A new method for preparing high-optical-purity piperitenone

Abstract

The application provides a preparation method of high-optical-purity piperlongumin, characterized by the following steps: 2H-pyrane-2,4(3H)-dione and styrene are used to generate a corresponding chiral intermediate under the catalysis of a transition metal and a chiral phosphoric acid ligand, and then the chiral intermediate is subjected to etherification to obtain high-optical-purity piperlongumin; the process is simple, efficient, high in yield, green and environment-friendly, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to the preparation of a high-optical-purity (6S)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one or (6R)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, i.e., high-optical-purity capsaicin. Background Technology

[0002] Capsaicin, a calvanolide extracted from pepper, possesses anticonvulsant properties and has been shown to effectively alleviate anxiety in clinical trials. It enhances GABAA receptors without relying on the classic benzodiazepine binding site. It also exhibits anti-inflammatory and antioxidant effects. Capsaicin and its derivatives are currently used to treat neurological disorders as relaxants, sedatives, and anti-anxiety drugs. Capsaicin is also used in the preparation of drugs for treating osteoporosis. It inhibits osteoclast and bone resorption by suppressing the calcium-mediated NFATc1 and MAPK signaling pathways, and capsaicin treatment has been found to reduce bone loss in OVX mice. M-CSF and RANKL are well-known key cytokines that initiate osteoclast differentiation and stimulate their bone resorption function. NFATc1 is the master transcription factor promoting osteoclast differentiation and is induced after RANKL / RANK axis activation.

[0003] NFATc1 expression depends on tumor necrosis factor receptor-associated factor 6 (TRAF6) as well as NF-κB, MAPK, and calcium signaling pathways. In turn, NFATc1 regulates the expression of target genes that enable osteoclast attachment to bone and mediate bone resorption. Previous studies have suggested that capsaicin and its derivatives regulate LPS-induced signaling pathways such as NF-κB, activator protein 1 (AP-1), and ERK.

[0004] However, the traditional method of obtaining capsaicin, which extracts it from the plant *Peppermint cinnamon*, has the following major drawbacks:

[0005] 1. Natural extracts are racemic mixtures of capsaicin. To obtain optically pure capsaicin, chiral chromatographic column separation is required, which is not only costly but also not suitable for mass production.

[0006] 2. Even racemic mixtures of capsaicin are very expensive;

[0007] 3. Plant extracts are often mixed with other similar substances, resulting in extremely low purity.

[0008] 4. The excessive consumption of kava pepper causes incalculable damage to the local ecosystem;

[0009] 5. The extraction process consumes a large amount of solvent, which can easily pollute the environment;

[0010] If prepared using chemical synthesis, it requires anhydrous and oxygen-free conditions and the use of hazardous reagents such as butyllithium. The preparation conditions are stringent, the cost is extremely high, it is not easy to scale up production, and it poses serious safety hazards and enormous environmental pressure.

[0011] Optically pure products allow for more precise clinical trials and provide the market with more effective and safer products. In particular, racemic compounds are often not recognized in the field of relevant certification and standards and must be optically pure. Therefore, the efficient production of optically pure products is of great significance to the market. Summary of the Invention

[0012] This invention aims to overcome the aforementioned deficiencies by providing a method for the efficient and concise synthesis of two independent diastereomers of (6S)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one or (6R)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, i.e., high-optical-purity capsaicin, through asymmetric addition and methylation reactions. This process utilizes inexpensive raw materials, is simple and efficient, yields high amounts, is environmentally friendly, and is suitable for large-scale industrial production.

[0013] This invention provides a method for preparing high-optical-purity capsaicin, characterized in that: 2H-pyran-2,4(3H)-dione and styrene are reacted under the catalysis of a transition metal catalyst and a chiral phosphoric acid catalyst to generate the corresponding chiral intermediate, which is then etherified to obtain high-optical-purity capsaicin.

[0014] The aforementioned high-optical-purity capsaicin refers to chiral compounds with the following structures:

[0015]

[0016] The reaction equations are shown below:

[0017]

[0018] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0019] The above-mentioned chiral intermediate is a chiral compound with the following structure:

[0020]

[0021] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0022] The etherifying reagent in the above etherification reaction is dimethyl sulfate.

[0023] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0024] The aforementioned transition metal catalysts are selected from VIIIB series metal salts or complexes, preferably iron salts, etc.

