A macrocyclic ketone compound and preparation method thereof

Abstract

The invention provides a macrocyclic ketone compound and a preparation method thereof, and belongs to the technical field of organic synthesis. (E)-3-methylcyclopentadecanone is subjected to an asymmetric catalytic hydrogenation reaction under the action of a catalyst to obtain a product (-)-(R)-3-methylcyclopentadecanone. The invention prepares an efficient chiral catalyst, which can selectively catalyze the hydrogenation reaction of (E)-3-methylcyclopentadecanone, prepare (-)-(R)-3-methylcyclopentadecanone with high yield and high selectivity, and the reaction conditions are mild and easy to realize industrial application.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a macrocyclic ketone compound and a preparation method thereof. Background Art

[0002] Musk ketone is the main fragrance component of natural musk, containing 0.5-2.0% in natural musk. Musk ketone was discovered by Walbaum in 1906, and its chemical structure was determined by Ruzicka in 1926. Natural musk ketone is (-)-(R)-3-methylcyclopentadecanone, but the commercially available product is a synthetic product and is a dl-body. Comparing the aroma of (-)-(R)- and (+)-(S)-body, the (R)-body is a musk with strong diffusion, and the (S)-body is a weak musk that does not diffuse chemically. The result is known that in terms of fragrance threshold, the (R)-body is 22 times that of the (S)-body.

[0003] Many reports have been made so far on the research of methods for producing musk ketone, especially (-)-(R)-musk ketone. Among them, the method of producing optically active musk ketone by 1,4-conjugated methyl addition reaction of 2-cyclopentadecenone is a promising approach. In particular, in recent years, there have been several reports on methods for producing (-)-(R)-musk ketone by asymmetric methylation reaction of optically active ligands.

[0004] Literature: J. Chem. Soc. Perkin Trans. I, 1193 (1992) discloses that a compound having an aminoalkanol chiral auxiliary group with a camphane skeleton is used in the synthesis, and good results are reported. However, the disadvantages of the reported synthesis of (-)-(R)-musk ketone using the chiral auxiliary group are that the synthesis reaction temperature is very low, only -78°C, the reaction time is long, and the chiral auxiliary group must be used under an excess condition of more than 1 equivalent, which makes it difficult to commercialize.

[0005] Literature: Synlett 1999, No. 11, PP. 1181-1183 discloses that specific compounds are good when tested with various chiral phosphate ligands in catalytic amounts. However, even with a solvent / substrate ratio of about 50 times, the yield remains at 53%, which is not satisfactory.

[0006] Patent document: Korean Patent Publication No. 2001-49811 discloses that musk ketone can be produced in high yield by using a copper complex of 4-(cis-2,6-dimethylpiperidine)-(R)-dinaphthodioxaphosphine or 4-(R,R-2,5-diphenylpyrrolidine)-(R)-dinaphthodioxaphosphine as a chiral ligand, but the document does not disclose the reaction at a high concentration. In the conventional method, when the reaction is carried out at a high concentration, a high molecular weight by-product is generated, and a satisfactory yield cannot be obtained.

[0007] Under reaction conditions such as extremely low temperature or low concentration or long reaction time, the manufacturing cost of musk ketone becomes high. In addition, the manufacturing cost also becomes high when the reaction yield is low. Therefore, it is necessary to develop a method for manufacturing musk ketone with high yield and mild conditions. Summary of the invention

[0008] The purpose of the present invention is to provide a macrocyclic ketone compound and a preparation method thereof, prepare an efficient chiral catalyst, which can selectively catalyze the hydrogenation reaction of (E)-3-methylcyclopentadecanone, prepare (-)-(R)-3-methylcyclopentadecanone with high yield and high selectivity, and the reaction conditions are mild and easy to realize industrial application.

[0009] The technical solution of the present invention is achieved in this way:

[0010] The invention provides a method for preparing a macrocyclic ketone compound. (E)-3-methylcyclopentadecanone-2-enone is subjected to an asymmetric catalytic hydrogenation reaction under the action of a catalyst to obtain a product (-)-(R)-3-methylcyclopentadecanone.

