Alpha hydroxyl beta keto ester compound and asymmetric hydrogenation preparation method thereof

Abstract

The invention relates to the technical field of organic chemistry, and particularly discloses an alpha hydroxyl beta keto ester compound and an asymmetric hydrogenation preparation method thereof.The asymmetric hydrogenation preparation method comprises the steps that in the presence of a chiral ligand f-phamidol and a metal precursor complex catalyst, a compound shown in the structural formula I reacts with hydrogen to obtain a key chiral intermediate II compound, and the key chiral intermediate II compound is subjected to asymmetric hydrogenation to obtain the alpha hydroxyl beta keto ester compound. According to the method, the specific chiral tetradentate phosphine ligand and metal iridium are adopted to form the catalyst to be applied to asymmetric hydrogenation of ketone, the reaction obtains excellent reaction activity under the condition of high conversion number, and the method has the advantages that the raw materials are cheap and easy to obtain, the operation steps are simple, the yield is high, and the method is suitable for industrial production. And the method has the advantages of high catalytic efficiency, high yield, high product enantioselectivity and the like.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric catalysis, and specifically provides an alpha hydroxy beta ketoate compound and an asymmetric hydrogenation preparation method thereof. Background Art

[0002] Chiral compounds are widely found in natural products, bioactive molecules, and clinical drug molecules (or their key intermediates). In the field of new drug research, 820 of the more than 1,200 drugs under development are chiral molecules, accounting for nearly 70%. Chiral drug research has been very rapid in recent years, and major drug research and development companies have developed small molecule drugs. The proportion of single chiral compounds has gradually increased. The importance of chiral research is self-evident. Among all chiral compounds, chiral alcohols belong to a common class of chiral molecules, which are widely used in the fields of small molecule drugs, pesticides, natural compounds and functional materials. The asymmetric hydrogenation reaction catalyzed by organometallics has the advantages of mild reaction conditions, high efficiency and selectivity, and a wide range of substrates, and has received extensive attention and in-depth research. Summary of the invention

[0003] The object of the present invention is to provide an α-hydroxy β-ketoate ester compound and a method for preparing the same by asymmetric hydrogenation. The synthesis method provided by the present invention has the advantages of easy availability of raw materials, good substrate applicability, and excellent reaction activity and enantioselectivity at a higher conversion number. During the reaction process, the method exhibits excellent reaction activity and enantioselectivity, and has broad application prospects.

[0004] To achieve the above-mentioned object, the first aspect of the present invention provides an α-hydroxy β-ketoate ester compound, as shown in the general formula II,

[0005]

[0006] R 1 , R 2 are independently substituted or unsubstituted alkyl;

[0007] R 3 is selected from hydrogen or hydroxyl;

[0008] Ar is selected from substituted or unsubstituted aryl;

[0009] The carbon atom marked with * is of R configuration or S configuration, or an achiral carbon atom.

[0010] In a specific embodiment of the first aspect of the present invention, Ar is selected from an aromatic group, and any H on the aromatic group is replaced by R a Substitution, the R a Each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, and / or, said R 1 , R 2Any H on R b Substitution, the R b is selected from substituted or unsubstituted aryl groups.

[0011] In a specific embodiment of the first aspect of the present invention, at least two H on Ar are replaced by R a Substitution, the R a The atoms connected to it form a ring with a structure like

[0012] The second aspect of the present invention provides an α-hydroxy β-ketoate compound as follows:

[0013]

[0014] The third aspect of the present invention provides a method for synthesizing a compound represented by general formula II, comprising:

[0015] In the presence of a catalyst, the compound represented by formula I is fully mixed with a catalyst and an organic solvent to form a reaction system, and a compound represented by formula II is obtained under a hydrogen atmosphere;

[0016] The reaction formula is as follows:

[0017]

[0018] In Formula I and Formula II, R 1 , R 2 are independently substituted or unsubstituted alkyl;

[0019] Ar is selected from substituted or unsubstituted aryl;

[0020] The catalyst is obtained by complexing a ligand with a transition metal precursor, and the ligand of the catalyst has the following structural formula:

[0021]

[0022] In some specific embodiments of the third aspect of the present invention, the R 1 , R 2 are independently substituted or unsubstituted C 1-6 alkyl.

