CN103553931A - Method for synthesizing chiral diketone compound - Google Patents

Abstract

The invention discloses a method for synthesizing chiral diketone compounds. The method comprises: using the compound shown in formula I as a catalyst, mixing it with a strong acid in an organic solvent, distilling off the solvent, and mixing the resulting mixture with a weak acid, 1,3-diketone shown in formula IV and α,β- The unsaturated ketone is mixed to carry out the Robinson reaction, and the compound represented by the formula III is obtained after the reaction is completed. The catalyst used in the method has the advantages of simple structure, short synthesis route, simple synthesis method and easy operation. The chiral diketone compound synthesized by the catalyst has high yield and enantioselectivity, and the synthesis method adopts a one-step, solvent-free synthesis, which greatly reduces the synthesis cost and synthesis period, is environmentally friendly, and is easy to scale up. Large-scale production, and the yield and enantioselectivity can be maintained after scale-up.

Description

Method for synthesizing chiral diketones

technical field

The invention belongs to the technical field of organic synthesis, and relates to a method for synthesizing chiral diketone compounds.

Background technique

In the early 1970s, Hajos et al. and Eder et al. independently developed L-proline (L-proline)-catalyzed asymmetric cyclization reactions of triketones 2a and 2b (2a and 2b were composed of 1a and 1b respectively reacted with methyl vinyl ketone), stereoselectively generate bicycloketene 3a and 3b, which is the well-known Hajos-Parrish-Eder-Sauer-Wiechert reaction (as shown in Figure 3). Usually, the reaction product of five-membered ring and six-membered ring bicycloketene is called Hajos-Parrish ketone (3a, referred to as H-P ketone), and the six-membered ring and six-membered ring bicycloketene is called Wieland-Miechert Ketones (3b, referred to as W-M ketones).

Chiral bicycloenones are very useful synthetic building blocks and have important applications in the total synthesis of many natural products, especially terpenoids and steroids. For example, Danishefsky synthesized the paclitaxel skeleton, YamamotoH. used W-M ketone and its analogues in the process of synthesizing the platymycin carbon skeleton, and recently when Bonjoch J. and Bradshaw B. et al. synthesized (-)-Anominine Synthetic blocks.

Synthesis of H-P ketones can achieve ideal results with proline catalysis, but synthesis of W-M ketones can only give moderate yield and enantioselectivity (70-75%ee) with proline catalysis. In order to obtain enantiomerically pure W-M ketone, subsequent multi-stage recrystallization is generally required, which is cumbersome and uneconomical. In addition, due to the need to use high-boiling polar aprotic solvents such as DMF and DMSO in the traditional method, the post-reaction treatment is also relatively troublesome, and due to the low catalytic activity of proline, the reaction needs to be heated, and the reaction time is long. The efficiency is very low, all of which do not meet the requirements of modern green chemistry.

In the last ten years, many new chiral organic small molecule catalysts for the synthesis of H-P ketones and W-M ketones have been reported successively, and their stereoselectivity and catalytic activity have been greatly improved compared with proline. However, most of these methods also have the following defects: first, the structure of the chiral catalyst is complex, and the synthetic route is relatively long; secondly, the amount of the chiral catalyst is too large (most of which are above 10mol%), and the cost is high; thirdly, the synthesis of H-P Ketones and W-M ketones require multi-step reactions and multiple purification operations, and the synthesis process requires a large amount of organic solvents. These defects are the key factors restricting its industrial production. Therefore, looking for a chiral catalyst with simple structure, high catalytic efficiency, and good enantioselectivity and exploring a one-step method (that is, direct catalytic synthesis of 3a, 3b from 1a, 1b), solvent-free green synthesis of H-P ketones, W-M ketones The synthetic method is of great significance.

Contents of the invention

The purpose of the present invention is to provide a method for synthesizing chiral diketones.

