound 2;
[0060] The specific operation steps of step S1 include: under the promotion of tetrahydropyrrole compounds, compound 1 (N-tert-butyloxycarbonyl-4-piperidone) (Formula I) and nitrosobenzene react in a first solvent, the reaction temperature is -20-100°C, the reaction time is 1 to 48 hours, and the reaction is concentrated to obtain a crude product of compound 2 (Formula II) after the reaction is completed.
[0061] In step S1, the tetrahydropyrrole compound is selected from any one or more of D-proline and 5-[(2S)-pyrrolidin-2-yl]-1H-1,2,3,4-tetrazole; preferably, the tetrahydropyrrole compound is D-proline.
[0062] In step S1, the molar ratio of the compound 1, the tetrahydropyrrole compound and the nitrosobenzene is 1:0.01-5:0.5-5.
[0063] In step S1, the first solvent is selected from any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, chloroform, 1,4-dioxane, tetrahydrofuran and dimethyl sulfoxide; preferably, the first solvent is any one or more of acetonitrile and dimethyl sulfoxide.
[0064] In step S1, the reaction temperature is -20-100°C, and the reaction time is 1 to 48 hours; preferably, the reaction temperature is 20-30°C, and the reaction time is 6 hours.
[0065] The next synthesis step is step S2: in a second solvent, compound 2 reacts in sulfate to obtain compound 3;
[0066] The specific operation steps of step S2 include: reacting compound 2 and sulfate in a second solvent, the reaction temperature is -10-60°C, the reaction time is 1-24h, and post-treatment and purification are performed to obtain compound 3 (Formula III).
[0067] In step S2, the sulfate is selected from any one or more of copper sulfate, sodium sulfate, magnesium sulfate and iron sulfate; preferably, the sulfate is solid copper sulfate.
[0068] In step S2, the second solvent is selected from any one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and 1,4-dioxane; preferably, the second solvent is methanol.
[0069] In step S2, the molar ratio of the compound 2 to the sulfate is 1:0.1-5.0.
[0070] In step S2, the reaction temperature is -10-60°C, and the reaction time is 1-24h; preferably, the reaction temperature is 0°C, and the reaction time is 12h.
[0071] The reaction conditions of step S1 and step S2 are further described below with reference to specific examples.
[0072] Embodiment 1:
[0073]
[0074] Under nitrogen atmosphere, 17.74 g (165.6 mmol, 1.1 eq.) of nitrosobenzene, 3.47 g (30.11 mmol, 0.2 eq.) of D-proline and 120 g of acetonitrile were added to the reaction flask, and a solution of 30 g of compound 1N-tert-butyloxycarbonyl-4-piperidone (150.56 mmol, 1.0 eq.) in acetonitrile (30 mL) was added dropwise. After the addition was completed, the temperature was raised to 20-30°C and the reaction was kept warm for 6 h. After the reaction was completed, 30 mL of 10% ammonium chloride aqueous solution was added to quench the reaction, the liquids were separated, the aqueous phase was extracted with 100 g of ethyl acetate, the organic phase was dried with 5 g of anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 2. In the reaction flask, the crude compound 2 and 90 g of methanol were added, the temperature was lowered to 0-10°C, 7.21 g of CuSO4 solid (0.3 eq.) was added in batches, and the reaction was kept warm for 12 h. After the reaction was completed, the mixture was concentrated, and 100 g of ethyl acetate and 30 g of 10% NaCl aqueous solution were added to extract the liquid. In the organic phase, 200 g of n-heptane was added dropwise and stirred for 2 h. The crystals were filtered to obtain 23.01 g (106.90 mmol) of compound 3 (3S)-N-tert-butyloxycarbonyl-3-hydroxy-4-piperidone as an off-white solid (yield: 71%, purity ≥98%, ee ≥95%).
[0075] get Figure 1 The NMR data of compound 3 shown are as follows:
[0076] 1 H NMR (400MHz, Chloroform-d): δ4.35-1.51(m,8H),1.50-1.36(m,9H).
[0077] The next synthesis step is step S3: in a third solvent, compound 3 generates compound 4 under the action of a reducing agent;
[0078] The specific operation steps of step S3 include: in a third solvent, compound 3 (Formula III) is reduced by a reducing agent to generate compound 4, the reaction temperature is -10-100°C, and compound 4 (Formula IV) is obtained through post-treatment and purification.
[0079] In step S3, the reducing agent is selected from any one or more of (S)-2-methyl-CBS-oxazaborolidine, sodium borohydride, potassium borohydride, lithium borohydride and lithium aluminum hydride; preferably, the reducing agent is (S)-2-methyl-CBS-oxazaborolidine.