[0023] In some specific embodiments of the third aspect of the present invention, the R 1 Any H on R c Substitution, the R c is selected from substituted or unsubstituted aryl groups.

[0024] In some specific embodiments of the third aspect of the present invention, Ar is selected from an aromatic group, and any H on the aromatic group is replaced by R d Substitution, the R dEach is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, and hydroxy.

[0025] In some specific embodiments of the third aspect of the present invention, at least two H on the aromatic group are replaced by R d Substitution, the R a The atoms connected to it form a ring with a structure like

[0026] In some specific embodiments of the third aspect of the present invention, the R d is selected from alkyl groups, wherein R d Any H is replaced by halogen.

[0027] In some specific embodiments of the third aspect of the present invention, the R d is selected from an alkoxy group, wherein the H on the alkoxy group is substituted by an aryl group.

[0028] In some specific embodiments of the third aspect of the present invention, the compound represented by formula II is selected from the following compounds:

[0029]

[0030] In some specific embodiments of the third aspect of the present invention, the transition metal precursor is [Ir(COD)Cl] 2 、[Ir(COD) 2 ] At least one of X; X includes Cl, Br, I, OH, BF 4 , SbF 6 PF 6 , OTf, B(Ar F ) 4 .

[0031] In some specific embodiments of the third aspect of the present invention, the hydrogen pressure is 10 to 90 atm. In some preferred embodiments of the third aspect of the present invention, the hydrogen pressure is 30 to 50 atm.

[0032] In some specific embodiments of the third aspect of the present invention, the organic solvent includes at least one of an alcohol solvent, ethyl acetate, and tetrahydrofuran, and the alcohol solvent includes at least one of methanol, ethanol, and isopropanol.

[0033] In some specific embodiments of the third aspect of the present invention, the reaction system also includes a base, and the base is selected from at least one of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium phosphate, and potassium phosphate.

[0034] In some specific embodiments of the third aspect of the present invention, the amount of the base used is 0.001 to 1.0 molar equivalent of the substrate represented by Formula I.

[0035] In some specific embodiments of the third aspect of the present invention, the amount of the catalyst is 0.00005 to 0.01 molar equivalents of the substrate shown in Formula I. In some preferred embodiments of the third aspect of the present invention, the amount of the catalyst is 0.0001 to 0.005 molar equivalents of the substrate shown in Formula I. In some more preferred embodiments of the third aspect of the present invention, the amount of the catalyst is 0.0001 to 0.001 molar equivalents of the substrate shown in Formula I.

[0036] In some specific embodiments of the third aspect of the present invention, the reaction temperature is 10-80°C. In some preferred embodiments of the third aspect of the present invention, the reaction temperature is 20-50°C.

[0037] The fourth aspect of the present invention provides a method for synthesizing a compound represented by formula III, characterized in that it comprises the following reaction formula:

[0038]

[0039] Ar, R 1 , R 2 As defined in any one of claims 1 to 4.

[0040] It should be noted that the main purpose of introducing inert gas into the reaction system in the present application is to form an anaerobic environment. If an anaerobic environment can be ensured, inert gas may not be used. In one implementation of the present application, even if inert gas is used, most of the entire reaction environment is still hydrogen, for example, more than 99% is hydrogen and the rest is inert gas.

