A method for asymmetric hydrogenation of single carbonyl of a cyclic butanedione compound

Abstract

The application provides a method for asymmetric hydrogenation of a single carbonyl group of a cyclobutanedione compound, which comprises: hydrogenating the cyclobutanedione compound under the action of a catalyst in the presence of hydrogen to obtain a 3-hydroxyl-cyclobutanone compound, wherein the catalyst comprises a complex of a group VIII metal and an amino acid. The method has the advantages of convenient ligand acquisition and good reaction selectivity without optical purification.

Description

Technical Field

[0001] This invention relates to a method for the asymmetric hydrogenation of a monocarbonyl group in cyclobutanedione compounds. Background Technology

[0002] Polymers used as the main raw material for photoresists need to have functional groups that have suitable affinity for the developer, suitable adhesion to the substrate, good corrosion resistance, and excellent resolution.

[0003] Acrylic resins are among the most commonly used photoresist resins, but they suffer from poor resistance to dry etching. Acrylic resins incorporating cycloalkyl acrylates with oxygen-substituent groups can effectively improve the adhesion of the photoresist resin to the substrate.

[0004] Alkyl acrylates formed by esterification of alkyl acrylic acid with 3-hydroxy-cyclobutanone can improve compatibility with other photosensitive resins and at the same time, impart higher transparency to the polymer. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems of low selectivity, poor product chiral selectivity, and complex catalyst preparation in the existing technology of single carbonyl hydrogenation reaction, and to provide a catalytic hydrogenation reaction involving amino acids and ligand metal complexes. This technical solution has the advantages of convenient ligand acquisition, no need for optical purification, and good reaction selectivity.

[0006] The present invention provides a method for monocarbonyl asymmetric hydrogenation of cyclobutanedione compounds, the method comprising: hydrogenating a cyclobutanedione compound represented by general formula (1) in the presence of hydrogen under the action of a catalyst to obtain a 3-hydroxy-cyclobutane compound represented by general formula (2), wherein the catalyst comprises a complex of a group VIII metal and an amino acid;

[0007]

[0008] In formulas (1) and (2), R1, R2, R3, and R4 are independently and not simultaneously derived from one of the following: hydrogen, halogen, C1-C6 straight-chain saturated alkanes, branched C3-C6 saturated alkanes, C2-C6 straight-chain unsaturated hydrocarbons, branched C3-C6 unsaturated hydrocarbons, C3-C6 cyclic hydrocarbons, or C6-C9 aromatic hydrocarbons.

[0009] The method of the present invention has the advantages of convenient ligand acquisition, no need for optical purification, and good reaction selectivity. Detailed Implementation

[0010] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0011] The present invention provides a method for monocarbonyl asymmetric hydrogenation of cyclobutanedione compounds, the method comprising: hydrogenating a cyclobutanedione compound represented by general formula (1) in the presence of hydrogen under the action of a catalyst to obtain a 3-hydroxy-cyclobutane compound represented by general formula (2), wherein the catalyst comprises a complex of a group VIII metal and an amino acid;

[0012]

[0013]

[0014] In formulas (1) and (2), R1, R2, R3, and R4 are independently and not simultaneously derived from one of the following: hydrogen, halogen, C1-C6 straight-chain saturated alkanes, branched C3-C6 saturated alkanes, C2-C6 straight-chain unsaturated hydrocarbons, branched C3-C6 unsaturated hydrocarbons, C3-C6 cyclic hydrocarbons, or C6-C9 aromatic hydrocarbons.

[0015] In this invention, there are no special requirements regarding the type of complex. According to a preferred embodiment of the invention, the group VIII metal complex in the catalyst is a non-chiral complex, preferably selected from one or more of monodentate phosphine ligand complexes, bidentate phosphine ligand complexes, multidentate phosphine ligand complexes, phosphine-nitrogen ligand complexes, phosphine-nitrogen-phosphine ligand complexes, and nitrogen ligand complexes; more preferably selected from one or more of monodentate phosphine ligand complexes, bidentate phosphine ligand complexes, and multidentate phosphine ligand complexes. In this invention, a multidentate phosphine ligand complex refers to a multidentate phosphine ligand complex containing three or more tridentate phosphine ligand complexes.

