Preparation method for synthesizing chiral beta-hydroxy propionaldehyde ethylene glycol with high enantioselectivity

Abstract

The invention provides a preparation method for synthesizing chiral beta-hydroxy propionaldehyde ethylene glycol with high enantioselectivity. The preparation method comprises the following step: catalyzing beta-ketopropionaldehyde ethylene glycol by utilizing a chiral ligand modified iridium metal catalyst to prepare the chiral beta-hydroxy propionaldehyde ethylene glycol through asymmetric hydrogenation. The method disclosed by the invention is simple in process, the beta-hydroxy propionaldehyde ethylene glycol is obtained by using a small amount of solvent and a short time of reaction, and the problems of more reaction steps, high reagent consumption and low optical purity of the obtained chiral beta-hydroxy propionaldehyde ethylene glycol in the existing synthesis method can be solved.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and more specifically to a method for preparing chiral beta-hydroxypropionaldehyde ethylene acetal with high enantioselectivity. Background Art

[0002] Atomoxetine is an important drug for the treatment of attention deficit disorder (ADHD). It can selectively inhibit the presynaptic norepinephrine transporter and enhance the function of norepinephrine, thereby improving the symptoms of ADHD and indirectly promoting cognitive completion and concentration. Fluoxetine is a selective 5-HT reuptake inhibitor (SSRI) widely used in clinical practice. It can selectively inhibit the 5-HT transporter, block the reuptake of 5-HT by the presynaptic membrane, prolong and increase the effect of 5-HT, and thus produce an antidepressant effect. Duloxetine is a selective 5-HT and norepinephrine (NE) reuptake inhibitor used to treat depression, generalized anxiety disorder and chronic musculoskeletal pain. Tolterodine is clinically used to treat symptoms such as frequent urination, urgency or urgency incontinence caused by overexcited bladder. The chemical structural formulas of the above drugs are shown below.

[0003]

[0004] The current preparation methods of these drugs not only involve the construction of key chiral alcohols, but also contain important functional groups that can be further modified. Through the retrosynthetic analysis of these compounds, chiral β-hydroxypropionaldehyde ethylene acetal can be used as a new important intermediate for the preparation of the above drugs. The chemical structure of chiral β-hydroxypropionaldehyde ethylene acetal is shown below.

[0005]

[0006] Racemic β-hydroxypropionaldehyde acetal can be prepared by reducing β-ketopropionaldehyde acetal with a reducing agent, but direct synthesis of chiral β-hydroxypropionaldehyde acetal is still very rare. Paul Knohl in Sc(OTf) 3 Catalytic addition of 2-vinyloxyethanol magnesium bromide to different aldehydes to generate protected aldol products, Synthetic Chemistry Express, 2016, Vol. 27, No. 11, pp. 1715-1719 (Sc(OTf) 3-Catalyzed Addition of Bromomagnesium 2-VinyloxyEthoxide to Various Aldehydes Leading to Protected Aldol Products, PaulKnochel, Synlett, 2016, 27(11):1715-1719), reported a Sc(OTf) 3 2-vinyloxyethanol magnesium bromide is catalyzed to convert into β-hydroxypropionaldehyde ethylene acetal with aldehyde, and then chiral β-hydroxypropionaldehyde ethylene acetal is obtained through Swern oxidation and Corey-Bakshi-Shibata reduction. However, the optical purity of chiral β-hydroxypropionaldehyde ethylene acetal obtained by this method is only 94%.

[0007] In general, there is a lack of direct methods for preparing optically pure β-hydroxypropionaldehyde ethylene acetal. Existing synthesis methods also have disadvantages such as many reaction steps, high reagent consumption, and low optical purity of the obtained chiral β-hydroxypropionaldehyde ethylene acetal.

[0008] Based on this, there is room for improvement in the preparation method of chiral β-hydroxypropionaldehyde ethylene acetal. Summary of the invention

[0009] In view of this, the purpose of the present invention is to provide a method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity, so as to solve the problems of multiple reaction steps and high reagent consumption in the existing synthesis methods.

[0010] In order to achieve the above-mentioned purpose, the technical scheme provided by the present invention is a method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity, comprising: using a chiral ligand modified iridium metal catalyst to catalyze the asymmetric hydrogenation of β-ketopropionaldehyde ethylene acetal to prepare chiral β-hydroxypropionaldehyde ethylene acetal.

[0011] In some embodiments, the chiral ligand comprises a chiral ligand of formula (IV) or a chiral ligand of formula (V),

[0012] The chiral ligand of structural formula (IV) is (1R)-N-(2-(bis(2-methoxyphenyl)phosphino)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methanamine; The chiral ligand of structural formula (V) is (1S)-N-(2-(bis(2-methoxyphenyl)phosphino)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methanamine.