[0041] The S1 compounds S1-d, S1-g, S1-i, S1-j, S1-k, S1-n, S1-o and S1-q in the present invention are as follows:

[0042]

[0043] The S2 compounds S2-1 and S2-2 in the present invention are as follows:

[0044]

[0045] In the present invention, I-a to I-r are as follows:

[0046]

[0047] In the present invention, II-a to II-r are as follows:

[0048]

[0049] In the present invention, III-b to III-g are as follows:

[0050]

[0051] Advantages of the present invention:

[0052] The present invention provides a method for asymmetric catalytic hydrogenation to reduce α-hydroxy β-ketoate derivatives, using a chiral ligand f-phamidol and a metal precursor complex catalyst to efficiently catalyze asymmetric hydrogenation to obtain a key chiral intermediate II. The key chiral intermediate II has high optical purity and can be used as an intermediate of many drug molecules. The chiral intermediate II is subjected to hydrosilylation reduction and dehydroxylation to obtain a chiral compound III, such as a chiral compound III-a. The chiral compound III is an important intermediate for the synthesis of many important drug molecules, such as Tesaglitazar. The chiral tetradentate phosphine ligand provided by the present invention forms a catalyst with metal iridium and is applied to the asymmetric hydrogenation of ketones. The reaction achieves excellent reaction activity at a high conversion number, has the advantages of cheap and readily available raw materials, simple operation steps, high catalytic efficiency, high yield, high product enantioselectivity, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 NMR hydrogen spectrum data of compound II-a;

[0054] Figure 2 NMR carbon spectrum data of compound II-a;

[0055] Figure 3 NMR hydrogen spectrum data of compound II-b;

[0056] Figure 4 NMR carbon spectrum data of compound II-b;

[0057] Figure 5 NMR hydrogen spectrum data of compound II-c;

[0058] Figure 6 NMR carbon spectrum data of compound II-c;

[0059] Figure 7 NMR hydrogen spectrum data of compound II-d;

[0060] Figure 8 NMR carbon spectrum data of compound II-d;

[0061] Fig. 9 NMR hydrogen spectrum data of compound II-g;

[0062] Fig.10 NMR carbon spectrum data of compound II-g;

[0063] Fig.11 NMR hydrogen spectrum data of compound II-i;

[0064] Fig.12 NMR carbon spectrum data of compound II-i;

[0065] Fig.13 NMR hydrogen spectrum data of compound II-k;

[0066] Fig.14 NMR carbon spectrum data of compound II-k;

[0067] Fig.15 NMR hydrogen spectrum data of compound II-n;

[0068] Fig.16 NMR carbon spectrum data of compound II-n;

[0069] Fig.17 NMR hydrogen spectrum data of compound II-o;

[0070] Fig.18 NMR carbon spectrum data of compound II-o;

[0071] Fig.19 NMR hydrogen spectrum data of compound II-q;

[0072] Fig. 20 Carbon NMR spectrum data of compound II-q;

[0073] Fig.21 High performance liquid chromatography spectrum of the chiral compound corresponding to compound II-a;

[0074] Fig. 22 High performance liquid chromatography spectrum of the racemic compound corresponding to compound II-a; DETAILED DESCRIPTION

[0075] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0076] Embodiment 1:

[0077]

[0078] Under the condition of -78℃ and argon protection, a solution of lithium diisopropylamide in tetrahydrofuran (LDA, 2.0M, 12mmol) was slowly dripped into a solution of S2-1 or S2-2 (10mmol) in anhydrous tetrahydrofuran (15mL), and stirred at low temperature for 1h. Keeping the low temperature condition at -78℃, one of S1-d, S1-g, S1-i, S1-j, S1-k, S1-n, S1-o, S1-q (12mmol) was added dropwise to the reaction system, and the reaction mixture was stirred for 5 hours and 1M NH 4 The reaction was quenched with Cl, and the resulting mixture was extracted with ethyl acetate (25 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The intermediate products Ⅰ-d, Ⅰ-g, Ⅰ-i, Ⅰ-j, Ⅰ-k, Ⅰ-n, Ⅰ-o, and Ⅰ-q were obtained by rapid column chromatography purification, as shown in Table 1, with a measured yield of %:

[0079] Table 1

[0080] Reactant 1 Reactant 2 product Yield (%) Group 1 S1-d S2-1 Ⅰ-d 77.3 Group 2 S1-g S2-1 Ⅰ-g 75.4 Group 3 S1-i S2-1 Ⅰ-i 70.8 Group 4 S1-j S2-1 Ⅰ-j 73.2 Group 5 S1-k S2-1 Ⅰ-k 74.0 Group 6 S1-n S2-1 Ⅰ-n 70.8 Group 7 S1-o S2-1 Ⅰ-o 69.2 Group 8 S1-q S2-2 Ⅰ-q 67.6

[0081] Embodiment 2:

[0082] First Synthesis Example of II-a

[0083] Under an inert gas atmosphere, 0.2 mmol of the compound shown in Ⅰ-a and 0.001 mmol of the metal precursor [Ir(COD)Cl] were added to the hydrogenation bottle. 2 , 0.002mmol of ligand f-phamidol, 0.002mmol of base (cesium carbonate), 1.0mL of solvent (ethyl acetate), and then transferred to a pressure autoclave. The inert gas in the reaction chamber is nitrogen, and more than 99% of the reaction atmosphere is hydrogen. The hydrogen pressure is set to 30atm, and the reaction is carried out at 25°C for 12h. Then, the hydrogen is slowly released, 10.0mL of dichloromethane is added for dilution, 8.0mL of water is used for quenching, the organic phase is separated, the aqueous phase is washed twice with 10.0mL of dichloromethane, and then the organic phases are combined, dried with anhydrous sodium sulfate, and concentrated to obtain a crude product, which is subsequently separated and purified by column chromatography to obtain a clean chiral alcohol shown in structural formula II-a.

[0084] pass 1 H NMR and 13 The structure of the hydrogenation product was determined by C NMR spectrum, the ee% value (enantioselectivity) of the product was determined by HPLC (high performance liquid chromatography), and the yield (yield%) was analyzed by hydrogen nuclear magnetic resonance spectrum. The results of nuclear magnetic resonance analysis showed that the product was a colorless oil with 98.7% yield, 98.5% ee, and 97:3 dr.

[0085]

[0086] The NMR data of product II-a is 1 H NMR (400 MHz, CDCl 3 )δ7.40–7.27(m,5H),5.02–4.94(m,1H),3.99(d,J=5.8Hz,1H),3.67(s,3H),3.37(s,3H),2.98(d,J=4.9Hz,1H).

[0087] 13 C NMR (101 MHz, CDCl 3 )δ169.8,138.3,127.2,127.1,125.5,83.4,73.0,57.9,50.9.

[0088] ee and dr were obtained by high performance liquid chromatography analysis. HPLC (Chiralpak IB column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 210 nm; t R =21.9min(anti),t R =26.8min(anti),t R =35.6min(syn),t R =53.3min(syn).

[0089] Embodiment 3:

[0090] Second Synthesis Example of II-a

[0091] Under an inert gas atmosphere, 0.005 mmol of the metal precursor [Ir(COD)Cl] 2 and 0.01 mmol of f-phamidol were dissolved in 5 mL of isopropanol solution and stirred at room temperature for 2 h until completely dissolved to obtain a catalyst solution.

[0092] Add 2.0 mmol of the compound shown in Ⅱ-a, 0.5 mL of the above catalyst solution, 0.1 mmol of cesium carbonate, and 3.0 mL of ethyl acetate to the hydrogenation bottle, and then transfer to a pressure autoclave. The reaction atmosphere is more than 99% hydrogen and the rest is nitrogen. Set the hydrogen pressure to 50 atm and react at 25°C for 48 hours. Then slowly release the hydrogen, add 30.0 mL of dichloromethane to dilute, quench with 20.0 mL of water, separate the organic phase, wash the aqueous phase twice with 30.0 mL of dichloromethane, then combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product, which is subsequently separated and purified by column chromatography to obtain a clean chiral alcohol shown in structural formula Ⅱ-a.

[0093] pass 1H NMR and 13 The structure of the hydrogenation product was determined by C NMR spectrum, the ee% value (enantioselectivity) of the product was determined by HPLC (high performance liquid chromatography), and the yield (yield%) was analyzed by hydrogen nuclear magnetic resonance spectrum. The results of nuclear magnetic resonance analysis showed that the product was a colorless oil with 99.2% yield, 98.4% ee, and 97:3 dr.