[0025] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0026] The chiral phosphoric acid catalysts mentioned above are selected from (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), (R)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphonate (361342-51-0), R-3,3'-bis(triphenylsilyl)binaphthol phosphonate (791616-55-2), S-3,3'-bis(triphenylsilyl)binaphthol phosphonate, and (R)-3,3'-bis(3,5-bistrifluoromethoxyphenyl) (S)-3,3'-bis(3,5-bis(trifluoromethoxyphenyl)-1,1'-bis(2-naphthol) phosphate, (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-dihydrogen phosphate (791616-63-2), (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-dihydrogen phosphate.

[0027] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0028] The molar ratio of the above-mentioned 2H-pyran-2,4(3H)-dione, styrene, transition metal catalyst, and chiral phosphoric acid catalyst is 1:1-5:0.01-0.05:0.01-0.05.

[0029] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0030] The molar ratio of the chiral intermediate to the etherifying agent is 1:1-2.

[0031] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0032] The above reaction for generating the chiral intermediate is carried out at a temperature of not less than 60°C for at least 8 hours.

[0033] The reaction solvent is selected from alkanes and aromatic solvents.

[0034] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0035] The above etherification reaction is carried out under alkaline conditions.

[0036] Furthermore, the present invention provides a method for preparing high-optical-purity capsaicin, characterized in that:

[0037] The above etherification reaction is carried out at 20-100℃ for more than 8 hours. Attached Figure Description

[0038] Figure 1 HPLC resolution of racemic products;

[0039] Peak 1 represents the product of the S configuration, and peak 2 represents the product of the R configuration. Detailed Implementation

[0040] This invention is capable of various modifications and embodiments, and therefore specific embodiments are illustrated and described in the accompanying drawings. However, this is not intended to limit the invention to specific implementations, but should be understood to include all modifications, equivalents, and even substitutions that fall within the spirit and scope of this invention.

[0041] This embodiment relates to a method for preparing high-optical-purity capsaicin, characterized by comprising the following steps:

[0042] S1. Using 2H-pyran-2,4(3H)-dione and styrene as raw materials, (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione or (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione (the purity of which is generally greater than 90%) is synthesized under the catalysis of transition metal catalyst and chiral phosphoric acid catalyst.

[0043] Among them, the transition metal catalyst can be selected from VIIIB series metal salts (such as metal halides) or complexes;

[0044] The chiral phosphoric acid catalyst is selected from (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), (R)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphonate (361342-51-0), R-3,3'-bis(triphenylsilyl)binaphthol phosphonate (791616-55-2), (R)-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-bin-(2-naphthol) phosphate (791616-62-1), and (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthol-2,2′-dihydrogen phosphate (791616-63-2).

[0045] The molar ratio of 2H-pyran-2,4(3H)-dione, styrene, transition metal catalyst, and chiral phosphoric acid catalyst is 1:1-5:0.01-0.05:0.01-0.05.

[0046] S2. Reaction of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione or (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione with an etherifying agent (e.g., dimethyl sulfate) yields (6S)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one or (6R)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, i.e., high optical purity capsaicin;

[0047] The molar ratio of the chiral intermediate to the etherifying agent is 1:1-2.

[0048] The following examples illustrate optimal selection conditions, optional conditions, and comparison conditions:

[0049] Example 1: (Optimal Conditions)

[0050] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 140.15 mg (2% mol, 0.2 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.8576 g of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 86%.

[0051] 1 H NMR(500MHz,CDCl3)d 2.55(dd,J=17.2,4.3Hz,1H),2.67(ddd,J=17.0,10.7,1.6Hz,1H),3.77(s,3H),5.07(dddd,J=10.6,6.2,4.4,1.6Hz,1H),5 HRMS m / z calcd for C14H15O3231.1016; found 231.1015.

[0052] In a 250 mL reactor, 1.080 g (5 mmol) of the product (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, 1.036 g (7.5 mmol) of potassium carbonate, 945.9 mg (7.5 mmol) of dimethyl sulfate, and 50 mL of anhydrous acetone were added sequentially, and the mixture was stirred at 25 °C for 12 hours. 100 mL of ethyl acetate and 100 mL of 0.5 M dilute hydrochloric acid were added. The aqueous phase was extracted twice with ethyl acetate, for a total of 200 mL. The solution was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 898.0 mg of (6S)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, yield 78%, er = 95:5, HPLC (Chiralcel AD column, 20% iPrOH:80% hexanes, 0.7 mL / min, 254 nm).

