Chiral camphorsulfonic acid derivative as well as preparation method and application thereof
Through the preparation and application of chiral camphorsulfonic acid derivative catalyst, the problem of low chiral conversion and yield in chiral α-hydroxyketone synthesis in the prior art is solved, and high efficiency and high purity chiral α-- is achieved. Hydroxyketone synthesis.
Patent Information
- Application Number
- CN202311185181.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-14
- Publication Date
- 2024-12-20
AI Technical Summary
When existing catalysts synthesize chiral α-hydroxyketone compounds asymmetrically, the chiral conversion and yield are low and are sensitive to functional group differences, resulting in changes in chiral configuration.
Chiral camphorsulfonic acid derivatives are used as catalysts and prepared by acid chloride, reaction, ammonia water, diazotization reagents and other steps, and are used to asymmetrically synthesize chiral α-hydroxyketones to improve catalytic performance and chiral purity.
The yield and purity of chiral α-hydroxyketone is improved, with simple operation, high yield of preparation method, high purity and excellent catalytic performance.
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Figure CN119161361A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chemical synthesis, and in particular to a chiral camphorsulfonic acid derivative and a preparation method and application thereof. Background Art
[0002] Chiral α-hydroxyketones are building blocks with many applications in organic and medicinal chemistry, such as in the synthesis of vitamin E, certain antifungal drugs, and the pesticide indoxacarb. (2S)-5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester is one of the chiral α-hydroxyketone compounds, which is an intermediate in the synthesis of indoxacarb. The optical properties of (2S)-5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester directly determine the optical properties of the final indoxacarb.
[0003] At present, chiral α-hydroxy ketone compounds are often synthesized asymmetrically using catalysts and chiral precursors. Commonly used catalysts are:
[0004] However, when the above catalyst is used to asymmetric synthesize chiral α-hydroxy ketone compounds, chiral precursors containing different functional groups have a great influence on the final chiral conversion rate and yield. Even if only one functional group is different, the chiral configuration will change. Therefore, it is necessary to provide a new catalyst to improve the chiral purity and yield of the chiral α-hydroxy ketone of the structure described in the present application. Summary of the invention
[0005] Based on the technical problems existing in the background technology, the present invention provides a chiral camphorsulfonic acid derivative and a preparation method and application thereof. The chiral camphorsulfonic acid derivative of the present invention has good catalytic performance. When asymmetric synthesis of chiral α-hydroxy ketone is performed, the catalytic performance is good, the yield of chiral α-hydroxy ketone is high, and the chiral purity is high.
[0006] The present invention provides a chiral camphorsulfonic acid derivative, the structural formula of which is shown in formula (I):
[0007]
[0008] The chiral camphorsulfonic acid derivatives of the present invention have good catalytic performance. When the chiral camphorsulfonic acid derivatives of the present invention are used for asymmetric synthesis of chiral α-hydroxy ketones, the catalytic performance is good, the yield of the chiral α-hydroxy ketone is high, and the chiral purity is high.
[0009] The present invention also provides a method for preparing the chiral camphorsulfonic acid derivative, comprising the following steps:
[0010] S1, subjecting D(+) camphorsulfonic acid to an acyl chlorination reaction with a chlorinating agent to obtain D(+) camphorsulfonyl chloride; then mixing D(+) camphorsulfonyl chloride with an organic solvent and aqueous ammonia to react to obtain an intermediate C1;
[0011] S2, mixing the intermediate C1 with sodium methoxide and an organic solvent, reacting, and purifying to obtain the intermediate C2;
[0012] S3, under the protection of inert gas, at -35 to -25°C, mix the intermediate C2, the organic solvent, and the diazotizing agent to obtain solution 1; mix N-chlorosuccinimide and the organic solvent, and under the protection of inert gas, dropwise add solution 1 at -35 to -25°C to react, and purify to obtain intermediate C3;
[0013] S4, mixing the intermediate C3, an acid condensing agent, an oxidizing agent, water and an organic solvent, reacting, and purifying to obtain a chiral camphorsulfonic acid derivative;
[0014] Among them, the structural formulas of intermediate C1, intermediate C2 and intermediate C3 are as follows:
[0015]
[0016] The preparation method of the invention has the advantages of simple operation, high yield and high purity.