[0094]

[0095] The NMR data of product II-a is 1 H NMR (400 MHz, CDCl 3 )δ7.40–7.27(m,5H),5.02–4.94(m,1H),3.99(d,J=5.8Hz,1H),3.67(s,3H),3.37(s,3H),2.98(d,J=4.9Hz,1H).

[0096] 13 C NMR (101 MHz, CDCl 3 )δ169.8,138.3,127.2,127.1,125.5,83.4,73.0,57.9,50.9.

[0097] ee and dr were obtained by high performance liquid chromatography analysis. HPLC (Chiralpak IB column, hexane / isopropanol = 95 / 5; flow rate = 1.0 mL / min; UV detection at 210 nm; t R =21.9min(anti),t R =26.8min(anti),t R =35.6min(syn),t R =53.3min(syn).

[0098] Embodiment 4:

[0099] Synthesis of III-a

[0100] Under ice bath conditions, 1.0 mmol of chiral alcohol II-a, 5 ml of dichloromethane, and 6.0 mmol of trifluoroacetic acid were added to a 25 mL round-bottom flask in sequence. After stirring for 10 min, 2.0 mmol of triethylsilane was added to the system. Stirring was continued overnight at room temperature, 15 mL of saturated sodium bicarbonate solution was added, and extraction and separation were performed with 15 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain a clean chiral alcohol represented by structural formula III-a (92.1% yield).

[0101]

[0102] Embodiment 5:

[0103] Synthesis of chiral alcohols represented by structural formulas III-b to III-g

[0104] Under ice bath conditions, 1.0 mmol of one of the chiral alcohols II-b to II-g, 5 ml of dichloromethane, and 6.0 mmol of trifluoroacetic acid were added to a 25 mL round-bottom flask in sequence. After stirring for 10 min, 2.0 mmol of triethylsilane was added to the system. Stirring was continued overnight at room temperature, 15 mL of saturated sodium bicarbonate solution was added, and extraction and separation were performed with 15 mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to obtain a crude product. Subsequently, the clean chiral alcohols represented by the structural formulas III-b to III-g were obtained by column chromatography separation and purification. The yields were measured and shown in Table 2.

[0105] Table 2

[0106] Chiral alcohol Ⅱ Chiral alcohol III Yield % Group 9 Ⅱ-b Ⅲ-b 74.2 Group 10 Ⅱ-c Ⅲ-c 71.3 Group 11 Ⅱ-d Ⅲ-d 83.4 Group 12 Ⅱ-e Ⅲ-e 77.5 Group 13 Ⅱ-f Ⅲ-f 78.9 Group 14 Ⅱ-g Ⅲ-g 82.2

[0107] Embodiment 6:

[0108] (1) Synthesis of chiral alcohols represented by structural formula II-b to II-r

[0109] Under an inert gas atmosphere, 0.2 mmol of one of the compounds Ⅰ-b to Ⅰ-r shown in Table 3 and 0.001 mmol of the metal precursor [Ir(COD)Cl] were added to the hydrogenation bottle. 2 , 0.002mmol of ligand f-phamidol, 0.002mmol of base (cesium carbonate), 1.0mL of solvent (ethyl acetate), then transferred to a pressure autoclave, more than 99% of the reaction atmosphere is hydrogen, the rest is nitrogen, set the hydrogen pressure to 30atm, and react at 25°C for 12h. Then slowly release hydrogen, add 10.0mL of dichloromethane to dilute, quench with 8.0mL of water, separate the organic phase, wash the aqueous phase twice with 10.0mL of dichloromethane, then combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product, which is subsequently separated and purified by column chromatography to obtain clean chiral alcohols shown in structural formulas Ⅱ-b to Ⅱ-r.