[0013] In some embodiments, the iridium metal catalyst comprises [Ir(COD)Cl] 2 .

[0014] In some embodiments, the β-ketopropionaldehyde ethylene acetal is β-ketopropionaldehyde ethylene acetal of formula (III),

[0015] Wherein R includes phenyl, alkyl-substituted phenyl or alkyl-substituted thienyl, halogen-substituted phenyl or halogen-substituted thienyl, or naphthyl.

[0016] In some embodiments, the chiral β-hydroxypropionaldehyde ethylene acetal includes chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (I) or chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (II). When the chiral ligand is a chiral ligand of structural formula (IV), the chiral β-hydroxypropionaldehyde ethylene acetal is the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (I). When the chiral ligand is a chiral ligand of structural formula (V), the chiral β-hydroxypropionaldehyde ethylene acetal is the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (II).

[0017] Wherein R includes phenyl, alkyl-substituted phenyl or alkyl-substituted thienyl, halogen-substituted phenyl or halogen-substituted thienyl, or naphthyl.

[0018] In some embodiments, a method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity comprises the following steps: Step 1, adding an iridium metal catalyst, a chiral ligand, β-ketopropionaldehyde ethylene acetal, a solvent, and a base into an autoclave respectively; Step 2, using hydrogen to replace the air in the autoclave; Step 3, after adjusting the hydrogen pressure in the autoclave, the reaction is carried out at a set temperature for a set time to obtain a reaction product; Step 4: Separate the reaction product to obtain pure chiral β-hydroxypropionaldehyde ethylene acetal.

[0019] In some embodiments, in step 1, the molar ratio of the chiral ligand to the iridium metal catalyst is 3:1-5:1, the molar ratio of β-ketopropionaldehyde ethylene acetal to the iridium metal catalyst is 100:1-1000:1, and the molar ratio of the base to the iridium metal catalyst is 13:1-14:1.

[0020] In some embodiments, in step 1, the base is barium hydroxide and the solvent is anhydrous ethanol.

[0021] In some embodiments, in step 2, the air in the autoclave is replaced three times with hydrogen.

[0022] In some embodiments, in step 3, the hydrogen pressure in the autoclave is adjusted to 4.0-8.0 MPa, the temperature is set to 25-50° C., and the time is set to 1-6 h.

[0023] Beneficial effects of the present invention: The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity of the present invention uses β-ketopropionaldehyde ethylene acetal as raw material, and can synthesize β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity through chiral ligand, so that β-ketopropionaldehyde ethylene acetal completes asymmetric selective hydrogenation reaction under normal temperature conditions to generate β-hydroxypropionaldehyde ethylene acetal with optical properties. The method of the present invention has a simple process, uses a small amount of solvent, and obtains β-hydroxypropionaldehyde ethylene acetal in a short time, which can overcome the problems of many reaction steps, large reagent consumption, and low optical purity of the obtained chiral β-hydroxypropionaldehyde ethylene acetal in the existing synthesis method. A new approach is provided for the synthesis of some existing commercial drugs, and the prepared chiral β-hydroxypropionaldehyde ethylene acetal has high optical purity and chemical purity, and can be further used for synthesizing commercial drugs such as atomoxetine, fluoxetine, duloxetine, and tolterodine. DETAILED DESCRIPTION

[0024] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the embodiments of the present invention are further described in detail below in conjunction with specific embodiments.

[0025] It should be noted that all expressions using "first" and "second" in the embodiments of the present invention are for distinguishing two non-identical entities with the same name or non-identical parameters. It can be seen that "first" and "second" are only for the convenience of expression and should not be understood as limitations on the embodiments of the present invention. The subsequent embodiments will not explain this one by one.

[0026] The invention provides a method for preparing chiral β-hydroxypropionaldehyde ethylene acetal by synthesizing it with high enantioselectivity, comprising: utilizing a chiral ligand-modified iridium metal catalyst to catalyze the asymmetric hydrogenation of β-ketopropionaldehyde ethylene acetal to prepare the chiral β-hydroxypropionaldehyde ethylene acetal.

[0027] In some embodiments, the chiral ligand comprises a chiral ligand of formula (IV) or a chiral ligand of formula (V).