[0011] As a further improvement of the present invention, the preparation method of the catalyst is as follows:

[0012] S1. dissolving alkyl orthosilicate in ethanol, adding porogen, ammonia and water, stirring the reaction, centrifuging, washing, drying and calcining to obtain porous silica nanospheres;

[0013] S2. Add the porous silica nanospheres prepared in step S1 into water, add cobalt nitrate and ferric sulfate, stir and mix evenly, add citric acid, adjust the pH value of the solution, heat and stir to react, centrifuge, wash, dry, and calcine to obtain ferromagnetic modified porous silica nanospheres;

[0014] S3. Tris-HCl solution and sodium hydroxide were added dropwise to water to adjust the pH value of the solution, and the ferromagnetic modified porous silica nanospheres and tannic acid obtained in step S2 were added, the reaction was stirred, centrifuged, washed, and dried to obtain modified porous silica nanospheres;

[0015] S4. Add the modified porous silica microspheres obtained in step S3 to water, add NHS and EDC, activate the reaction, then add L-threonine and L-phenylalanine, stir the reaction, centrifuge, wash, and dry to obtain chiral amino acid modified nanospheres;

[0016] S5. Dissolve rhodium chloride and zinc chloride in an ethanol aqueous solution, add the chiral amino acid modified nanospheres prepared in step S4 under the protection of an inert gas, heat and stir to react, separate with a magnet, wash, and dry to obtain a catalyst.

[0017] As a further improvement of the present invention, the alkyl orthosilicate in step S1 is methyl orthosilicate or ethyl orthosilicate, the mass ratio of the alkyl orthosilicate, ethanol, porogen, ammonia water and water is 12-15:100-120:0.5-1:7-10:4-7, the porogen is selected from at least one of the ethylene oxide-propylene oxide triblock copolymers PEO20-PPO70-PEO20 and PEO106-PPO70-PEO106, the stirring reaction temperature is 40-50°C, the time is 10-12h, the calcination temperature is 500-600°C, and the time is 1-3h.

[0018] As a further improvement of the present invention, the mass ratio of the porous silica nanospheres, cobalt nitrate and citric acid in step S2 is 10:1-2:7-10, the molar ratio of the cobalt nitrate and ferric sulfate is 1:2, the pH value of the adjusted solution is 8-9, the temperature of the heated and stirred reaction is 75-85°C, the time is 2-4h, and the calcination temperature is 400-500°C, and the time is 1-3h.

[0019] As a further improvement of the present invention, the pH value of the solution is adjusted to 8.5-9.5 in step S3, the mass ratio of the ferromagnetic modified porous silica nanospheres to tannic acid is 10:2-4, the temperature of the stirring reaction is 40-50°C, and the time is 2-4h.

[0020] As a further improvement of the present invention, the mass ratio of the modified porous silica microspheres, NHS, EDC, L-threonine and L-phenylalanine in step S4 is 10-15:3-5:4-6:2-3:1-2, the temperature of the activation reaction is 0-4°C, the time is 20-40min, and the stirring reaction time is 5-7h.

[0021] As a further improvement of the present invention, the mass ratio of rhodium chloride, zinc chloride and chiral amino acid modified nanospheres in step S5 is 1-2:3-4:20-30, and the temperature of the heating and stirring reaction is 70-80°C and the time is 3-5h.

[0022] As a further improvement of the present invention, the catalyst is 1-2wt% of the mass of (E)-3-methylcyclopentadeca-2-enone, and is replaced with N2 and H2 at 0.3-0.5MPa for 2-4 times respectively, and then the hydrogen pressure in the reactor is adjusted to 2.5-3.5MPa, and the pressure is maintained to check for leaks. If the air tightness is good, the temperature is raised to 45-55°C and the reaction is stirred for 1-3h.

[0023] The present invention further protects (-)-(R)-3-methylcyclopentadecanone prepared by the above preparation method.

[0024] The present invention further protects a catalyst as described above, the preparation method of which comprises the following steps:

[0025] S1. 12-15 parts by weight of alkyl orthosilicate is dissolved in 100-120 parts by weight of ethanol, 0.5-1 parts by weight of a porogen, 7-10 parts by weight of aqueous ammonia and 4-7 parts by weight of water are added, the reaction is stirred at 40-50 ° C for 10-12h, centrifuged, washed, dried, and calcined at 500-600 ° C for 1-3h to obtain porous silica nanospheres;

[0026] S2. Add 10 parts by weight of the porous silica nanospheres prepared in step S1 to 100 parts by weight of water, add 1-2 parts by weight of cobalt nitrate and ferric sulfate, wherein the molar ratio of cobalt nitrate to ferric sulfate is 1:2, stir and mix evenly, add 7-10 parts by weight of citric acid, adjust the pH value of the solution to 8-9, heat to 75-85°C, stir and react for 2-4h, centrifuge, wash, dry, and calcine at 400-500°C for 1-3h to obtain ferromagnetic modified porous silica nanospheres;

[0027] S3. Tris-HCl solution and sodium hydroxide were added dropwise to 100 parts by weight of water to adjust the pH value of the solution to 8.5-9.5, 10 parts by weight of the ferromagnetic modified porous silica nanospheres prepared in step S2 and 2-4 parts by weight of tannic acid were added, the reaction was stirred at 40-50 ° C for 2-4h, centrifuged, washed, and dried to obtain modified porous silica nanospheres;