The present invention firstly provides a catalyst used in the synthesis of chiral diketone compounds, namely the compound shown in formula I,

In the formula I, R ₃ , R ₄ and R ₅ are all selected from any one of the following groups: hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert Butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indolyl;

n ₂ is an integer of 1-9, specifically, n ₂ is 1;

Specifically, the compound shown in the formula I is

The method for preparing the compound represented by the formula I provided by the present invention comprises the following steps: reflux the compound represented by the formula II and a reducing agent in an organic solvent for a reduction reaction, and obtain the compound represented by the formula I after the reaction is completed;

In the formula II, the definitions of R ₃ , R ₄ , and R ₅ are the same as the definitions of R ₃ , R ₄ , and R ₅ in formula I, respectively;

n ₃ is an integer of 0-9.

Specifically, the compound represented by the formula II is

In the formula II, _n3 is specifically 0;

In the above method, the reducing agent is selected from at least one of lithium aluminum hydride, red aluminum solution, B ₂ H ₆ , NaBH(CH ₃ COO) ₃ , sodium aluminum hydride and potassium aluminum hydride;

The molar ratio of the compound represented by the formula II, the reducing agent and the organic solvent is 1:2-4:5-10, specifically 1:3:10;

In the reduction reaction step, the time is 1-4 hours;

The organic solvent is at least one selected from tetrahydrofuran, dichloromethane, ether, acetonitrile, toluene and benzene.

A method for preparing a chiral diketone compound represented by formula III provided by the present invention comprises the following steps: using the aforementioned compound represented by formula I provided by the present invention as a catalyst, mixing it with a strong acid in an organic solvent, and distilling off the solvent Mix the obtained mixture with weak acid, 1,3-diketone represented by formula IV and α,β-unsaturated ketone represented by formula V to perform Robinson reaction, and the compound represented by formula III is obtained after the reaction is completed;

In the formula _III , R and R are selected from any _one of the following groups: hydrogen atom, methyl, ethyl, propyl, allyl, propargyl, butyl, benzyl, benzene Base, pyridyl, thienyl, imidazolyl, furyl and indolyl;

n ₁ is an integer of 0-5;

In the formula IV, R _is selected from any one of the following groups: hydrogen atom, methyl, ethyl, propyl, allyl, propargyl, butyl, benzyl, phenyl, pyridyl , thienyl, imidazolyl, furyl and indolyl; n ₁ is an integer of 0-5;

In the formula V, R ₇ , R ₈ and R ₉ are all selected from any one of the following groups: hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert Butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl, indolyl.

In the above method, in the formula III and formula IV, n ₁ is specifically 1, 2 or 1-2;

The strong acid is selected from trifluoroacetic acid, trichloroacetic acid, acetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid containing substituents, tetrafluoroboric acid, tetraarylboronic acid, hexafluorophosphoric acid, At least one of hydrochloric acid, sulfuric acid, nitric acid, perchloric acid and hypochlorous acid;

Wherein, in the benzenesulfonic acid containing substituents, the substituents are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, nitro, hydroxyl, amine At least one of radical, fluorine atom, chlorine atom, bromine atom, iodine atom;

The weak acid is selected from at least one of benzoic acid, naphthoic acid, benzoic acid containing substituents and naphthoic acid containing substituents, specifically m-nitrobenzoic acid;

In the benzoic acid and naphthoic acid containing substituents, the substituents are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, nitro, hydroxyl, amine group, fluorine atom, chlorine atom, bromine atom and iodine atom.

In the above method, the molar ratio of the compound represented by the formula I, the strong acid and the weak acid is 1:0.5-2:0.1-2, specifically 1:1:0.5;

The molar ratio of 1,3-diketone represented by formula IV to α,β-unsaturated ketone represented by formula V is 1:1-5, specifically 1:1.2 or 1:1.5 or 1:1.2-1.5;

The compound shown in formula I is 0.5-10% of the molar dosage of 1,3-diketone shown in formula IV, specifically 2%;

In the Robinson reaction, the temperature is 20°C-100°C, specifically 60°C; the time is 1-6 days, specifically 2 days, 3 days, 5 days or 2-5 days.