[0017] Preferably, in S1, the chlorinating agent is thionyl chloride.
[0018] Preferably, in S1, the molar ratio of D(+) camphorsulfonic acid to the chlorinating agent is 1:2.5-3.5.
[0019] Preferably, in S1, the temperature of the acyl chlorination reaction is 45-55°C, and the reaction time is 2.5-3.5h.
[0020] Preferably, in S1, the mass fraction of aqueous ammonia is 22-25wt%.
[0021] Preferably, in S1, the ratio of D(+) camphorsulfonic acid to aqueous ammonia is 1 g:10-20 ml.
[0022] Preferably, in S1, D(+) camphorsulfonyl chloride is mixed with an organic solvent and aqueous ammonia, and the reaction temperature is -5 to 5°C and the reaction time is 2.5 to 3.5 hours.
[0023] Preferably, in S1, the organic solvent is dichloromethane.
[0024] In the above S1, a reaction is carried out and then purified to obtain an intermediate C1. The purification specifically comprises the following steps: after the reaction is completed, an organic phase is taken, concentrated and dried to remove the organic solvent, to obtain an intermediate C1.
[0025] Preferably, in S2, the intermediate C1 is mixed with sodium methoxide and an organic solvent at 5-10°C with stirring for 1.5-2.5h.
[0026] Preferably, in S2, the reaction temperature is 35-45°C, and the reaction time is 20-24h.
[0027] Preferably, in S2, the molar ratio of the intermediate C1 to sodium methoxide is 1:1.2-1.3.
[0028] Preferably, in S2, the organic solvent is methanol.
[0029] Preferably, in S2, the specific steps of purification include: cooling and crystallization, and solid-liquid separation to obtain the intermediate C2.
[0030] Preferably, in S3, the diazotizing agent is sodium hexamethyldisilazide.
[0031] Preferably, in S3, the reaction temperature is -5 to 5°C, and the reaction time is 2.5 to 3.5 hours.
[0032] Preferably, in S3, the molar ratio of the intermediate C2, the diazotizing agent and N-chlorosuccinimide is 1:2.1-2.2:2.5.
[0033] Preferably, in S3, the organic solvent is tetrahydrofuran.
[0034] Preferably, in S3, the specific steps of purification include: adding water to the reaction solution for precipitation treatment, then heating to 20-30°C, dissolving the precipitate in an organic solvent, concentrating and drying the organic phase to obtain a solid, dissolving the solid with dichloromethane, washing the solution with aqueous hydrochloric acid solution, water, and saturated brine in sequence, and concentrating and drying the organic phase to obtain the intermediate C3.
[0035] Preferably, in S4, the acid shrinking agent is potassium carbonate.
[0036] Preferably, in S4, the oxidizing agent is 3-chloroperbenzoic acid.
[0037] Preferably, in S4, the molar ratio of the intermediate C3, the acid condensing agent and the oxidizing agent is 1:4.5-5.5:1.4-1.6.
[0038] Preferably, in S4, the reaction temperature is room temperature and the reaction time is 16-20 hours.
[0039] Preferably, in S4, the organic solvent is dichloromethane.
[0040] Preferably, in S4, the specific steps of purification include: adding sodium thiosulfate and mixing, taking the organic phase, concentrating and drying to obtain a crude product; and recrystallizing the crude product with ethanol to obtain a chiral camphorsulfonic acid derivative.
[0041] The present invention also proposes the use of the chiral camphorsulfonic acid derivative as a catalyst in the asymmetric synthesis of chiral α-hydroxy ketone; wherein the chiral α-hydroxy ketone has a structural formula as shown in formula (II):
[0042]
[0043] R1 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R2 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R3 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R4 is an alkyl group, an alkoxy group, a carboxyl group or an ester group; n is 1 or 2; "*" indicates a chiral center.