[0028] S4. 10-15 parts by weight of the modified porous silica microspheres prepared in step S3 are added to 100 parts by weight of water, 3-5 parts by weight of NHS and 4-6 parts by weight of EDC are added, and the reaction is activated at 0-4°C for 20-40 min, and then 2-3 parts by weight of L-threonine and 1-2 parts by weight of L-phenylalanine are added, the reaction is stirred for 5-7 h, centrifuged, washed, and dried to obtain chiral amino acid modified nanospheres;

[0029] S5. Dissolve 1-2 parts by weight of rhodium chloride and 3-4 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 20-30 parts by weight of chiral amino acid modified nanospheres obtained in step S4 under the protection of inert gas, heat to 70-80°C, stir the reaction for 3-5h, separate with a magnet, wash, and dry to obtain a catalyst.

[0030] The present invention has the following beneficial effects:

[0031] The catalyst of the invention uses porous nano-silicon dioxide as a carrier, and the carrier has the characteristics of large specific surface area and high porosity. Tannic acid can be coated on the surface of the carrier to form abundant carboxyl active groups. After being activated by NHS (N-hydroxysuccinimide) and EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide), the carboxyl groups can react with L-phenylalanine and L-threonine through coupling reaction, thereby introducing a chiral structure into the catalyst. The chiral amino acids of the two structures can well exert regional selectivity, and efficiently and selectively catalyze and produce (-)-(R)-3-methylcyclopentadecanone. The catalyst has the advantages of stable catalytic properties, long-term storage at room temperature, being applicable to various organic or water solvent systems, and having the advantages of small catalytic amount and the like. At the same time, the catalyst of the invention can form a complex with transition metal rhodium and metal zinc through the benzene ring structure on the carrier, the lone pair of electrons of N or O, etc., greatly reducing the reaction activation energy in the catalytic hydrogenation reaction, improving the reaction selectivity, and mild reaction conditions. The cobalt ferrite obtained through ferromagnetic modification can not only facilitate the separation and reuse of the catalyst, but also the iron and cobalt can play a synergistic catalytic role with rhodium and zinc in the reaction, greatly reducing the amount of catalyst used, and also improving the conversion rate of the reactants and the ee value.

[0032] The invention prepares an efficient chiral catalyst, which can selectively carry out catalytic hydrogenation reaction on (E)-3-methylcyclopentadecanone, prepare (-)-(R)-3-methylcyclopentadecanone with high yield and high selectivity, and has mild reaction conditions and is easy to realize industrial application. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] Preparation Example 1 Preparation of Catalyst

[0035] The method comprises the following steps:

[0036] S1. 12 parts by weight of methyl orthosilicate were dissolved in 100 parts by weight of ethanol, 0.5 parts by weight of PEO106-PPO70-PEO106, 7 parts by weight of ammonia and 4 parts by weight of water were added, the reaction was stirred at 40 ° C for 10 h, centrifuged, washed, dried, and calcined at 500 ° C for 1 h to obtain porous silica nanospheres;

[0037] S2. Add 10 parts by weight of the porous silica nanospheres prepared in step S1 to 100 parts by weight of water, add 1 part by weight of cobalt nitrate and ferric sulfate, the molar ratio of cobalt nitrate to ferric sulfate is 1:2, stir and mix evenly, add 7 parts by weight of citric acid, adjust the pH value of the solution to 8, heat to 75°C, stir and react for 2h, centrifuge, wash, dry, and calcine at 400°C for 1h to obtain ferromagnetic modified porous silica nanospheres;

[0038] S3. Tris-HCl solution and sodium hydroxide were added dropwise to 100 parts by weight of water to adjust the pH value of the solution to 8.5, 10 parts by weight of the ferromagnetic modified porous silica nanospheres prepared in step S2 and 2 parts by weight of tannic acid were added, the reaction was stirred at 40 ° C for 2h, centrifuged, washed, and dried to obtain modified porous silica nanospheres;

[0039] S4. 10 parts by weight of the modified porous silica microspheres prepared in step S3 were added to 100 parts by weight of water, 3 parts by weight of NHS and 4 parts by weight of EDC were added, and the reaction was activated at 0°C for 20 min, followed by the addition of 2 parts by weight of L-threonine and 1 part by weight of L-phenylalanine, and the reaction was stirred for 5 h, centrifuged, washed, and dried to obtain chiral amino acid modified nanospheres;

[0040] S5. Dissolve 1 part by weight of rhodium chloride and 3 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 20 parts by weight of chiral amino acid modified nanospheres obtained in step S4 under nitrogen protection, heat to 70°C, stir to react for 3 hours, separate with a magnet, wash, and dry to obtain a catalyst.