Specifically, the 1,3-diketone shown in formula IV is

The α,β-unsaturated ketone represented by the formula V is methyl vinyl ketone

The compound shown in formula III is any one of the following compounds:

Compared with the prior art, the present invention has the following advantages:

1. The structure of the catalyst used in the present invention is simple, the synthesis route is short, the synthesis method is simple and easy to operate, and the obtained chiral bicycloketene compounds have higher yield and enantioselectivity;

2. The method for synthesizing chiral bicycloketene involved in the present invention adopts one-step synthesis, which greatly reduces the synthesis cost and synthesis cycle;

3. In the synthesis method of the catalyst involved in the present invention and the final product, these methods such as vacuum distillation, recrystallization and extraction are used for purification, and the operation is simple and efficient;

4. The amount of catalyst used in the synthetic method involved in the present invention can be reduced to 2mol%, the catalytic efficiency is high, the enantioselectivity is good, and the production cost is effectively reduced;

5. The present invention adopts a solvent-free synthesis method, which is environmentally friendly;

6. The method involved in the present invention is easy for large-scale production, and the yield and enantioselectivity can be maintained after amplification.

Description of drawings

Figure 1 is the ¹ H NMR of compound 8.

Fig. 2 is the ¹³ C NMR of compound 8.

Figure 3 is the Hajos-Parrish-Eder-Sauer-Wiechert reaction equation.

Detailed ways

The present invention will be further described below in conjunction with specific examples, but the present invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The raw materials can be obtained from open commercial channels unless otherwise specified.

The reactant compound 7 used in the following embodiment 1 is prepared according to the following steps:

1) Add sodium hydroxide, L-tert-leucine, and water into the reactor at a molar ratio of 1:1:5 to 1:1:10, and then add (Boc ) ₂ O was dissolved in 5-10 times of 1,4-dioxane, slowly dropped into the reactor, and stirred at room temperature for 2-12 hours after the drop was completed. Concentrate the solvent to half, add ethyl acetate of equal volume to the concentrated reaction solution, then add 4 mol/L hydrochloric acid half of the volume of ethyl acetate, separate the layers, wash the organic phase once with an equal volume of water, and dry over anhydrous sodium sulfate The solvent was evaporated to obtain compound 5.

2) Add compound 5 and dry dichloromethane into the reactor at a molar ratio of 1:5 to 1:10, and then slowly add DCC (N,N'-di Cyclohexylcarbodiimide) dichloromethane solution, and then add diethylamine in an equimolar amount to compound 5 after dropping, and stir at room temperature for 2 to 12 hours after dropping. The white precipitate was removed by filtration, and the organic phase was washed with 2% hydrochloric acid, 4% sodium bicarbonate, and saturated brine respectively, dried over anhydrous sodium sulfate, and evaporated to obtain compound 6.

3) Add compound 6 and anhydrous methanol into the reactor at a molar ratio of 1:5 to 1:10, then slowly add acetyl chloride 1 to 5 times the molar amount of compound 6 dropwise, heat and reflux for 1 to 5 hours and then evaporate Solvent, then add dichloromethane and water equal to the volume of methanol, adjust the pH value of the aqueous phase to weak alkalinity with potassium carbonate, and separate the organic phase. An equal volume of water was added to the organic phase, and the pH value of the aqueous phase was adjusted to weak acidity with dilute hydrochloric acid, and then the aqueous phase was separated. An equal volume of dichloromethane was added to the aqueous phase, and the pH value of the aqueous phase was adjusted to weak alkaline with potassium carbonate, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound 7.

Embodiment 1, preparation of the compound shown in formula I (ie compound 8)

The reaction process is as follows:

Compound 7 (n ₃ =0, R ₃ is tert-butyl, R ₄ and R ₅ are both ethyl) and dry tetrahydrofuran are added to the reactor at a molar ratio of 1:10, and then In an ice-water bath, the reducing agent lithium aluminum hydride, which is 3 times the molar amount of compound 7, is heated to reflux for reduction reaction for 4 hours and then cooled to room temperature. Under an ice-water bath, add a saturated aqueous solution of sodium sulfate with half the volume of tetrahydrofuran dropwise. After the addition, filter to remove the precipitate. Compound 8 shown in formula I is obtained;

Its NMR data are as follows (the spectrograms are shown in Figures 1 and 2): ¹ H NMR(300MHz, CDCl ₃ ):2.67-2.53(m,3H),2.45-2.34(m,3H),2.15-2.07(m, 1H),1.49(br,2H),0.99(t,J=6.90Hz,6H),0.89(s,9H); ¹³ C NMR(75MHz,CDCl ₃ ):57.4,55.6,47.5,33.2,26.4,12.2 .