[0053] 1 H NMR (300MHz, CDCl3) δ7.44-7.24 (m, 5H), 6.74 (d, 1H, J = 16.0Hz), 6.26 (dd, 1H, J = 16.0, 6.2Hz), 5.20 (s 1H),5.11-5.02(m,1H),3.77(s,3H),2.67(dd,1H,J=17.1,10.7Hz),2.55(dd,1H,J=17.1,4.6Hz); 13C NMR (75MHz, CDCl3) δ172.7,167.2,136.2,133.6,129.1,128.8,127.1,125.9,91.0,76.3,56.5,33.7; HRMS: Exact mass calcd forC14H14O3:230.0943; Found:230.0941

[0054] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 140.15 mg (2% mol, 0.2 mmol) of (R)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphonate (361342-51-0), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.836 g of (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 85%.

[0055] In a 250 mL reactor, 1.080 g (5 mmol) of the product (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, 1.036 g (7.5 mmol) of potassium carbonate, 945.9 mg (7.5 mmol) of dimethyl sulfate, and 50 mL of anhydrous acetone were added sequentially, and the mixture was stirred at 25 °C for 12 hours. 100 mL of ethyl acetate and 100 mL of 0.5 M dilute hydrochloric acid were added. The aqueous phase was extracted twice with ethyl acetate, for a total of 200 mL. The solution was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 921.04 mg of the product (6R)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, yield 80%, er = 95:5.

[0056] Example 2: (Chiral ligand screening 1)

[0057] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 173.0 mg (2% mol, 0.2 mmol) of R-3,3'-bis(triphenylsilyl)binaphthol phosphonate (791616-55-2), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.188 g of (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 55%.

[0058] In a 250 mL reactor, 1.080 g (5 mmol) of the product (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, 1.036 g (7.5 mmol) of potassium carbonate, 945.9 mg (7.5 mmol) of dimethyl sulfate, and 50 mL of anhydrous acetone were added sequentially, and the mixture was stirred at 25 °C for 12 hours. Then, 100 mL of ethyl acetate and 100 mL of 0.5 M dilute hydrochloric acid were added. The aqueous phase was extracted twice with ethyl acetate, for a total of 200 mL. The solution was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 863.5 mg of the product (6R)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, yield 75%, er = 65:35.

[0059] Example 3: (Chiral ligand screening 2)

[0060] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 154.5 mg (2% mol, 0.2 mmol) of (R)-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-bi-(2-naphthol) phosphate (791616-62-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.470 g of (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 68%.

[0061] In a 250 mL reactor, 1.080 g (5 mmol) of the product (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, 1.036 g (7.5 mmol) of potassium carbonate, 945.9 mg (7.5 mmol) of dimethyl sulfate, and 50 mL of anhydrous acetone were added sequentially, and the mixture was stirred at 25 °C for 12 hours. Then, 100 mL of ethyl acetate and 100 mL of 0.5 M dilute hydrochloric acid were added. The aqueous phase was extracted twice with ethyl acetate, for a total of 200 mL. The solution was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 898.0 mg of (6R)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, yield 78%, er = 74:26.

[0062] Example 4: (Chiral ligand screening 3)

[0063] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 150.59 mg (2% mol, 0.2 mmol) of (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diphosphate hydrogen ester (791616-63-2), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.665 g of (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 77%.

[0064] In a 250 mL reactor, 1.080 g (5 mmol) of the product (6R)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, 1.036 g (7.5 mmol) of potassium carbonate, 945.9 mg (7.5 mmol) of dimethyl sulfate, and 50 mL of anhydrous acetone were added sequentially, and the mixture was stirred at 25 °C for 12 hours. Then, 100 mL of ethyl acetate and 100 mL of 0.5 M dilute hydrochloric acid were added. The aqueous phase was extracted twice with ethyl acetate, for a total of 200 mL. The solution was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 874.9 mg of (6R)-4-methoxy-6-[(1E)-2-phenylvinyl]-5,6-dihydro-2H-pyran-2-one, yield 76%, er = 83:17.

[0065] Example 5: (Solvent Screening 1)

[0066] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 140.15 mg (2% mol, 0.2 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of toluene were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 0.259 g of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 12%.

[0067] Example 6: (Solvent Screening 2)

[0068] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 140.15 mg (2% mol, 0.2 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of N,N-dimethylformamide were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. HPLC analysis showed no product formation.

[0069] Example 7: (Catalyst Screening 1)

[0070] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 26.89 mg (2% mol, 0.2 mmol) of copper dichloride, 140.15 mg (2% mol, 0.2 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. HPLC analysis showed no product formation.