[0041] Preparation Example 2 Preparation of Catalyst

[0042] The method comprises the following steps:

[0043] S1. 15 parts by weight of tetraethyl orthosilicate were dissolved in 120 parts by weight of ethanol, 1 part by weight of ethylene oxide-propylene oxide triblock copolymer PEO20-PPO70-PEO20, 10 parts by weight of aqueous ammonia and 7 parts by weight of water were added, the reaction was stirred at 50 ° C for 12 h, centrifuged, washed, dried, and calcined at 600 ° C for 3 h to obtain porous silica nanospheres;

[0044] S2. Add 10 parts by weight of the porous silica nanospheres prepared in step S1 to 100 parts by weight of water, add 2 parts by weight of cobalt nitrate and ferric sulfate, the molar ratio of cobalt nitrate to ferric sulfate is 1:2, stir and mix evenly, add 10 parts by weight of citric acid, adjust the pH value of the solution to 9, heat to 85°C, stir and react for 4h, centrifuge, wash, dry, and calcine at 500°C for 3h to obtain ferromagnetic modified porous silica nanospheres;

[0045] S3. Tris-HCl solution and sodium hydroxide were added dropwise to 100 parts by weight of water to adjust the pH value of the solution to 9.5, 10 parts by weight of the ferromagnetic modified porous silica nanospheres prepared in step S2 and 4 parts by weight of tannic acid were added, the reaction was stirred at 50 ° C for 4h, centrifuged, washed, and dried to obtain modified porous silica nanospheres;

[0046] S4. 15 parts by weight of the modified porous silica microspheres prepared in step S3 were added to 100 parts by weight of water, 5 parts by weight of NHS and 6 parts by weight of EDC were added, and the reaction was activated at 4°C for 40 min, and then 3 parts by weight of L-threonine and 2 parts by weight of L-phenylalanine were added, and the reaction was stirred for 7 h, centrifuged, washed, and dried to obtain chiral amino acid modified nanospheres;

[0047] S5. Dissolve 2 parts by weight of rhodium chloride and 4 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 30 parts by weight of chiral amino acid modified nanospheres obtained in step S4 under nitrogen protection, heat to 80°C, stir to react for 5 hours, separate with a magnet, wash, and dry to obtain a catalyst.

[0048] Preparation Example 3 Preparation of Catalyst

[0049] The method comprises the following steps:

[0050] S1. 13 parts by weight of tetraethyl orthosilicate was dissolved in 110 parts by weight of ethanol, 0.7 parts by weight of ethylene oxide-propylene oxide triblock copolymer PEO20-PPO70-PEO20, 8.5 parts by weight of aqueous ammonia and 5.5 parts by weight of water were added, the reaction was stirred at 45°C for 11h, centrifuged, washed, dried, and calcined at 550°C for 2h to obtain porous silica nanospheres;

[0051] S2. Add 10 parts by weight of the porous silica nanospheres prepared in step S1 to 100 parts by weight of water, add 1.5 parts by weight of cobalt nitrate and ferric sulfate, the molar ratio of cobalt nitrate to ferric sulfate is 1:2, stir and mix evenly, add 8.5 parts by weight of citric acid, adjust the pH value of the solution to 8.5, heat to 80°C, stir and react for 3h, centrifuge, wash, dry, and calcine at 450°C for 2h to obtain ferromagnetic modified porous silica nanospheres;

[0052] S3. Tris-HCl solution and sodium hydroxide were added dropwise to 100 parts by weight of water to adjust the pH value of the solution to 9, 10 parts by weight of the ferromagnetic modified porous silica nanospheres prepared in step S2 and 3 parts by weight of tannic acid were added, the reaction was stirred at 45 ° C for 3h, centrifuged, washed, and dried to obtain modified porous silica nanospheres;

[0053] S4. 125 parts by weight of the modified porous silica microspheres prepared in step S3 were added to 100 parts by weight of water, 4 parts by weight of NHS and 5 parts by weight of EDC were added, and the reaction was activated at 2°C for 30 min, and then 2.5 parts by weight of L-threonine and 1.5 parts by weight of L-phenylalanine were added, the reaction was stirred for 6 h, centrifuged, washed, and dried to obtain chiral amino acid modified nanospheres;

[0054] S5. Dissolve 1.5 parts by weight of rhodium chloride and 3.5 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 25 parts by weight of chiral amino acid modified nanospheres obtained in step S4 under nitrogen protection, heat to 75°C, stir to react for 4 hours, separate with a magnet, wash, and dry to obtain a catalyst.

[0055] Comparative Preparation Example 1

[0056] Compared with Preparation Example 3, the difference is that no porogen is added in step S1.