[0044] The present invention also provides a method for asymmetric synthesis of chiral α-hydroxy ketone, comprising the following steps: under the protection of inert gas, sodium diazonium hexamethyldisilane, a chiral precursor and an organic solvent are mixed, reacted at -5 to 5°C, then the temperature is adjusted to -40 to -30°C, the chiral camphorsulfonic acid derivative is added, the temperature is kept to react, and the chiral α-hydroxy ketone is purified;
[0045] Wherein, the chiral precursor structure is shown in formula (III);
[0046]
[0047] R1 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R2 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R3 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R4 is an alkyl group, an alkoxy group, a carboxyl group or an ester group; n is 1 or 2.
[0048] Preferably, the reaction is carried out at -5 to 5°C for 30 to 50 min.
[0049] Preferably, the reaction is carried out for 2.5-3.5 hours.
[0050] Preferably, sodium hexamethyldisilazide, a chiral precursor and an organic solvent are mixed at -40 to -30°C.
[0051] Preferably, the molar ratio of the chiral precursor, sodium hexamethyldisilazide, and the chiral camphorsulfonic acid derivative is 1:1.1-1.3:1.1-1.3.
[0052] Preferably, the organic solvent is tetrahydrofuran.
[0053] Preferably, the specific steps of purification include: after the reaction is completed by heat preservation, adding saturated ammonium chloride aqueous solution for crystallization, adding methyl tert-butyl ether to dissolve the crystals, taking the organic phase, concentrating and drying to obtain the chiral α-hydroxy ketone.
[0054] Beneficial effects:
[0055] The chiral camphorsulfonic acid derivatives of the present invention have good catalytic performance. When the chiral camphorsulfonic acid derivatives of the present invention are used for asymmetric synthesis of chiral α-hydroxy ketones, the catalytic performance is good, the yield of the chiral α-hydroxy ketones is high, and the chiral purity is high. The preparation method of the chiral camphorsulfonic acid derivatives of the present invention is simple to operate, has high yield, and high purity. BRIEF DESCRIPTION OF THE DRAWINGS
[0056] Figure 1 The (2S)-5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester prepared in Example 5 1 HNMR spectrum. DETAILED DESCRIPTION
[0057] The technical solution of the present invention is described in detail below through specific embodiments.
[0058] Example 1
[0059] The synthetic route is:
[0060]
[0061] The preparation of intermediate C1 comprises the following steps:
[0062] Add 78.87g (0.66mol) of thionyl chloride to a 250ml three-necked flask, cool to -10-0°C, add 50.03g (0.22mol) of D(+) camphorsulfonic acid in batches within 20min, the system has degassing phenomenon, and the temperature does not change significantly, stir for 15min, gradually increase the temperature to 45-55°C, keep warm and stir for 3h; then concentrate under reduced pressure at 30°C to remove thionyl chloride to obtain a solid, and then steam the solid twice with dichloromethane, each time using 50ml of dichloromethane to obtain 49.5g of D(+) camphorsulfonyl chloride;
[0063] Add 375 ml of dichloromethane to camphorsulfonyl chloride for dissolution, control the temperature at -5 to 5°C, add 500 ml of concentrated ammonia water with a mass fraction of 22-25wt%, keep warm and stir to react for 3 hours, let stand to separate the liquids and take the organic phase, extract the aqueous phase twice with dichloromethane, each time with 100 ml of dichloromethane, combine the extract phase with the organic phase, dry over anhydrous sodium sulfate, and then concentrate to dryness under reduced pressure at 25°C to obtain 40.78 g of intermediate C1 with a yield of 81.9%.
[0064] Example 2
[0065] The synthetic route is:
[0066]
[0067] The preparation of intermediate C2 comprises the following steps:
[0068] Take 6.07 g (0.11 mol) of sodium methoxide and dissolve it in 30 ml of methanol to obtain a sodium methoxide solution;
[0069] Add 0.5 g (0.09 mol) of intermediate C12 and 100 ml of methanol into a 250 ml three-necked flask, cool to 5-10 ° C, then add sodium methoxide solution dropwise, the solid first gradually dissolves and then comes out, keep warm and stir for 2 hours, then raise the temperature to 35-45 ° C, react for 22 hours, cool to 2-5 ° C, stir and crystallize for 1 hour, filter, rinse the filter cake with 40 ml of petroleum ether, and dry to obtain 16.20 g of intermediate C2 with a yield of 85.7%.