[0071] Example 8: (Catalyst Screening 2)

[0072] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 55.01 mg (2% mol, 0.2 mmol) of bis-(1,5-cyclooctadiene)nickel, 140.15 mg (2% mol, 0.2 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. HPLC analysis showed no product formation.

[0073] Example 9: (Catalyst Dosage Screening)

[0074] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 81.1 mg (5% mol, 0.5 mmol) of ferric chloride, 350.4 mg (5% mol, 0.5 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.8576 g of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 86%.

[0075] Example 10: (Catalyst Dosage Screening)

[0076] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 81.1 mg (1% mol, 0.1 mmol) of ferric chloride, 350.4 mg (1% mol, 0.1 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.4252 g of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 66%.

[0077] Example 11: (Styrene Dosage Screening 1)

[0078] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 2.084 g (20 mmol) of styrene, 81.1 mg (5% mol, 0.5 mmol) of ferric chloride, 350.4 mg (5% mol, 0.5 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.8570 g of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 86%.

[0079] Example 12: (Styrene Dosage Screening 2)

[0080] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 5.209 g (50 mmol) of styrene, 81.1 mg (5% mol, 0.5 mmol) of ferric chloride, 350.4 mg (5% mol, 0.5 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.728 g of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 80%.

[0081] Example 13: (Reaction Temperature Screening 1)

[0082] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 140.15 mg (2% mol, 0.2 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially, and the mixture was stirred at 25 °C for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The mixture was then evaporated to dryness, and no product was detected by HPLC.

[0083] Example 14: (Reaction Temperature Screening 2)

[0084] In a 500 mL reactor, 1.112 g (10 mmol) of 2H-pyran-2,4(3H)-dione, 1.146 g (11 mmol) of styrene, 32.44 mg (2% mol, 0.2 mmol) of ferric chloride, 140.15 mg (2% mol, 0.2 mmol) of (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (361342-52-1), and 100 mL of n-octane were added sequentially. The mixture was heated to 100 °C and stirred for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and 200 mL of water and 400 mL of dichloromethane were added for extraction. The extract was evaporated to dryness and purified by rapid silica gel column chromatography to obtain 1.340 g of (6S)-6-[(1E)-2-phenylvinyl]tetrahydropyran-2,4-dione, with a yield of 62%.

[0085] While the foregoing has focused on embodiments, these are merely illustrative and do not limit the invention. Those skilled in the art will understand that various modifications and applications not illustrated above can be made without departing from the essential characteristics of these embodiments. For example, the constituent elements specifically shown in the embodiments can be implemented through modifications. Furthermore, various differences related to such modifications and applications should be interpreted as being included within the scope of the invention as defined in the appended claims.

Claims

1. A method for preparing high optical purity capsaicin, characterized in that: 2H-pyran-2,4(3H)-dione reacts with styrene under the catalysis of transition metal catalysts and chiral phosphoric acid catalysts to generate the corresponding chiral intermediates, which are then etherified to obtain capsaicin with high optical purity. The high-optical-purity capsaicin refers to the chiral compound with the following structure: The reaction solvent is n-octane; The transition metal catalyst is ferric chloride; The etherification reaction is carried out at 20-100°C for more than 8 hours; The reaction for generating the chiral intermediate is carried out at a temperature not lower than 60°C; The chiral phosphoric acid catalyst is selected from (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate, (R)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphonate, S-3,3'-bis(triphenylsilyl)binaphthol phosphonate, R-3,3'-bis(triphenylsilyl)binaphthol phosphonate, and (S)-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1' -Bi-(2-naphthol) phosphate, (R)-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-bi-(2-naphthol) phosphate, (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-dihydrogen phosphate, (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-dihydrogen phosphate; The chiral intermediate is a chiral compound with the following structure:

2. The method for preparing high optical purity capsaicin as described in claim 1, characterized in that: The etherifying agent used in the etherification reaction is dimethyl sulfate.

3. The method for preparing high optical purity capsaicin as described in claim 1, characterized in that: The molar ratio of the 2H-pyran-2,4(3H)-dione, styrene, transition metal catalyst, and chiral phosphoric acid catalyst is 1:1-5:0.01-0.05:0.01-0.

05.

4. The method for preparing high optical purity capsaicin as described in claim 2, characterized in that: The molar ratio of the chiral intermediate to the etherifying agent is 1:1-2.

5. The method for preparing high optical purity capsaicin as described in claim 1, characterized in that: The etherification reaction is carried out under alkaline conditions.

6. The method for preparing high optical purity capsaicin as described in claim 1, characterized in that: The reaction to generate the chiral intermediate needs to be carried out for more than 8 hours.

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