[0110] pass 1 H NMR and 13 The structure of the hydrogenated product was determined by C NMR spectrum, the ee% value (enantioselectivity) and Dr value of the product were determined by HPLC (high performance liquid chromatography), and the yield (yield%) was analyzed by hydrogen nuclear magnetic resonance spectrum, as shown in Table 3.

[0111] Table 3 Analysis of asymmetric synthesis of II-b to II-q

[0112] Substrate type Chiral alcohol yield% ee% Dr Group 9 Ⅰ-b Ⅱ-b 99.0 98.1 95:5 Group 10 Ⅰ-c Ⅱ-c 99.1 98.2 99:1 Group 11 Ⅰ-d Ⅱ-d 99.3 96.5 96:4 Group 12 Ⅰ-e Ⅱ-e 99.0 96.7 95:5 Group 13 Ⅰ-f Ⅱ-f 99.2 97.6 95:5 Group 14 Ⅰ-g Ⅱ-g 99.4 96.1 94:6 Group 15 Ⅰ-h Ⅱ-h 99.3 98.0 96:4 Group 16 Ⅰ-i Ⅱ-i 99.5 99.0 95:5 Group 17 Ⅰ-j Ⅱ-j 99.3 99.2 99:1 Group 18 Ⅰ-k Ⅱ-k 99.4 96.8 95:5 Group 19 Ⅰ-l Ⅱ-l 99.6 97.3 95:5 Group 20 Ⅰ-m Ⅱ-m 99.3 95.9 95:5 Group 21 Ⅰ-n Ⅱ-n 99.5 99.4 94:6 Group 22 Ⅰ-p Ⅱ-p 99.1 98.3 99:1 Group 23 Ⅰ-q Ⅱ-q 99.5 96.7 99:1 Group 24 Ⅰ-r Ⅱ-r 99.3 99.4 99:1

[0113] Example 6

[0114] In the first step, under nitrogen atmosphere, 0.2 mmol of Ⅰ-a and 0.001 mmol of metal precursor [Ir(COD)OH] were added into a hydrogenation bottle. 2 , 0.002mmol ligand f-phamidol, 0.002mmol cesium carbonate, 1.0ml ethyl acetate, and then transferred to a pressure autoclave. The reaction atmosphere was more than 99% hydrogen and the rest nitrogen. The hydrogen pressure was set to 30atm and the reaction was carried out at 25°C for 12h.

[0115] In the second step, hydrogen was slowly released, 10.0 ml of dichloromethane was added to dilute, 8.0 ml of water was used to quench, the organic phase was separated, the aqueous phase was washed twice with 10.0 ml of dichloromethane, and then the organic phases were combined.

[0116] The third step is drying with anhydrous sodium sulfate and concentrating to obtain a crude product. The nuclear magnetic resonance analysis results show that no target product II-a is generated.

[0117] Example 7

[0118]

[0119] In the first step, under nitrogen atmosphere, 0.2 mmol of Ⅰ-a and 0.001 mmol of metal precursor [Ir(COD)Cl] were added into a hydrogenation bottle. 2 , 0.002mmol of ligand f-ampha, 0.002mmol of cesium carbonate, 1.0ml of ethyl acetate, and then transferred to a pressure autoclave. The reaction atmosphere was more than 99% hydrogen and the rest nitrogen. The hydrogen pressure was set to 30atm and the reaction was carried out at 25°C for 12h.

[0120] In the second step, hydrogen was slowly released, 10.0 ml of dichloromethane was added to dilute, 8.0 ml of water was used to quench, the organic phase was separated, the aqueous phase was washed twice with 10.0 ml of dichloromethane, and then the organic phases were combined.

[0121] The third step is to dry with anhydrous sodium sulfate and concentrate to obtain a crude product, which is then separated and purified by column chromatography to obtain clean II-a.

[0122] The analysis results showed that the product was colorless oil with 89% yield, 15% ee, 9:1 dr. The NMR data of product II-a were 1 HNMR (400MHz, CDCl 3)δ7.40–7.27(m,5H),5.02–4.94(m,1H),3.99(d,J=5.8Hz,1H),3.67(s,3H),3.37(s,3H),2.98(d,J=4.9Hz,1H).