Specific rotation[α] _D ²⁰ =+124.1(c=0.50,MeOH).

It can be seen from the above that the product has a correct structure and is a compound belonging to formula I, wherein _n2 is 1, _R3 is tert-butyl, and _R4 and _R5 are both ethyl groups.

Example 2

1) Dissolve 1,3-cyclohexanedione (150mmol) in aqueous sodium hydroxide solution (5M, 30mL), add iodomethane (200mmol), and heat to 65°C for 24h. After cooling, the resulting white solid was filtered to obtain 2-methyl-1,3-cyclohexanedione (n ₁ is 2, R ₆ is methyl) belonging to formula IV, with a yield of 65%.

2) Add 2-methyl-1,3-cyclohexanedione (50mmol) and methyl vinyl ketone belonging to formula V (R ₇ and R ₉ are both methyl groups, R ₈ is a hydrogen atom) (60mmol) In the reactor, the catalyst compound 8 (1mmol) prepared in Example 1 was dissolved with 1ml of organic solvent dichloromethane, and the strong acid trifluoromethanesulfonic acid (1mmol) was added dropwise, and the catalyst was added to the reactor after distilling off the dichloromethane Add the weak acid m-nitrobenzoic acid (0.5mmol) at the end, heat to 60°C, and carry out Robinson reaction with mechanical stirring for 3 days. After the reaction is complete, use an oil pump to distill under reduced pressure to obtain WM ketone, with a yield of 83% and an ee value of 90%. .

The NMR data of WM ketone are as follows: ¹ H NMR (300MHz, CDCl ₃ ): δ (ppm) = 5.83 (s, 1H), 2.65-2.76 (m, 2H), 2.41-2.52 (m, 4H), 2.08-2.17 ( m,3H),1.69(m,1H),1.43(s,3H); ¹³ CNMR(100MHz,CDCl ₃ ):211.0,198.3,165.8,125.8,50.6,37.6,33.6,31.7,29.6,23.3,22.9.

Its specific rotation [α] _D ²⁰ =-13 (c=0.5, CHCl ₃ ). Its ee value is determined by high performance liquid chromatography [DaicelChiralpak OD-H column, λ=254nm, 2-propanol:n-Hexane=3 :97,flow rate=0.8mL/min]:t _R =35.47min(minor),t _R =38.24min(major).

As can be seen from the above, the product has a correct structure and is the target compound shown in formula III, wherein R ₁ is methyl, R ₂ is hydrogen, and n ₁ is 2.

Example 3

1) Dissolve 1,3-cyclopentanedione (20mmol) in aqueous sodium hydroxide solution (5M, 4mL), add tetrabutylammonium bromide (2mmol) and methyl iodide (40mmol), heat to 65°C for 24h . After cooling, add dilute hydrochloric acid (15mL), extract three times with ethyl acetate (15mL×3), dry over anhydrous sodium sulfate, evaporate the solvent and perform column chromatography to obtain 2-methyl-1,3-cyclo Pentanedione (n ₁ is 1, R ₆ is methyl), yield 45%.

2) Combine 2-methyl-1,3-cyclopentadione (10mmol) obtained in step 1) and methyl vinyl ketone belonging to formula V (R ₇ and R ₉ are both methyl groups, R ₈ is a hydrogen atom) (15mmol) was added in the reactor, then the catalyst compound 8 (0.2mmol) prepared in Example 1 was dissolved with 0.5ml dichloromethane, dripped into trifluoromethanesulfonic acid (0.2mmol), and the dichloromethane was evaporated Add the catalyst into the reactor, add m-nitrobenzoic acid (0.1mmol) at the end, heat to 60°C, and carry out Robinson reaction with magnetic stirring for 5 days. After the reaction is complete, use petroleum ether: ethyl acetate = 2:1 column chromatography to obtain HP ketone, yield 80%, ee value 76%.