[0057] The details are as follows:

[0058] S1. Dissolve 13 parts by weight of tetraethyl orthosilicate in 110 parts by weight of ethanol, add 8.5 parts by weight of aqueous ammonia and 5.5 parts by weight of water, stir and react at 45°C for 11 hours, centrifuge, wash, dry, and calcine at 550°C for 2 hours to obtain porous silica nanospheres.

[0059] Comparative Preparation Example 2

[0060] Compared with Preparation Example 3, the difference is that step S2 is not performed.

[0061] The details are as follows:

[0062] S1. 13 parts by weight of tetraethyl orthosilicate was dissolved in 110 parts by weight of ethanol, 0.7 parts by weight of ethylene oxide-propylene oxide triblock copolymer PEO20-PPO70-PEO20, 8.5 parts by weight of aqueous ammonia and 5.5 parts by weight of water were added, the reaction was stirred at 45°C for 11h, centrifuged, washed, dried, and calcined at 550°C for 2h to obtain porous silica nanospheres;

[0063] S2. Tris-HCl solution and sodium hydroxide were added dropwise to 100 parts by weight of water to adjust the pH value of the solution to 9, 10 parts by weight of the porous silica nanospheres prepared in step S2 and 3 parts by weight of tannic acid were added, the reaction was stirred at 45 ° C for 3 h, centrifuged, washed, and dried to obtain modified porous silica nanospheres;

[0064] S3. 125 parts by weight of the modified porous silica microspheres prepared in step S2 were added to 100 parts by weight of water, 4 parts by weight of NHS and 5 parts by weight of EDC were added, and the reaction was activated at 2°C for 30 min, and then 2.5 parts by weight of L-threonine and 1.5 parts by weight of L-phenylalanine were added, and the reaction was stirred for 6 h, centrifuged, washed, and dried to obtain chiral amino acid modified nanospheres;

[0065] S4. Dissolve 1.5 parts by weight of rhodium chloride and 3.5 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 25 parts by weight of chiral amino acid modified nanospheres prepared in step S3 under nitrogen protection, heat to 75°C, stir to react for 4 hours, separate with a magnet, wash, and dry to obtain a catalyst.

[0066] Comparative Preparation Example 3

[0067] Compared with Preparation Example 3, the difference is that step S3 is not performed.

[0068] The details are as follows:

[0069] S1. 13 parts by weight of tetraethyl orthosilicate was dissolved in 110 parts by weight of ethanol, 0.7 parts by weight of ethylene oxide-propylene oxide triblock copolymer PEO20-PPO70-PEO20, 8.5 parts by weight of aqueous ammonia and 5.5 parts by weight of water were added, the reaction was stirred at 45°C for 11h, centrifuged, washed, dried, and calcined at 550°C for 2h to obtain porous silica nanospheres;

[0070] S2. Add 10 parts by weight of the porous silica nanospheres prepared in step S1 to 100 parts by weight of water, add 1.5 parts by weight of cobalt nitrate and ferric sulfate, the molar ratio of cobalt nitrate to ferric sulfate is 1:2, stir and mix evenly, add 8.5 parts by weight of citric acid, adjust the pH value of the solution to 8.5, heat to 80°C, stir and react for 3h, centrifuge, wash, dry, and calcine at 450°C for 2h to obtain ferromagnetic modified porous silica nanospheres;

[0071] S3. 125 parts by weight of the ferromagnetic modified porous silica microspheres prepared in step S2 were added to 100 parts by weight of water, 4 parts by weight of NHS and 5 parts by weight of EDC were added, and the reaction was activated at 2°C for 30 min, and then 2.5 parts by weight of L-threonine and 1.5 parts by weight of L-phenylalanine were added, the reaction was stirred for 6 h, centrifuged, washed, and dried to obtain chiral amino acid modified nanospheres;

[0072] S4. Dissolve 1.5 parts by weight of rhodium chloride and 3.5 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 25 parts by weight of chiral amino acid modified nanospheres prepared in step S3 under nitrogen protection, heat to 75°C, stir to react for 4 hours, separate with a magnet, wash, and dry to obtain a catalyst.

[0073] Comparative Preparation Example 4

[0074] Compared with Preparation Example 3, the difference is that L-phenylalanine is not added in step S4.

[0075] The details are as follows:

[0076] S4. Add 125 parts by weight of the modified porous silica microspheres obtained in step S3 to 100 parts by weight of water, add 4 parts by weight of NHS and 5 parts by weight of EDC, activate the reaction at 2°C for 30 minutes, then add 4 parts by weight of L-threonine, stir the reaction for 6 hours, centrifuge, wash, and dry to obtain chiral amino acid modified nanospheres.