[0016] According to a preferred embodiment of the present invention, the complex of the group VIII metal is one or more of IrH(CO)(PPh3)3, IrCl(CO)(PPh3)2, IrH2(CO)(PPh3)3, RuH2(PPh3)4, RuHCl(CO)(PPh3)3, RhCl(CO)(PPh3)2, RhCl(PPh3)3, and PdCl2(PPh3)2. In the embodiments of the present invention, IrH(CO)(PPh3)3 and IrCl(CO)(PPh3)2 are exemplarily described, but this does not limit the scope of the present invention.

[0017] According to a preferred embodiment of the present invention, the complex of the group VIII metal is IrH(CO)(PPh3)3.

[0018] All of the aforementioned group VIII metal complexes can be used in this invention, and there are no special requirements for their preparation methods. According to a preferred embodiment of the invention, the preparation method of the group VIII metal complex in the catalyst includes adding a metal precursor, a non-chiral ligand, and a solvent to a Schlenk tube under argon protection, refluxing the mixture, cooling to room temperature, diluting the reaction solution with solvent, filtering, evaporating the solvent, and purifying to obtain the group VIII metal complex. The type of ligand is determined based on the type of complex, and there are no special requirements for solvent selection, reflux method, and purification, as long as the target complex can be prepared. This invention will not be described in detail here.

[0019] This invention does not have any special requirements for the type of amino acid. According to a preferred embodiment of this invention, in the catalyst, the carbon atom in the amino acid attached to the α-position of the carboxyl group is chiral.

[0020] All of the aforementioned amino acids can be used in this invention. According to a preferred embodiment of this invention, the amino acid is preferably selected from one or more of Boc-O-tert-butyl-L-tyrosine, N-acetyl-L-tyrosine, O-phospho-L-tyrosine, Fmoc-N-methyl-L-valine, glycine-L-phenylalanine, L-canavanine sulfate, β-alanyl-L-histidine, L-aspartic acid, N-acetyl-S-benzyl-L-cysteine, L-(+)-arginine, N-acetyl-L-alanine, N-acetyl-L-valine, and L-alanyl-L-tyrosine.

[0021] According to a preferred embodiment of the present invention, the amino acid is selected from one or more of Boc-O-tert-butyl-L-tyrosine, Fmoc-N-methyl-L-valine, O-phospho-L-tyrosine, and L-alanyl-L-tyrosine.

[0022] This invention does not have any special requirements for the selection of Group VIII metals. According to a preferred embodiment of the invention, the Group VIII metal in the catalyst is selected from one or more of Ir, Ru, Pd, Co and Rh, preferably Ir.

[0023] According to a preferred embodiment of the present invention, the hydrogenation is carried out in the presence of a solvent, preferably selected from alkylbenzene, and more preferably toluene.

[0024] According to a preferred embodiment of the present invention, the mass ratio of the solvent to the cyclobutanedione compound is preferably 1-100:1, more preferably 5-50:1, for example 5:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1.

[0025] In this invention, the catalyst having the aforementioned components can be added individually and then used together as a catalyst to exert a catalytic effect, or the catalyst can be prepared in advance. According to a preferred embodiment of this invention, the method for preparing the catalyst in advance includes: under argon protection, adding a complex of a group VIII metal, an amino acid, and a solvent to a Schlenk tube, heating the reaction for a specified time, cooling to room temperature, evaporating part of the solvent, and then crystallizing to obtain the catalyst.

[0026] In this invention, the direct mixing method includes: under an inert atmosphere, directly adding the complex of the group VIII metal, amino acids, and heating and stirring for a certain time, then introducing hydrogen gas and the cyclobutanedione compound represented by the general formula (1) of the raw material to react directly. The heating temperature is, for example, 30-50°C, and the time is, for example, 10-60 min.

[0027] In this invention, when the hydrogenation is carried out in the presence of a solvent, the direct mixing method includes adding the complex of the group VIII metal, amino acid, and solvent directly to the reaction system under an inert atmosphere, heating and stirring for a certain time, and then introducing hydrogen gas and the cyclobutanedione compound represented by the general formula (1) of the raw material to react directly. The heating temperature is, for example, 30-50°C, such as 30°C, 35°C, 40°C, 45°C, or 50°C, and the time is, for example, 10-60 min.