The NMR data of HP ketone are as follows: ¹ H NMR (300MHz, CDCl ₃ ): δ(ppm)=5.96(s,1H),3.05-2.92(m,1H),2.86-2.75(m,2H),2.60-2.38( m,3H),2.20-2.09(m,1H),1.91-1.80(m,1H),1.34(s,3H); ¹³ C NMR(100MHz,CDCl ₃ ):216.4,198.0,169.7,123.8,48.6, 35.8, 32.9, 29.2, 26.8, 20.5.

Its specific rotation [α] _D ²⁰ =-150 (c=0.5, CHCl ₃ ). Its ee value is determined by high performance liquid chromatography [DaicelChiralpak AD-H column, λ=254nm, 2-propanol:n-Hexane=1 :9,flow rate=1.0mL/min]:t _R =10.09min(minor),t _R =10.53min(major).

As can be seen from the above, the product has a correct structure and is the target compound shown in formula III, wherein R ₁ is methyl, R ₂ is hydrogen, and n ₁ is 1.

Example 4

1) Dissolve 1,3-cyclohexanedione (20mmol) in aqueous sodium hydroxide solution (5M, 4mL), add copper powder (0.1g) and allyl bromide (24mmol), stir at room temperature for 8h and filter, and the resulting precipitate Dissolved with methanol and then filtered to remove copper powder, evaporated to remove methanol and then column chromatography to obtain a white solid that is 2-allyl-1,3-cyclohexanedione belonging to formula IV (n ₁ is 2, R ₆ is Allyl), yield 54%.

2) 2-allyl-1,3-cyclohexanedione (10mmol) and methyl vinyl ketone belonging to formula V (R ₇ and R ₉ are both methyl groups, R ₈ is a hydrogen atom) (12mmol) Add in the reactor, then dissolve the catalyst compound 8 (0.2mmol) prepared in Example 1 with 0.5ml of dichloromethane, drop trifluoromethanesulfonic acid (0.2mmol), and add the catalyst to the reaction after distilling off the dichloromethane Finally, add m-nitrobenzoic acid (0.1mmol), heat to 60°C, and perform Robinson reaction with mechanical stirring for 3 days. After the reaction is complete, use petroleum ether: ethyl acetate = 2:1 column chromatography to obtain the target product. Yield 84%, ee value 88%.

¹ H NMR (300MHz, CDCl ₃ ): δ(ppm)=5.90(s,1H),,5.89-5.54(m,1H),5.16(d,J=16.0Hz,1H),5.12(d,J= 8.5Hz,1H,),2.81-2.38(m,8H),2.25-1.99(m,3H),1.76-1.66(m,1H); ¹³ C NMR(75MHz,CDCl ₃ ):δ(ppm)=209.1 ,198.2,164.9,131.6,126.5,119.5,54.7,39.9,38.4,33.3,31.9,26.2,23.3.

Its specific rotation [α] _D ²⁰ =-43 (c=0.5, CHCl3). Its ee value is determined by high performance liquid chromatography [DaicelChiralpak OD-H column, λ=254nm, 2-propanol:n-Hexane=1: 19, flow rate=1.0mL/min]:t _R =14.89min(major),t _R =16.29min(minor).

It can be known from the above that the product has a correct structure and is the target compound shown in formula III, wherein R ₁ is -CH ₂ CH=CH ₂ , R ₂ is hydrogen, and n ₁ is 2.

Example 5

1) Dissolve 1,3-cyclohexanedione (20mmol) in methanol (20mL), add sodium methoxide (20mmol) and propargyl bromide (24mmol), and heat to 60°C for 24h. After cooling, distill off methanol, add water (15mL), extract three times with dichloromethane (15mL×3), dry over anhydrous sodium sulfate, evaporate the solvent and perform column chromatography to obtain 2-propargyl-1 of formula IV , 3-cyclohexanedione (n ₁ is 2, R ₆ is propargyl), the yield is 42%.

2) Mix 2-propargyl-1,3-cyclohexanedione (10mmol) and methyl vinyl ketone belonging to formula V (R ₇ and R ₉ are both methyl groups, R ₈ is a hydrogen atom) (12mmol) Add in the reactor, then dissolve the catalyst compound 8 (0.2mmol) prepared in Example 1 with 0.5ml of dichloromethane, drop trifluoromethanesulfonic acid (0.2mmol), and add the catalyst to the reaction after distilling off the dichloromethane Finally, add m-nitrobenzoic acid (0.1mmol), heat to 60°C, and carry out Robinson reaction with magnetic stirring for 3 days. After the reaction is complete, use petroleum ether: ethyl acetate = 2:1 column chromatography to obtain the target product. Yield 81%, ee value 92%.