[0077] Comparative Preparation Example 5

[0078] Compared with Preparation Example 3, the difference is that L-threonine is not added in step S4.

[0079] The details are as follows:

[0080] S4. Add 125 parts by weight of the modified porous silica microspheres obtained in step S3 to 100 parts by weight of water, add 4 parts by weight of NHS and 5 parts by weight of EDC, activate the reaction at 2°C for 30 minutes, then add 4 parts by weight of L-threonine, stir the reaction for 6 hours, centrifuge, wash, and dry to obtain chiral amino acid modified nanospheres.

[0081] Comparative Preparation Example 6

[0082] Compared with Preparation Example 3, the difference is that step S4 is not performed.

[0083] The details are as follows:

[0084] S1. 13 parts by weight of tetraethyl orthosilicate was dissolved in 110 parts by weight of ethanol, 0.7 parts by weight of ethylene oxide-propylene oxide triblock copolymer PEO20-PPO70-PEO20, 8.5 parts by weight of aqueous ammonia and 5.5 parts by weight of water were added, the reaction was stirred at 45°C for 11h, centrifuged, washed, dried, and calcined at 550°C for 2h to obtain porous silica nanospheres;

[0085] S2. Add 10 parts by weight of the porous silica nanospheres prepared in step S1 to 100 parts by weight of water, add 1.5 parts by weight of cobalt nitrate and ferric sulfate, the molar ratio of cobalt nitrate to ferric sulfate is 1:2, stir and mix evenly, add 8.5 parts by weight of citric acid, adjust the pH value of the solution to 8.5, heat to 80°C, stir and react for 3h, centrifuge, wash, dry, and calcine at 450°C for 2h to obtain ferromagnetic modified porous silica nanospheres;

[0086] S3. Tris-HCl solution and sodium hydroxide were added dropwise to 100 parts by weight of water to adjust the pH value of the solution to 9, 10 parts by weight of the ferromagnetic modified porous silica nanospheres prepared in step S2 and 3 parts by weight of tannic acid were added, the reaction was stirred at 45 ° C for 3h, centrifuged, washed, and dried to obtain modified porous silica nanospheres;

[0087] S4. Dissolve 1.5 parts by weight of rhodium chloride and 3.5 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 25 parts by weight of modified porous silica nanospheres obtained in step S3 under nitrogen protection, heat to 75°C, stir to react for 4 hours, separate with a magnet, wash, and dry to obtain a catalyst.

[0088] Comparative Preparation Example 7

[0089] Compared with Preparation Example 3, the difference is that zinc chloride is not added in step S5.

[0090] The details are as follows:

[0091] S5. Dissolve 5 parts by weight of rhodium chloride in 200 parts by weight of ethanol aqueous solution, add 25 parts by weight of chiral amino acid modified nanospheres obtained in step S4 under nitrogen protection, heat to 75°C, stir to react for 4 hours, separate with a magnet, wash, and dry to obtain a catalyst.

[0092] Test Example 1

[0093] The specific surface area and pore structure of the catalysts prepared in Preparation Examples 1-3 and Comparative Preparation Examples 1-7 were characterized by a fully automatic specific surface area and porosity analyzer (Brunauer-EmmettTeller method, BET method). The results are shown in Table 1.

[0094] Table 1

[0095] Group <![CDATA[Specific surface area (m 2 / g)]]> <![CDATA[Pore volume (cm 3 / g)]]> Preparation Example 1 457.6 0.412 Preparation Example 2 462.2 0.408 Preparation Example 3 468.9 0.417 Comparative Preparation Example 1 201.6 0.231 Comparative Preparation Example 2 402.5 0.389 Comparative Preparation Example 3 423.8 0.392 Comparative Preparation Example 4 441.1 0.397 Comparative Preparation Example 5 437.8 0.401 Comparative Preparation Example 6 423.3 0.392 Comparative Preparation Example 7 452.1 0.405

[0096] It can be seen from the above table that the catalysts prepared in Preparation Examples 1-3 of the present invention have a higher specific surface area and a larger pore volume.

[0097] Example 1

[0098] The present embodiment provides a method for preparing macrocyclic ketone compounds, wherein (E)-3-methylcyclopentadecan-2-enone is subjected to an asymmetric catalytic hydrogenation reaction under the action of the catalyst prepared in Preparation Example 1, wherein the catalyst is 1wt% of the mass of (E)-3-methylcyclopentadecan-2-enone, and the mixture is replaced with N2 and H2 at 0.3MPa twice respectively, and then the hydrogen pressure in the reactor is adjusted to 2.5MPa, and the pressure is maintained to check for leaks. If the airtightness is good, the temperature is raised to 45°C and the reaction is stirred for 3 hours to obtain the product (-)-(R)-3-methylcyclopentadecanone.