[0028] According to a preferred embodiment of the present invention, in preferred formulas (1) and (2), R1, R2, R3, and R4 are each independently and not simultaneously derived from one of hydrogen, halogen, C1-C6 straight-chain saturated alkanes, branched C3-C6 saturated alkanes, C2-C6 straight-chain unsaturated hydrocarbons, branched C3-C6 unsaturated hydrocarbons, C3-C6 cyclic hydrocarbons, or C6-C9 aromatic hydrocarbons.

[0029] According to a preferred embodiment of the present invention, in formulas (1) and (2), the halogen is chlorine.

[0030] According to a preferred embodiment of the present invention, in formulas (1) and (2), the C1-C6 straight-chain saturated alkanes are selected from methyl, ethyl or n-propyl.

[0031] According to a preferred embodiment of the present invention, in formulas (1) and (2), the branched C3-C6 saturated alkane is selected from isopropyl, isobutyl or sec-butyl.

[0032] According to a preferred embodiment of the present invention, in formulas (1) and (2), the C2-C6 straight-chain unsaturated hydrocarbons are selected from vinyl, allyl, 1-propenyl or butenyl.

[0033] According to a preferred embodiment of the present invention, in formulas (1) and (2), the branched C3-C6 unsaturated hydrocarbons are selected from 2-propenyl, isobutylenyl or sec-butene.

[0034] According to a preferred embodiment of the present invention, in formulas (1) and (2), the C3-C6 cyclic hydrocarbons are selected from cyclopropyl, cyclobutyl, cyclopentyl, methylcyclobutyl or cyclohexyl.

[0035] According to a preferred embodiment of the present invention, in formulas (1) and (2), the aromatic hydrocarbons of C6-C9 are selected from phenyl, methylphenyl, benzyl, 3,5-dimethylphenyl or 3,4,5-trimethylphenyl.

[0036] According to a preferred embodiment of the present invention, in formulas (1) and (2), R1, R2, R3, and R4 are independently and not simultaneously derived from one of the following: hydrogen, halogen (chlorine), C1-C6 straight-chain saturated alkanes (methyl, ethyl, n-propyl), branched C3-C6 saturated alkanes (isopropyl, isobutyl, sec-butyl), C2-C6 straight-chain unsaturated hydrocarbons (vinyl, allyl, 1-propenyl, butenyl), branched C3-C6 unsaturated hydrocarbons (2-propenyl, isobutylenyl, sec-butylenyl), C3-C6 cyclic hydrocarbons (cyclopropyl, cyclobutyl, cyclopentyl, methylcyclobutyl, cyclohexyl), or C6-C9 aromatic hydrocarbons (phenyl, methylphenyl, benzyl, 3,5-dimethylphenyl, 3,4,5-trimethylphenyl).

[0037] According to a preferred embodiment of the present invention, the cyclobutanedione compound represented by general formula (1) is selected from one or more of 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione, 2,2-dimethyl-4,4-dipropyl-1,3-cyclobutanedione, 2,2-dimethyl-4,4-diallyl-1,3-cyclobutanedione and 2,2-dimethyl-4,4-dicyclohexyl-1,3-cyclobutanedione.

[0038] The present invention does not have special requirements for the hydrogenation conditions. According to a preferred embodiment of the present invention, the hydrogenation conditions include: a temperature of 0-120°C, preferably 30-60°C, for example 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, and 60°C; the pressure and time can be determined according to the temperature adjustment. For the present invention, the preferred pressure is atmospheric pressure to 65 bar, preferably atmospheric pressure to 50 bar; the preferred time is 0.01-20 h, preferably 5-12 h.

[0039] In this invention, the mass ratio of the group VIII metal complex to the amino acid can be selected from a wide range. According to a preferred embodiment of the invention, the mass ratio of the group VIII metal complex to the amino acid in the catalyst is 30-1:1, preferably 10-1:1, for example 1:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.

[0040] In this invention, the mass ratio of cyclobutanedione compounds to catalyst can be selected from a wide range. For this invention, the preferred mass ratio of cyclobutanedione compounds to catalyst is 80-1:1, more preferably 40-10:1, for example 10:1, 15:1, 20:1, 25:1, 30:1, 357:1, 40:1.