[0080] In step S3, the third solvent is selected from any one or more of ethanol, isopropanol, methanol, tetrahydrofuran, acetonitrile and 1,4-dioxane; preferably, the third solvent is methanol.
[0081] In step S3, the molar ratio of the compound 3 to the reducing agent is 1:1.0-5.0.
[0082] In step S3, the reaction temperature is -10-100°C, and the reaction time is 1-24h; preferably, the reaction temperature is 0°C, and the reaction time is 6h.
[0083] The reaction conditions of step S3 are further described below with reference to specific examples.
[0084] Embodiment 2:
[0085]
[0086] 30g of compound 3 (3S)-N-tert-butoxycarbonyl-3-hydroxy-4-piperidone (139.37mmol, 1.0eq.) was added to methanol, the temperature was lowered to 0°C, and 57.95g of (S)-2-methyl-CBS-oxazolidinone (209.06mmol, 1.5eq.) was added in batches. After the reaction was completed, 10g of 10% ammonium chloride aqueous solution was added to quench, and the mixture was concentrated under reduced pressure. 30g of toluene was added to the concentrate for separation. The organic phase was dried and concentrated, and column chromatography was performed to obtain 25.13g (115.68mmol) of chiral N-tert-butoxycarbonyl-3,4-dihydroxypiperidine of compound 4 as a white solid (yield: 83%, purity: 98%).
[0087] Embodiment 3:
[0088]
[0089] 30 g of compound 3 (3S) -N-tert-butoxycarbonyl-3-hydroxy-4-piperidone (139.37 mmol, 1.0 eq.) was added to methanol, the temperature was lowered to 0°C, and 13.18 g of NaBH4 (348.43 mmol, 2.5 eq.) was added in batches. After the reaction was completed, 10 g of 10% ammonium chloride aqueous solution was added to quench, and the reaction was concentrated under reduced pressure. 30 g of toluene was added to the concentrate for separation. The organic phase was dried and concentrated, and column chromatography was used to obtain 19.08 g (87.81 mmol) of chiral N-tert-butoxycarbonyl-3,4-dihydroxypiperidine of compound 4 as a white solid (yield: 63%, purity: 98%).
[0090] get Figure 2 The NMR data of compound 4 shown are as follows:
[0091] 1H NMR (600MHz, Chloroform-d): δ4.14(d,J=13.0Hz,2H), 3.60-3.34(m,3H), 2.59(t,J=11.7Hz,2H), 1.92(dd,J=13.7,4.6Hz,1H), 1.44(s,9H).
[0092] The next synthesis step is step S4: under the action of a base, compound 4 is attacked by a fluorine reagent in a fourth solvent to generate compound 5;
[0093] The specific operation steps of step S4 include: under the action of a base, compound 4 is attacked by a fluorine reagent in a fourth solvent to generate compound 5 (Formula V), the reaction temperature is -30-100°C, and the crude product of compound 5 (Formula V) is obtained by concentration under reduced pressure.
[0094] In step S4, the fluorine reagent is selected from any one or more of N-fluorobisbenzenesulfonamide, a selective fluorine reagent, KF, perfluorobutylsulfonyl fluoride and CsF; preferably, the fluorine reagent is perfluorobutylsulfonyl fluoride.
[0095] In step S4, the base is any one or more of 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), triethylamine, pyridine and diisopropylamine; preferably, the base is DBU.
[0096] In step S4, the fourth solvent is selected from any one or more of ethylene glycol dimethyl ether (DME), tetrahydrofuran, acetonitrile and 1,4-dioxane; preferably, the fourth solvent is DME.
[0097] In step S4, the molar ratio of the compound 4, the fluorine reagent and the base is 1:1.0-5.0:1.0-3.0.
[0098] In step S4, the reaction temperature is -30-100°C, and the reaction time is 1-48h; preferably, the reaction temperature is 0°C, and the reaction time is 24h.
[0099] The reaction conditions of step S4 are further described below with reference to specific examples.
[0100] Embodiment 4:
[0101]
[0102] Under nitrogen atmosphere, add 20.0g compound 4 chiral N-tert-butyloxycarbonyl-3,4-dihydroxypiperidine (92.05mmol, 1.0eq.), 14.01g DBU (92.05mmol, 1.0eq.) and 60g tetrahydrofuran into the reaction bottle. Cool down to 0℃, add 27.81g perfluorobutylsulfonyl fluoride (92.05mmol, 1.0eq.) tetrahydrofuran (40g) solution dropwise, and keep warm for 24h. After the reaction is completed, filter and concentrate, column chromatography directly obtains compound 5 chiral N-tert-butyloxycarbonyl-3-hydroxy-4-fluoropiperidine mixture crude product 9.08g (41.42mmol), light yellow liquid (yield: 45%, purity: 96%, ee≥90%).