[0070] Example 3
[0071] The synthetic route is:
[0072]
[0073] The preparation of intermediate C3 comprises the following steps:
[0074] Add 10.00 g (0.047 mol) of intermediate C2 and 200 ml of tetrahydrofuran into a 500 ml three-necked flask, cool to -35 to -25°C under nitrogen protection, add 100 ml of 1 mol / l sodium hexamethyldisilazide tetrahydrofuran solution dropwise over 50 min, mix well to obtain solution 1;
[0075] Add 15.67 g (0.12 mol) of N-chlorosuccinimide and 250 ml of tetrahydrofuran to a 1L three-necked flask, cool to -35 to -25°C, add solution 1 dropwise within 1 hour under nitrogen protection, then heat to -5 to 5°C, keep warm and stir to react for 3 hours;
[0076] 40 ml of water was added dropwise, and a colloidal solid appeared at the bottom of the bottle. The temperature was then raised to 20-30°C, and the colloidal solid was dissolved in tetrahydrofuran. The tetrahydrofuran phase was concentrated under reduced pressure to obtain a light yellow wet solid. The light yellow solid was dissolved in 200 ml of dichloromethane, washed with 40 ml of a 1 mol / l hydrochloric acid aqueous solution, then washed twice with water, each time using 100 ml of water, and then washed once with 100 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and then concentrated and dried under reduced pressure at 25°C to obtain 9.76 g of intermediate C3, with a yield of 73.8%.
[0077] Example 4
[0078] The synthetic route is:
[0079]
[0080] The preparation of chiral camphorsulfonic acid derivatives comprises the following steps:
[0081] Dissolve 19.60 g (0.14 mol) of anhydrous potassium carbonate in 80 ml of water to obtain a potassium carbonate solution;
[0082] Dissolve 7.34 g (0.04 mol) of 3-chloroperoxybenzoic acid in 112 ml of dichloromethane to obtain a 3-chloroperoxybenzoic acid solution;
[0083] Add 8.00 g (0.028 mol) of intermediate C3 and 56 ml of dichloromethane to a 1L three-necked flask, add potassium carbonate solution dropwise at room temperature, then add 3-chloroperbenzoic acid solution dropwise, stir at room temperature for 18 h, and monitor the complete reaction of the raw materials by thin layer chromatography;
[0084] Then add 5.63g of sodium thiosulfate, stir for 30min to remove the remaining 3-chloroperoxybenzoic acid, let stand and take the organic phase, wash the aqueous phase with 120ml of dichloromethane and extract once, combine the organic phases, wash the organic phase with 60ml of saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product;
[0085] Add 32 ml of ethanol to the crude product, heat to 70-80°C to dissolve, stir for 10 min, cool to 10-20°C, stir for 2 h to recrystallize, filter, and obtain 4.5 g of chiral camphorsulfonic acid derivative with a yield of 53.2%.
[0086] Example 5
[0087] The synthetic route is:
[0088]
[0089] Preparation of indoxacarb intermediate (2S)-5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester comprises the following steps:
[0090] 0.15 g (0.0007 mol) of 5-chloro-2-methoxycarbonyl-1-indanone ester was dissolved in 4 ml of dry tetrahydrofuran to obtain a 5-chloro-2-methoxycarbonyl-1-indanone ester solution;
[0091] 0.24 g (0.0008 mol) of the chiral camphorsulfonic acid derivative prepared in Example 4 was dissolved in 6 ml of dry tetrahydrofuran to obtain a chiral camphorsulfonic acid derivative solution;
[0092] Add 5 ml of dry tetrahydrofuran to a 100 ml three-necked flask, cool to -40 to -30 °C under nitrogen protection, add 0.8 ml of 1 mol / l sodium hexamethyldisilazide tetrahydrofuran solution, then drop 5-chloro-2-methoxycarbonyl-1-indanone ester solution, add over 5 min, heat to -5 to 5 °C, keep warm and stir for 40 min, then cool to -40 to -30 °C, drop chiral camphorsulfonic acid derivative solution, add over 20 min, keep warm and react for 3 h;
[0093] Then, 6 ml of saturated aqueous ammonium chloride solution was added, and solid precipitated. 20 ml of methyl tert-butyl ether was added, and the temperature was raised to 20-30° C., and the solid dissolved. The mixture was allowed to stand for separation, and the organic phase was taken. The aqueous phase was extracted twice with methyl tert-butyl ether, and the amount of methyl tert-butyl ether used each time was 10 ml. The organic phases were combined, and washed twice with saturated aqueous sodium thiosulfate solution (each time with 10 ml), and then washed twice with saturated brine (each time with 10 ml). The organic phase was then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (2S)-5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester, with a yield of 87% and a chiral purity of 98.5%.