¹ H NMR (300MHz, CDCl ₃ ): δ=5.92(d, J=1.6Hz, 1H), 2.82-2.66(m, 4H), 2.58-2.45(m, 4H), 2.35(dt, J=14.4, 4.6Hz,1H),2.20-2.10(m,3H),1.72(qt,J=13.4,4.4Hz,1H); ¹³ C NMR(100MHz,CDCl ₃ ):δ=208.0,197.8,163.0,127.3,78.0 ,73.3,53.5,38.1,33.5,31.9,27.3,26.1,23.2.

Its specific rotation [α] _D ²⁰ =-18 (c=0.5, CHCl ₃ ). Its ee value is determined by high performance liquid chromatography [DaicelChiralpak AD-H column, λ=254nm, 2-propanol:n-Hexane=1 :9,flow rate=1.0mL/min]:t _R =13.05min(major),t _R =13.95min(minor).

It can be known from the above that the product has a correct structure and is the target compound shown in formula III, wherein R ₁ is -CH ₂ C≡CH, R ₂ is hydrogen, and n ₁ is 2.

Example 6

Add 2-methyl-1,3-cyclohexanedione (50mmol) and methyl vinyl ketone belonging to formula V ( _R7 and _R9 are both methyl groups, _R8 is a hydrogen atom) (60mmol) into the reactor , then dissolve the catalyst compound 8 (2.5mmol) obtained in Example 1 with 1ml of dichloromethane, drop trifluoromethanesulfonic acid (2.5mmol), and add the catalyst into the reactor after distilling off the dichloromethane, and finally Add m-nitrobenzoic acid (2.5mmol), stir at room temperature and carry out Robinson reaction for 10h. After the reaction is complete, use an oil pump to distill under reduced pressure to obtain WM ketone, with a yield of 85% and an ee value of 92%.

The structure confirmation result of this product is the same as that of Example 2, and will not be repeated here.

As can be seen from the above, the product has a correct structure and is the target compound shown in formula III, wherein R ₁ is methyl, R ₂ is hydrogen, and n ₁ is 2.

Example 7

Add 2-methyl-1,3-cyclohexanedione (1.0mol) and methyl vinyl ketone belonging to formula V ( _R7 and _R9 are both methyl groups, _R8 is a hydrogen atom) (1.2mol) In the reactor, the obtained catalyst compound 8 (20mmol) prepared in Example 1 was dissolved with 10ml of dichloromethane, and trifluoromethanesulfonic acid (20mmol) was added dropwise. After dichloromethane was evaporated, the catalyst was added to the reactor, and finally Add m-nitrobenzoic acid (10mmol), heat to 60°C, and mechanically stir for Robinson reaction for 2 days. After the reaction is complete, use an oil pump to distill under reduced pressure to obtain WM ketone, with a yield of 90% and an ee value of 90%. Recrystallize with a mixed solvent of ethyl acetate and n-hexane to obtain a product with an ee value greater than 99%.

The structure confirmation result of this product is the same as that of Example 2, and will not be repeated here.

As can be seen from the above, the product has a correct structure and is the target compound shown in formula III, wherein R ₁ is methyl, R ₂ is hydrogen, and n ₁ is 2.

Claims (10)

1. the compound shown in formula I,

In the formula I, R ₃ , R ₄ and R ₅ are all selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, phenyl, Any one of pyridyl, thienyl, imidazolyl, furyl and indolyl; n ₂ is an integer of 1-9. 2. The compound according to claim 1, characterized in that: the compound shown in the formula I is

3. A method for preparing the compound shown in the formula I described in claim 1 or 2, comprising the steps of: the compound shown in the formula II and the reducing agent are refluxed in an organic solvent to carry out a reduction reaction, and the reaction is completed to obtain the compound shown in the formula I ;