[0123] 13 C NMR (101 MHz, CDCl 3 )δ169.8,138.3,127.2,127.1,125.5,83.4,73.0,57.9,50.9.

[0124] Ee and dr were obtained by high performance liquid chromatography analysis. HPLC (Chiralpak IB column, hexane / isopropanol = 95 / 5; flow rate = 1.0 ml / min; UV detection at 210 nm; tR = 21.9 min (anti), tR = 26.8 min (anti), tR = 35.6 min (syn), tR = 53.3 min (syn).

[0125] Example 8

[0126]

[0127] In the first step, under nitrogen atmosphere, 0.2 mmol of Ⅰ-a and 0.001 mmol of metal precursor [Ir(COD)Cl] were added into a hydrogenation bottle. 2 , 0.002mmol of ligand f-amphol, 0.002mmol of cesium carbonate, 1.0ml of ethyl acetate, and then transferred to a pressure autoclave. The reaction atmosphere was more than 99% hydrogen and the rest nitrogen. The hydrogen pressure was set to 30atm and the reaction was carried out at 25°C for 12h.

[0128] In the second step, hydrogen was slowly released, 10.0 ml of dichloromethane was added to dilute, 8.0 ml of water was used to quench, the organic phase was separated, the aqueous phase was washed twice with 10.0 ml of dichloromethane, and then the organic phases were combined.

[0129] The third step is drying with anhydrous sodium sulfate and concentrating to obtain a crude product, which is then separated and purified by column chromatography to obtain a clean chiral α-hydroxy β-ketoate ester represented by structural formula II-a.

[0130] The analysis results showed that the product was colorless oil with a yield of 27%, 3% ee, 1:2dr. The NMR data of product II-a were 1 H NMR (400 MHz, CDCl 3)δ7.40–7.27(m,5H),5.02–4.94(m,1H),3.99(d,J=5.8Hz,1H),3.67(s,3H),3.37(s,3H),2.98(d,J=4.9Hz,1H).

[0131] 13 C NMR (101 MHz, CDCl 3 )δ169.8,138.3,127.2,127.1,125.5,83.4,73.0,57.9,50.9.

[0132] Ee and dr were obtained by high performance liquid chromatography analysis. HPLC (Chiralpak IB column, hexane / isopropanol = 95 / 5; flow rate = 1.0 ml / min; UV detection at 210 nm; tR = 21.9 min (anti), tR = 26.8 min (anti), tR = 35.6 min (syn), tR = 53.3 min (syn).

[0133] Example 9

[0134]

[0135] In the first step, under nitrogen atmosphere, 0.2 mmol of Ⅰ-a and 0.001 mmol of metal precursor [Ir(COD)Cl] were added into a hydrogenation bottle. 2 , 0.002 mmol of ligand O-SpiroPAP and 0.002 mmol of cesium carbonate, 1.0 ml of ethyl acetate, and then transferred to a pressure autoclave. The reaction atmosphere was more than 99% hydrogen and the rest nitrogen. The hydrogen pressure was set to 30 atm and the reaction was carried out at 25°C for 12 hours.

[0136] In the second step, hydrogen was slowly released, 10.0 ml of dichloromethane was added to dilute, 8.0 ml of water was used to quench, the organic phase was separated, the aqueous phase was washed twice with 10.0 ml of dichloromethane, and then the organic phases were combined.

[0137] The third step is drying with anhydrous sodium sulfate and concentrating to obtain a crude product, which is then separated and purified by column chromatography to obtain a clean chiral α-hydroxy β-ketoate ester represented by structural formula II-a.

[0138] The analysis results showed that the product was colorless oil with a yield of 77%, 13% ee, 8:1dr. The NMR data of product II-a were 1 HNMR (400MHz, CDCl 3)δ7.40–7.27(m,5H),5.02–4.94(m,1H),3.99(d,J=5.8Hz,1H),3.67(s,3H),3.37(s,3H),2.98(d,J=4.9Hz,1H).