[0041] The advantages of the present invention will be described in detail below through examples, but the scope of the present invention is not limited thereto.

[0042] In this invention, the selective calculation method is as follows: gas chromatography is used to detect the reaction, and the area normalization method is used to calculate the peak area of ​​the product / the peak area of ​​the total product * 100%; the test method for the ee value includes: gas chromatography is used to detect the reaction, and the area normalization method is used to calculate the peak area of ​​the desired configuration / the peak area of ​​the product * 100%.

[0043]

Example 1

[0044] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging, the autoclave was closed and the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 94%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 99%, and the ee value was 95%.

[0045]

Example 2

[0046] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Fmoc-N-methyl-L-valine (8.84 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added under a nitrogen atmosphere, followed by purging with nitrogen three times. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging with hydrogen three times, the autoclave was closed. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography for the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 93%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 99%, and the ee value was 94%.

[0047]

Example 3

[0048] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Boc-O-tert-butyl-L-tyrosine (25.2 mg, 2.99 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added under a nitrogen atmosphere, followed by purging with nitrogen three times. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45 °C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After closing the autoclave, the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45 °C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography for the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 94%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 99%, and the ee value was 95%.

[0049]

Example 4

[0050] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (2.52 mg, 0.3 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45 °C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging, the autoclave was closed and the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45 °C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 92%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 99%, and the ee value was 91%.

[0051]

Example 5

[0052] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (336.4 mg, 1.27 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging, the autoclave was closed and the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 97%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 99%, and the ee value was 96%.

[0053]

Example 6

[0054] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (1345.6 mg, 5.1 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging, the autoclave was closed and the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 90%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 98%, and the ee value was 92%.

[0055]

Example 7

[0056] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging, the autoclave was closed and the mixture was purged with hydrogen three times. The system pressure was increased to 50 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 98%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 98%, and the ee value was 94%.

[0057]

Example 8

[0058] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Then, 10 mL of toluene was added, stirred to dissolve, and reacted at 45 °C for 20 minutes. Next, 2,2-dimethyl-4,4-dipropyl-1,3-cyclobutanedione (490.725 mg, 2.5 mmol) was added under a nitrogen atmosphere. The hydrogenation flask was then transferred to an autoclave, and after purging with hydrogen three times, the autoclave was closed. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45 °C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-dipropyl-1,3-cyclobutanedione was 93%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-dipropyl-cyclobutanedione was 99%, and the ee value was 94%.

[0059]

Example 9

[0060] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diallyl-1,3-cyclobutanedione (480.645 mg, 2.5 mmol) was added under a nitrogen atmosphere. The hydrogenation flask was then transferred to an autoclave, and the autoclave was closed and purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood. The residue was analyzed by liquid chromatography for the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diallyl-1,3-cyclobutanedione was 94%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diallyl-cyclobutanedione was 99%, and the ee value was 94%.

[0061]

Example 10

[0062] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-dicyclohexyl-1,3-cyclobutanedione (691.05 mg, 2.5 mmol) was added under a nitrogen atmosphere. The hydrogenation flask was then transferred to an autoclave, and the autoclave was closed and purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood. The residue was analyzed by liquid chromatography for the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-dicyclohexyl-1,3-cyclobutanedione was 93%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-dicyclohexyl-cyclobutanedione was 98%, and the ee value was 93%.

[0063]

Example 11

[0064] The method is the same as in Example 1, except that the amino acid used is L-aspartic acid.

[0065] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. L-Aspartic acid (3.32 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added under a nitrogen atmosphere, followed by purging with nitrogen three times. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging with hydrogen three times, the autoclave was closed. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography for the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 90%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 96%, and the ee value was 91%.

[0066]

Example 12

[0067] The method is the same as in Example 1, except that the metal complex is IrCl(CO)(PPh3)3.

[0068] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrCl(CO)(PPh3)3 (26.1 mg, 1 mol%) were added, followed by three purgings with nitrogen. Toluene (10 mL) was then added, stirred to dissolve, and reacted at 45°C for 20 minutes. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, and the hydrogenation flask was transferred to an autoclave. After purging, the autoclave was closed and the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 92%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 99%, and the ee value was 92%.