In the formula II, the definitions of R ₃ , R ₄ , and R ₅ are the same as the definitions of R ₃ , R ₄ , and R ₅ in formula I, respectively; n ₃ is an integer of 0-9. 4. The method according to claim 3, characterized in that: the compound shown in the formula II is

5. The method according to claim 3 or 4, characterized in that: the reducing agent is selected from lithium aluminum hydride, _red aluminum solution, _B2H6 , NaBH( _CH3COO ) ₃ , sodium aluminum hydride and aluminum hydride at least one of potassium; The molar ratio of the compound represented by the formula II, the reducing agent and the organic solvent is 1:2-4:5-10, specifically 1:3:10; In the reduction reaction step, the time is 1-4 hours; The organic solvent is at least one selected from tetrahydrofuran, dichloromethane, ether, acetonitrile, toluene and benzene. 6. A method for the compound shown in the preparation formula III, comprising the steps of: using the compound shown in the arbitrary formula I of claim 1 or 2 as a catalyzer, mixing it with a strong acid in an organic solvent, and distilling the resulting mixture after removing the solvent Mix with weak acid, 1,3-diketone shown in formula IV and α, β-unsaturated ketone shown in formula V to carry out Robinson reaction, and the compound shown in formula III is obtained after the reaction is completed;

In the formula _III , R and R are selected from any _one of the following groups: hydrogen atom, methyl, ethyl, propyl, allyl, propargyl, butyl, benzyl, benzene Base, pyridyl, thienyl, imidazolyl, furyl and indolyl; n ₁ is an integer of 0-5; In the formula IV, R _is selected from any one of the following groups: hydrogen atom, methyl, ethyl, propyl, allyl, propargyl, butyl, benzyl, phenyl, pyridyl , thienyl, imidazolyl, furyl and indolyl; n ₁ is an integer of 0-5;

In the formula V, R ₇ , R ₈ and R ₉ are all selected from any one of the following groups: hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert Butyl, benzyl, phenyl, pyridyl, thienyl, imidazolyl, furyl and indolyl. 7. The method according to claim 6, characterized in that: the strong acid is selected from trifluoroacetic acid, trichloroacetic acid, acetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid containing substituents At least one of acid, tetrafluoroboric acid, tetraarylboronic acid, hydrochloric acid, sulfuric acid, nitric acid, hexafluorophosphoric acid, perchloric acid and hypochlorous acid; Wherein, in the benzenesulfonic acid containing substituents, the substituents are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, nitro, hydroxyl, amine At least one of radical, fluorine atom, chlorine atom, bromine atom and iodine atom; The weak acid is selected from at least one of benzoic acid, naphthoic acid, benzoic acid containing substituents and naphthoic acid containing substituents, specifically m-nitrobenzoic acid; In the benzoic acid and naphthoic acid containing substituents, the substituents are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, nitro, hydroxyl, amine group, fluorine atom, chlorine atom, bromine atom and iodine atom. 8. The method according to claim 6 or 7, characterized in that: the molar ratio of the compound shown in formula I, strong acid and weak acid is 1:0.5-2:0.1-2, specifically 1:1:0.5 ; The molar ratio of 1,3-diketone represented by formula IV to α,β-unsaturated ketone represented by formula V is 1:1-5, specifically 1:1.2 or 1:1.5 or 1:1.2-1.5; The compound shown in formula I is 0.5-10% of the molar dosage of 1,3-diketone shown in formula IV, specifically 2%; In the Robinson reaction, the temperature is 20°C to 100°C, specifically 60°C; The time is 5 hours-6 days, specifically 10 hours, 2 days, 3 days, 5 days or 2-5 days. 9. The method according to any one of claims 6-8, characterized in that: the 1,3-diketone shown in the formula IV is 2-methyl-1,3-cyclopentanedione or 2-methyl -1,3-cyclohexanedione; or 2-allyl-1,3-cyclohexanedione, 2-propargyl-1,3-cyclohexanedione, 2-benzyl-1,3- Cyclohexanedione, 2-phenyl-1,3-cyclohexanedione; The α,β-unsaturated ketone represented by the formula V is methyl vinyl ketone or ethyl vinyl ketone. 10. The method according to any one of claims 6-9, characterized in that: the compound shown in formula III is any one of the following compounds:

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