[0094] The (2S)-5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylic acid methyl ester prepared above was tested. 1 The results of HNMR are as follows Figure 1 As shown: 1 H NMR (600MHz, DMSO-d6) δ7.79–7.69(m,2H),7.56(dd,J=8.3,1.8Hz,1H),6.77(s,1H),3.68–3.60(m,4H),3.11(d,J=17.7Hz,1H).
[0095] Example 6
[0096] The "chiral camphorsulfonic acid derivative prepared in Example 4" in Example 5 is replaced by the structural formula: The substance was used as a catalyst in the same molar amount as in Example 5. The corresponding chiral α-hydroxy ketone was prepared according to the method in Example 5, and the yield and chiral purity of each product were calculated. The results are shown in Table 1.
[0097] Table 1 Results of yield and chiral purity
[0098]
[0099] It can be seen from the results in Table 1 that when the chiral camphorsulfonic acid derivatives of the present invention are used to prepare the chiral α-hydroxy ketones of the structure of the present invention, a higher yield and chiral purity are achieved.
[0100] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A chiral camphorsulfonic acid derivative, characterized in that: Its structural formula is shown in formula (I):
2. A method for preparing a chiral camphorsulfonic acid derivative as claimed in claim 1, characterized in that: The steps include: S1, subjecting D(+) camphorsulfonic acid to an acyl chlorination reaction with a chlorinating agent to obtain D(+) camphorsulfonyl chloride; then mixing D(+) camphorsulfonyl chloride with an organic solvent and aqueous ammonia to react to obtain an intermediate C1; S2, mixing the intermediate C1 with sodium methoxide and an organic solvent, reacting, and purifying to obtain the intermediate C2; S3, under the protection of inert gas, at -35 to -25°C, mix the intermediate C2, the organic solvent, and the diazotizing agent to obtain solution 1; mix N-chlorosuccinimide and the organic solvent, and under the protection of inert gas, dropwise add solution 1 at -35 to -25°C to react, and purify to obtain intermediate C3; S4, mixing the intermediate C3, an acid condensing agent, an oxidizing agent, water and an organic solvent, reacting, and purifying to obtain a chiral camphorsulfonic acid derivative; Among them, the structural formulas of intermediate C1, intermediate C2 and intermediate C3 are as follows:
3. The method for preparing a chiral camphorsulfonic acid derivative according to claim 2, characterized in that: In S1, the chlorinating agent is thionyl chloride; preferably, in S1, the molar ratio of D(+) camphorsulfonic acid to the chlorinating agent is 1:2.5-3.5; preferably, in S1, the temperature of the chlorination reaction is 45-55°C, and the reaction time is 2.5-3.5h; preferably, in S1, the mass fraction of ammonia water is 22-25wt%; preferably, in S1, the ratio of D(+) camphorsulfonic acid to ammonia water is 1g:10-20ml; preferably, in S1, D(+) camphorsulfonyl chloride is mixed with an organic solvent and ammonia water, the reaction temperature is -5 to 5°C, and the reaction time is 2.5-3.5h; preferably, in S1, the organic solvent is dichloromethane.