[0069]

Example 13

[0070] The method is the same as in Example 1, except for the ratio of complex to amino acids.

[0071] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (0.252 mg, 0.03 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Then, 10 mL of toluene was added, stirred to dissolve, and reacted at 45 °C for 20 minutes. Under a nitrogen atmosphere, 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added, and the hydrogenation flask was transferred to an autoclave. After closing the autoclave, the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45 °C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 76%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 82%, and the ee value was 88%.

[0072]

Example 14

[0073] The method of Example 1 was followed, except that the solvent was replaced with dichloromethane.

[0074] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Then, 10 mL of dichloromethane was added, stirred to dissolve, and reacted at 45°C for 20 minutes. Next, 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere. The hydrogenation flask was then transferred to an autoclave, and after purging with hydrogen three times, the autoclave was closed. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45°C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood, and the residue was analyzed by liquid chromatography to identify the remaining raw materials and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 94%, the selectivity of the target product 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanedione was 99%, and the ee value was 93%.

[0075] Comparative Example 1

[0076] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. 2,2-Dimethyl-4,4-diphenyl-1,3-cyclobutanedione (660.81 mg, 2.5 mmol) was added under a nitrogen atmosphere, followed by three purgings with nitrogen. Then, 10 mL of toluene was added. After stirring and dissolving, IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) was added. The hydrogenation flask was then transferred to an autoclave, and the autoclave was closed and purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45 °C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood. The residue was analyzed by liquid chromatography for the remaining raw material and the target product. The results showed that the conversion rate of the raw material 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutanedione was 0%.

[0077] Comparative Example 2

[0078] A 25 mL hydrogenation flask was dehydrated and deoxygenated using standard Schlenk techniques. Under a nitrogen atmosphere, Boc-O-tert-butyl-L-tyrosine (8.44 mg, 1 mol%) and IrH(CO)(PPh3)3 (25.2 mg, 1 mol%) were added, followed by three purgings with nitrogen. Then, 10 mL of toluene was added, stirred to dissolve, and reacted at 45 °C for 20 minutes. Under a nitrogen atmosphere, 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanone (665.85 mg, 2.5 mmol) was added, and the flask was transferred to an autoclave. After purging, the autoclave was closed and the mixture was purged with hydrogen three times. The system pressure was increased to 30 bar with hydrogen, and the reaction was carried out at 45 °C for 8 hours. After natural cooling, the hydrogen was carefully released in a fume hood. The residue was analyzed by liquid chromatography for the remaining raw material and the target product. The results showed that the conversion rate of the raw material 3-hydroxy-2,2-dimethyl-4,4-diphenyl-cyclobutanone was 0%. Comparative Example 2 shows that when the product of monocarbonyl hydrogenation was reacted again under the same experimental conditions, it was not converted, proving that the catalyst system of the present invention has unique selectivity.

[0079] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for the asymmetric hydrogenation of the single carbonyl group of a cyclic dione compound, characterized in that, The method includes hydrogenating a cyclobutanedione compound represented by general formula (1) in the presence of hydrogen to obtain a 3-hydroxy-cyclobutanone compound represented by general formula (2) using a catalyst including a complex of a Group VIII metal and an amino acid. In formula (1) and formula (2), R1, R2, R3, R4 are each independently and simultaneously not from one of hydrogen, halogen, C1-C6 straight chain saturated alkane, C3-C6 branched saturated alkane, C2-C6 straight chain unsaturated hydrocarbon, C3-C6 branched unsaturated hydrocarbon, C3-C6 cyclic hydrocarbon or C6-C9 aromatic hydrocarbon. The mass ratio of the complex of the Group VIII metal to the amino acid is 30-1:

1. The mass ratio of the cyclobutanedione compound to the catalyst is 80-1:

1. The complex of the Group VIII metal is selected from one or more of a monodentate phosphine ligand complex, a bidentate phosphine ligand complex, a polydentate phosphine ligand complex, a phosphine nitrogen ligand complex, a phosphine nitrogen phosphine ligand complex and a nitrogen ligand complex. The Group VIII metal is selected from one or more of Ir, Ru, Pd, Co and Rh.