[0139] 13 C NMR (101 MHz, CDCl 3 )δ169.8,138.3,127.2,127.1,125.5,83.4,73.0,57.9,50.9.

[0140] ee and dr were obtained by high performance liquid chromatography analysis. HPLC (Chiralpak IB column, hexane / isopropanol = 95 / 5; flow rate = 1.0 ml / min; UV detection at 210 nm; tR = 21.9 min (anti), tR = 26.8 min (anti), tR = 35.6 min (syn), tR = 53.3 min (syn).

[0141] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An α-hydroxy β-ketoate compound, as shown in formula II, R 1 , R 2 are independently substituted or unsubstituted alkyl; R 3 is selected from hydrogen or hydroxyl; Ar is selected from substituted or unsubstituted aryl; The carbon marked with * is in R configuration or S configuration.

2. The α-hydroxy β-ketoate compound according to claim 1, characterized in that Ar is selected from an aromatic group, and any H on the aromatic group is replaced by R a Substitution, the R a Each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, and / or, said R 1 , R 2 Any H on R b Substitution, the R b is selected from substituted or unsubstituted aryl groups.

3. The α-hydroxy β-ketoate compound according to claim 1, characterized in that At least two H on Ar are R a Substitute, the R a The atoms connected to it form a ring with a structure like 4. An α-hydroxy β-ketoate compound, as follows:

5. A method for synthesizing a compound of formula II, characterized in that: include: In the presence of a catalyst, the compound represented by formula I is fully mixed with a catalyst, a base, and an organic solvent to form a reaction system, and a compound represented by formula II is obtained under a hydrogen atmosphere; The reaction formula is as follows: In Formula I and Formula II, R 1 , R 2 are independently substituted or unsubstituted alkyl; Ar is selected from substituted or unsubstituted aryl; The catalyst is obtained by complexing a ligand with a transition metal precursor, and the ligand of the catalyst has the following structural formula:

6. The method according to claim 5, characterized in that: The R 1 , R 2 are independently substituted or unsubstituted C 1-6 Alkyl, and / or, the R 1 Any H on R c Substitution, the R c is selected from substituted or unsubstituted aryl, and / or, Ar is selected from aryl, any H on the aryl is replaced by R d Substitution, the R d Each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, Or, at least two H on the aromatic group are replaced by R d Substitute, the R d The atoms connected to it form a ring with a structure like 7. The method according to claim 5, characterized in that: The R d is selected from alkyl groups, wherein R d Any H on the R is substituted by halogen, or a is selected from an alkoxy group, wherein the H on the alkoxy group is substituted by an aryl group.

8. The method according to claim 5, characterized in that The compound shown in formula II is selected from the following compounds:

9. The method according to claim 5, characterized in that The transition metal precursor is at least one of [Ir(COD)Cl]2 and [Ir(COD)2]X; X includes Cl, Br, I, OH, BF4, SbF6, PF6, OTf, B(Ar F )4, and / or, the hydrogen pressure is 10 to 90 atm, preferably 30 to 50 atm, and / or, the organic solvent includes at least one of an alcohol solvent, ethyl acetate, and tetrahydrofuran, the alcohol solvent includes at least one of methanol, ethanol, and isopropanol, and / or, the base is selected from triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, hydroxide At least one of sodium, potassium hydroxide, sodium phosphate, and potassium phosphate, and / or, the amount of the base is 0.001 to 1.0 molar equivalent of the substrate shown in formula I, and / or, the amount of the catalyst is 0.00005 to 0.01 molar equivalent of the substrate shown in formula I, preferably 0.0001 to 0.005 molar equivalent, more preferably 0.0001 to 0.001 molar equivalent, and / or, the reaction temperature is 10 to 80°C, preferably 20 to 50°C.

10. A method for synthesizing a compound represented by formula III, characterized in that: Contains the following reaction formula: Ar, R 1 , R 2 As defined in any one of claims 1 to 4.

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