4. The method for preparing the chiral camphorsulfonic acid derivative according to claim 2 or 3, characterized in that: In S2, the intermediate C1, sodium methoxide and an organic solvent are mixed at 5-10°C with stirring for 1.5-2.5h; preferably, in S2, the reaction temperature is 35-45°C, and the reaction time is 20-24h; preferably, in S2, the molar ratio of the intermediate C1 to sodium methoxide is 1:1.2-1.3; preferably, in S2, the organic solvent is methanol; preferably, in S2, the specific steps of purification include: cooling and crystallization, and solid-liquid separation to obtain the intermediate C2.
5. The method for preparing the chiral camphorsulfonic acid derivative according to any one of claims 2 to 4, characterized in that: In S3, the diazotizing agent is sodium hexamethyldisilazide; preferably, in S3, the reaction temperature is -5 to 5°C, and the reaction time is 2.5-3.5h; preferably, in S3, the molar ratio of intermediate C2, diazotizing agent, and N-chlorosuccinimide is 1:2.1-2.2:2.5; preferably, in S3, the organic solvent is tetrahydrofuran; preferably, in S3, the specific steps of purification include: adding water to the reaction solution for precipitation treatment, then heating to 20-30°C, dissolving the precipitate in the organic solvent, concentrating and drying the organic phase to obtain a solid, dissolving the solid with dichloromethane, washing the solution with aqueous hydrochloric acid, water, and saturated brine in sequence, and concentrating and drying the organic phase to obtain the intermediate C3.
6. The method for preparing the chiral camphorsulfonic acid derivative according to any one of claims 2 to 5, characterized in that: In S4, the acid-contracting agent is potassium carbonate; preferably, in S4, the oxidant is 3-chloroperoxybenzoic acid; preferably, in S4, the molar ratio of the intermediate C3, the acid-contracting agent and the oxidant is 1:4.5-5.5:1.4-1.6; preferably, in S4, the reaction temperature is room temperature and the reaction time is 16-20h; preferably, in S4, the organic solvent is dichloromethane; preferably, in S4, the specific steps of purification include: adding sodium thiosulfate and mixing, taking the organic phase, concentrating and drying to obtain a crude product; and recrystallizing the crude product with ethanol to obtain a chiral camphorsulfonic acid derivative.
7. Use of a chiral camphorsulfonic acid derivative as claimed in claim 1 as a catalyst in the asymmetric synthesis of chiral α-hydroxy ketone; wherein: The structural formula of chiral α-hydroxy ketone is shown in formula (II): R1 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R2 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R3 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R4 is an alkyl group, an alkoxy group, a carboxyl group or an ester group; n is 1 or 2; "*" indicates a chiral center.
8. A method for asymmetric synthesis of α, characterized in that: The method comprises the following steps: under the protection of an inert gas, mixing sodium hexamethyldisilazide, a chiral precursor and an organic solvent, reacting at -5 to 5°C, then adjusting the temperature to -40 to -30°C, adding the chiral camphorsulfonic acid derivative as claimed in claim 1, keeping the temperature to react, and purifying to obtain a chiral α-hydroxy ketone; Wherein, the chiral precursor structure is shown in formula (III); R1 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R2 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R3 is a hydrogen atom, a halogen, an alkyl group, an alkoxy group or a cycloalkyl group; R4 is an alkyl group, an alkoxy group, a carboxyl group or an ester group; n is 1 or 2.
9. The method for asymmetric synthesis of chiral α-hydroxy ketone according to claim 8, characterized in that: The reaction is carried out at -5 to 5°C for 30 to 50 minutes; preferably, the reaction is carried out at a temperature of -40 to -30°C with heat preservation for 2.5 to 3.5 hours; preferably, sodium hexamethyldisilazide, a chiral precursor and an organic solvent are mixed at -40 to -30°C.
10. The method for asymmetric synthesis of chiral α-hydroxy ketone according to claim 8 or 9, characterized in that: The molar ratio of the chiral precursor, sodium hexamethyldisilazide and the chiral camphorsulfonic acid derivative is 1:1.1-1.3:1.1-1.3; preferably, the organic solvent is tetrahydrofuran; preferably, the specific steps of purification include: after the reaction is completed by heat preservation, adding saturated ammonium chloride aqueous solution for crystallization, adding methyl tert-butyl ether to dissolve the crystals, taking the organic phase, concentrating and drying to obtain the chiral α-hydroxy ketone.