[0099] Example 2

[0100] The present embodiment provides a method for preparing macrocyclic ketone compounds, wherein (E)-3-methylcyclopentadecan-2-enone is subjected to an asymmetric catalytic hydrogenation reaction under the action of the catalyst prepared in Preparation Example 2, wherein the catalyst is 2wt% of the mass of (E)-3-methylcyclopentadecan-2-enone, and the mixture is replaced with N2 and H2 at 0.5 MPa for 4 times respectively, and then the hydrogen pressure in the reactor is adjusted to 3.5 MPa, and the pressure is maintained to check for leaks. If the airtightness is good, the temperature is raised to 55°C and the reaction is stirred for 1 hour to obtain the product (-)-(R)-3-methylcyclopentadecanone.

[0101] Example 3

[0102] The present embodiment provides a method for preparing macrocyclic ketone compounds, wherein (E)-3-methylcyclopentadecan-2-enone is subjected to an asymmetric catalytic hydrogenation reaction under the action of the catalyst prepared in Preparation Example 3, wherein the catalyst is 1.5wt% of the mass of (E)-3-methylcyclopentadecan-2-enone, and the reaction mixture is replaced with N2 and H2 at 0.4MPa for 3 times respectively. Then, the hydrogen pressure in the reactor is adjusted to 3MPa, and the pressure is maintained to check for leaks. If the airtightness is good, the temperature is raised to 50°C and the reaction is stirred for 2h to obtain the product (-)-(R)-3-methylcyclopentadecanone.

[0103] Comparative Examples 1-7

[0104] Compared with Example 3, the difference is that the catalysts are prepared using Comparative Preparation Examples 1-7 respectively.

[0105] Test Example 1

[0106] The reactions in Examples 1-3 of the present invention and Comparative Examples 1-7 were evaluated.

[0107] The results are shown in Table 2.

[0108] Table 2

[0109] Group Conversion rate of (E)-3-methylcyclopentadeca-2-enone (%) ee value (%) Example 1 94.8 98.5 Example 2 95.1 98.3 Example 3 95.2 98.9 Comparative Example 1 90.4 97.2 Comparative Example 2 91.6 98.0 Comparative Example 3 82.7 82.4 Comparative Example 4 86.5 87.6 Comparative Example 5 87.0 86.3 Comparative Example 6 83.2 84.9 Comparative Example 7 88.7 92.7

[0110] It can be seen from the above table that the reactions in Examples 1-3 of the present invention can produce (-)-(R)-3-methylcyclopentadecanone with high conversion rate and high selectivity.

[0111] Test Example 2 Reproduction Experiment

[0112] After the catalyst in Example 3 was separated, the catalytic reaction was repeated 4 times to reproduce the experiment.

[0113] The results are shown in Table 3.

[0114] Table 3

[0115] Group Conversion rate (%) ee value (%) first 95.2 98.9 Repeat 1 time 94.4 98.4 Repeat 2 times 93.0 97.7 Repeat 3 times 92.2 97.1 Repeat 4 times 91.1 96.4

[0116] It can be seen from the above table that the catalyst of the present invention has good reproducibility and can be used repeatedly while still maintaining high selectivity and conversion rate.

[0117] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a macrocyclic ketone compound, characterized in that: (E)-3-methylcyclopentadecan-2-enone is subjected to an asymmetric catalytic hydrogenation reaction under the action of a catalyst to obtain a product (-)-(R)-3-methylcyclopentadecanone; The preparation method of the catalyst is as follows: S1. dissolving an alkyl orthosilicate in ethanol, adding a porogen, ammonia water and water, stirring the reaction, centrifuging, washing, drying and calcining to obtain porous silica nanospheres; the alkyl orthosilicate is methyl orthosilicate or ethyl orthosilicate, and the mass ratio of the alkyl orthosilicate, ethanol, porogen, ammonia water and water is 12-15:100-120:0.5-1:7-10:4-7; the stirring reaction temperature is 40-50°C, the time is 10-12h, the calcination temperature is 500-600°C, and the time is 1-3h; S2. Add the porous silica nanospheres prepared in step S1 into water, add cobalt nitrate and ferric sulfate, stir and mix evenly, add citric acid, adjust the pH value of the solution, heat and stir to react, centrifuge, wash, dry, and calcine to obtain ferromagnetic modified porous silica nanospheres; the mass ratio of the porous silica nanospheres, cobalt nitrate, and citric acid is 10:1-2:7-10, and the molar ratio of the cobalt nitrate and ferric sulfate is 1:2; the temperature of the heating and stirring reaction is 75-85°C, the time is 2-4h, and the temperature of the calcination is 400-500°C, and the time is 1-3h; S3. Tris-HCl solution and sodium hydroxide are added dropwise to water to adjust the pH value of the solution, and the ferromagnetic modified porous silica nanospheres and tannic acid prepared in step S2 are added, stirred for reaction, centrifuged, washed, and dried to obtain modified porous silica nanospheres; the mass ratio of the ferromagnetic modified porous silica nanospheres to tannic acid is 10:2-4, the stirring reaction temperature is 40-50°C, and the time is 2-4h; S4. Add the modified porous silica microspheres obtained in step S3 into water, add NHS and EDC, activate the reaction, then add L-threonine and L-phenylalanine, stir the reaction, centrifuge, wash, and dry to obtain chiral amino acid modified nanospheres; the mass ratio of the modified porous silica microspheres, NHS, EDC, L-threonine and L-phenylalanine is 10-15:3-5:4-6:2-3:1-2, the activation reaction temperature is 0-4°C, the time is 20-40min, and the stirring reaction time is 5-7h; S5. Dissolve rhodium chloride and zinc chloride in an ethanol aqueous solution, add the chiral amino acid modified nanospheres obtained in step S4 under the protection of an inert gas, heat and stir to react, separate with a magnet, wash, and dry to obtain a catalyst; the mass ratio of the rhodium chloride, zinc chloride, and chiral amino acid modified nanospheres is 1-2:3-4:20-30, the temperature of the heating and stirring reaction is 70-80°C, and the time is 3-5h.