[0103] The next synthetic step is step S5: in a fifth solvent, compound 5 is purified by a resolving agent to obtain compound 6.
[0104] The specific operation steps of step S5 include: in a fifth solvent, compound 5 (Formula V) is purified by a resolving agent at a reaction temperature of 0-80° C. to obtain compound 6 (Formula VI).
[0105] In step S5, the resolving agent is selected from any one or more of L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-tartaric acid, and D-tartaric acid; preferably, the resolving agent is D-dibenzoyltartaric acid.
[0106] In step S5, the fifth solvent is any one or more of toluene, methanol, n-heptane, tetrahydrofuran and acetonitrile; preferably, the fifth solvent is toluene.
[0107] In step S5, the molar ratio of the compound 5 to the resolving agent is 1:1.0-5.0.
[0108] In step S5, the reaction temperature is 0-80°C, and the reaction time is 1-48h; preferably, the reaction temperature is 80°C, and the reaction time is 24h.
[0109] Step S5: In a fifth solvent, compound 5 is purified by a resolving agent to obtain compound 6.
[0110] The reaction conditions of step S5 are further described below with reference to specific examples.
[0111] Embodiment 5:
[0112]
[0113] Add 50 mL of toluene and 17.17 g of D-dibenzoyltartaric acid (42.9 mmol, 1.05 eq.) into the reaction flask, heat to 50°C, add dropwise a toluene (50 mL) solution of 10.0 g of a chiral N-tert-butoxycarbonyl-3-hydroxy-4-fluoropiperidine mixture of compound 5 (45.6 mmol, 1.0 eq.), keep warm and stir for 1 h, slowly cool to -10 to 10°C, and filter to obtain 9.44 g of compound 6 N-tert-butoxycarbonyl-(3S, 4R)-3-hydroxy-4-fluoropiperidine as a white solid (yield: 85%, purity: 100%, ee: 100%).
[0114] get Figure 3 The NMR data of compound 6 shown are as follows:
[0115] 1 H NMR (400MHz, Chloroform-d): δ4.78(m,1H),3.74(m,2H),3.65-3.46(m,1H),3.3 7-3.13(m,2H),2.46(s,1H),2.15-1.98(m,1H),1.84-1.62(m,1H),1.44(s,9H).
[0116] The specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.
Claims
1. A method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative, characterized in that: Its synthetic route is as follows: The synthesis method comprises the following steps: (1) Step S1, in a first solvent, using compound 1 (N-tert-butyloxycarbonyl-4-piperidone) as a starting material, a tetrahydropyrrole compound is first used to activate the carbonyl group, and then reacted with nitrosobenzene to obtain compound 2; (2) Step S2, in a second solvent, compound 2 reacts in sulfate to obtain compound 3; (3) Step S3, in a third solvent, compound 3 generates compound 4 under the action of a reducing agent; (4) Step S4: Under the action of a base, compound 4 is attacked by a fluorine reagent in a fourth solvent to generate compound 5; (5) Step S5: In a fifth solvent, compound 5 is purified by a resolving agent to obtain compound 6.
2. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: The tetrahydropyrrole compound in step S1 is selected from any one or more of D-proline and 5-[(2S)-pyrrolidin-2-yl]-1H-1,2,3,4-tetrazole.
3. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: In step S1, the first solvent is selected from any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran and dimethyl sulfoxide.
4. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: The sulfate in step S2 is selected from any one or more of copper sulfate, sodium sulfate, magnesium sulfate and iron sulfate.
5. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: The reducing agent in step S3 is selected from any one or more of (S)-2-methyl-CBS-oxazaborolidine, sodium borohydride, potassium borohydride, lithium borohydride and lithium aluminum hydride.
6. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: The fluorine reagent in step S4 is selected from any one or more of N-fluorobisbenzenesulfonamide, a selective fluorine reagent, KF, perfluorobutylsulfonyl fluoride and CsF.
7. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: The base in step S4 is any one or more of 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), triethylamine, pyridine and diisopropylamine.
8. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: The fourth solvent in step S4 is selected from any one or more of ethylene glycol dimethyl ether (DME), tetrahydrofuran, acetonitrile and 1,4-dioxane.
9. The method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to claim 1, characterized in that: The resolving agent in step S5 is selected from any one or more of L-dibenzoyltartaric acid, D-dibenzoyltartaric acid, L-tartaric acid, and D-tartaric acid.
10. A chiral 3-hydroxy-4-fluoropiperidine derivative, synthesized according to the method for synthesizing a chiral 3-hydroxy-4-fluoropiperidine derivative according to any one of claims 1 to 9.