2. The method of claim 1, wherein, In the catalyst, The complex of the Group VIII metal is selected from one or more of a monodentate phosphine ligand complex, a bidentate phosphine ligand complex and a polydentate phosphine ligand complex.

3. The method of claim 2, wherein, In the catalyst, The complex of the Group VIII metal is selected from one or more of IrH(CO)(PPh3)3, IrCl(CO)(PPh3)2, IrH2(CO)(PPh3)3, RuH2(PPh3)4, RuHCl(CO)(PPh3)3, RhCl(CO)(PPh3)2, RhCl(PPh3)3, PdCl2(PPh3)2.

4. The method of claim 1, wherein, In the catalyst, The carbon atom connected to the carboxyl α position in the amino acid has chirality.

5. The method of claim 4, wherein, In the catalyst, The amino acid is selected from one or more of Boc-O-tert-butyl-L-tyrosine, N-acetyl-L-tyrosine, O-phosphoryl-L-tyrosine, Fmoc-N-methyl-L-valine, glycine-L-phenylalanine, L-canavanine sulfate, β-alanyl-L-histidine, L-aspartic acid, N-acetyl-S-benzyl-L-cysteine, L-(+)-arginine, N-acetyl-L-alanine, N-acetyl-L-valine and L-alanyl-L-tyrosine.

6. The method of claim 5, wherein, In the catalyst, The amino acid is selected from one or more of Boc-O-tert-butyl-L-tyrosine, Fmoc-N-methyl-L-valine, O-phosphoryl-L-tyrosine, L-alanyl-L-tyrosine.

7. The method of claim 1, wherein, In the catalyst, the Group VIII metal is selected from Ir.

8. The method of claim 1, wherein, The hydrogenation is performed in the presence of a solvent.

9. The method of claim 8, wherein, The solvent is selected from alkylbenzene.

10. The method of claim 9, wherein, The solvent is selected from toluene.

11. The method of claim 8, wherein, The mass ratio of the solvent to the cyclobutanedione compound is 1-100:

1.

12. The method of claim 11, wherein, The mass ratio of the solvent to the cyclobutanedione compound is 5-50:

1.

13. The method of claim 1, wherein, In formula (1) and formula (2), The halogen is chlorine; and / or The C1-C6 straight chain saturated alkane is selected from methyl, ethyl or n-propyl; and / or The C1-C6 straight chain saturated alkane is selected from methyl, ethyl or n-propyl; and / or C3-C6 saturated alkyl with branching selected from isopropyl, isobutyl or sec-butyl; C2-C6 linear unsaturated hydrocarbon selected from vinyl, allyl, 1-propenyl or butenyl; C3-C6 unsaturated hydrocarbon with branching selected from 2-propenyl, isobutenyl or sec-butenyl; C3-C6 cyclic hydrocarbon selected from cyclopropyl, cyclobutyl, cyclopentyl, methylcyclobutyl or cyclohexyl; C6-C9 aromatic hydrocarbon selected from phenyl, methylphenyl, benzyl, 3,5-dimethylphenyl or 3,4,5-trimethylphenyl.

14. The method of claim 1, wherein, The cyclic butandione compound represented by general formula (1) is selected from one or more of 2,2-dimethyl-4,4-diphenyl-1,3-cyclobutandione, 2,2-dimethyl-4,4-dipropyl-1,3-cyclobutandione, 2,2-dimethyl-4,4-diallyl-1,3-cyclobutandione and 2,2-dimethyl-4,4-dicyclohexyl-1,3-cyclobutandione.

15. The method of claim 1, wherein, The conditions of the hydrogenation include: temperature of 0-120°C; and / or, pressure of normal pressure~65 bar; and / or, time of 0.01-20h.

16. The method of claim 15, wherein, The conditions of the hydrogenation include: temperature of 30-60°C; and / or, pressure of normal pressure~50 bar; and / or, time of 5-12h.

17. The method of claim 1, wherein, In the catalyst, The mass ratio of the complex of Group VIII metal to the amino acid is 10-1:

1.

18. The method of claim 1, wherein, The mass ratio of the cyclic butandione compound to the catalyst is 40-10:1.

Images