2. The preparation method according to claim 1, characterized in that: The porogen in step S1 is selected from at least one of oxyethylene-oxypropylene triblock copolymers PEO20-PPO70-PEO20 and PEO106-PPO70-PEO106.

3. The preparation method according to claim 1, characterized in that: The pH value of the solution is adjusted to 8-9 in step S2.

4. The preparation method according to claim 1, characterized in that: The pH value of the solution is adjusted to 8.5-9.5 in step S3.

5. The preparation method according to claim 1, characterized in that: The catalyst is 1-2wt% of the mass of (E)-3-methylcyclopentadeca-2-enone, and is replaced with N2 and H2 at 0.3-0.5MPa for 2-4 times respectively, and then the hydrogen pressure in the reactor is adjusted to 2.5-3.5MPa, and the pressure is maintained to check for leaks. If the air tightness is good, the temperature is raised to 45-55°C and the reaction is stirred for 1-3h.

6. A catalyst as claimed in claim 1, characterized in that The preparation method comprises the following steps: S1. 12-15 parts by weight of alkyl orthosilicate is dissolved in 100-120 parts by weight of ethanol, 0.5-1 parts by weight of a porogen, 7-10 parts by weight of aqueous ammonia and 4-7 parts by weight of water are added, the reaction is stirred at 40-50 ° C for 10-12h, centrifuged, washed, dried, and calcined at 500-600 ° C for 1-3h to obtain porous silica nanospheres; S2. Add 10 parts by weight of the porous silica nanospheres prepared in step S1 to 100 parts by weight of water, add 1-2 parts by weight of cobalt nitrate and ferric sulfate, wherein the molar ratio of cobalt nitrate to ferric sulfate is 1:2, stir and mix evenly, add 7-10 parts by weight of citric acid, adjust the pH value of the solution to 8-9, heat to 75-85°C, stir and react for 2-4h, centrifuge, wash, dry, and calcine at 400-500°C for 1-3h to obtain ferromagnetic modified porous silica nanospheres; S3. Tris-HCl solution and sodium hydroxide were added dropwise to 100 parts by weight of water to adjust the pH value of the solution to 8.5-9.5, 10 parts by weight of the ferromagnetic modified porous silica nanospheres prepared in step S2 and 2-4 parts by weight of tannic acid were added, the reaction was stirred at 40-50 ° C for 2-4h, centrifuged, washed, and dried to obtain modified porous silica nanospheres; S4. 10-15 parts by weight of the modified porous silica microspheres prepared in step S3 are added to 100 parts by weight of water, 3-5 parts by weight of NHS and 4-6 parts by weight of EDC are added, and the reaction is activated at 0-4°C for 20-40 min, and then 2-3 parts by weight of L-threonine and 1-2 parts by weight of L-phenylalanine are added, the reaction is stirred for 5-7 h, centrifuged, washed, and dried to obtain chiral amino acid modified nanospheres; S5. Dissolve 1-2 parts by weight of rhodium chloride and 3-4 parts by weight of zinc chloride in 200 parts by weight of ethanol aqueous solution, add 20-30 parts by weight of chiral amino acid modified nanospheres obtained in step S4 under the protection of inert gas, heat to 70-80°C, stir the reaction for 3-5h, separate with a magnet, wash, and dry to obtain a catalyst.