[0028]

[0029] The chiral ligand of structural formula (IV) is (1R)-N-(2-(bis(2-methoxyphenyl)phosphino)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methanamine. (1R)-N-(2-(bis(2-methoxyphenyl)phosphinoyl)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methylamine has the effect of affecting the selectivity of the reaction. In the asymmetric catalytic reaction of asymmetric synthesis, it coordinates with metal ions to form a chiral metal complex. For example, in the asymmetric hydrogenation reaction, it can selectively catalyze the reaction as a catalyst, so that unsaturated compounds (such as olefins) are selectively hydrogenated from a certain direction to generate products with specific stereo configurations. In the synthesis of chiral drugs in asymmetric synthesis, it can help synthesize compounds with a single configuration, and by controlling the stereochemical process of the reaction, the synthesized drug molecules can exist in the expected chiral form, thereby improving the effectiveness and safety of the drugs.

[0030] The chiral ligand of structural formula (V) is (1S)-N-(2-(bis(2-methoxyphenyl)phosphonyl)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methylamine. (1S)-N-(2-(bis(2-methoxyphenyl)phosphonyl)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methylamine has stereoselective induction in asymmetric catalytic reactions and can coordinate with metal catalysts to form chiral metal complexes. In asymmetric catalytic reactions (such as asymmetric hydrogenation, asymmetric epoxidation, etc.), it can provide an asymmetric environment for the reaction substrate. For example, in an asymmetric hydrogenation reaction, when the substrate (such as an unsaturated compound) approaches the active site of the catalyst, the substrate will bind in a specific direction and manner due to the steric hindrance and electronic effects of the chiral ligand. This allows hydrogen atoms to be selectively added to one side of the unsaturated bond, thereby generating products with specific stereo configurations; it has the effect of controlling enantioselectivity, and the chiral center (1S, 2R, 5R) of the chiral ligand itself plays a key role in the reaction. In many organic reactions (such as allylation reactions, alkylation reactions, etc.), the chiral ligand can distinguish the enantiomers of the substrate. In addition, for example, in the reaction of synthesizing chiral drug intermediates, the chiral ligand can guide the reaction to generate products with high optical purity, and drug intermediates of different enantiomers may produce final drug products with different pharmacological activities or toxicities in subsequent reactions.

[0031] In some embodiments, the iridium metal catalyst comprises [Ir(COD)Cl] 2, named (1,5-cyclooctadiene) iridium (I) chloride dimer, also known as dichloro 1,5-cyclooctadiene iridium dimer. [Ir(COD)Cl] 2 Its role in asymmetric hydrogenation is to form a catalytically active center, which can undergo ligand exchange reactions with other ligands in the reaction system to form a mononuclear iridium complex with catalytic activity. For example, in some asymmetric hydrogenation reactions, [Ir(COD)Cl] 2 It will exchange ligands with chiral ligands. This newly formed complex is the active center of asymmetric hydrogenation reaction. It has an activation effect on substrates. The iridium center can coordinate with unsaturated substrates (such as olefins, alkynes, carbonyl compounds, etc.) to activate the substrate molecules. Taking olefins as an example, when olefins are coordinated with iridium complexes, the double bond electron cloud of the olefin will be affected by the iridium center, the activity of the double bond will increase, and it will be more likely to accept the addition of hydrogen atoms. It guides stereoselective reactions. In asymmetric hydrogenation reactions, [Ir(COD)Cl] 2 Chiral catalysts combined with chiral ligands can guide hydrogen atoms to selectively add from one side of the substrate, thereby highly selectively generating products with specific stereo configurations. For example, when synthesizing chiral drugs or intermediates of natural products, this stereoselective hydrogenation can effectively control the chiral purity of the product.

[0032] In some embodiments, the β-ketopropionaldehyde ethylene acetal is β-ketopropionaldehyde ethylene acetal of formula (III).

[0033]

[0034] Wherein R includes phenyl, alkyl-substituted phenyl or alkyl-substituted thienyl, halogen-substituted phenyl or halogen-substituted thienyl, or naphthyl.

[0035] In some embodiments, the chiral β-hydroxypropionaldehyde ethylene acetal includes chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (I) or chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (II). When the chiral ligand is a chiral ligand of structural formula (IV), the chiral β-hydroxypropionaldehyde ethylene acetal is the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (I). When the chiral ligand is a chiral ligand of structural formula (V), the chiral β-hydroxypropionaldehyde ethylene acetal is the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (II).

[0036]

[0037] Wherein R includes phenyl, alkyl-substituted phenyl or alkyl-substituted thienyl, halogen-substituted phenyl or halogen-substituted thienyl, or naphthyl.

[0038] The chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (I) is a chiral β-hydroxypropionaldehyde ethylene acetal of S configuration, and the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (II) is a chiral β-hydroxypropionaldehyde ethylene acetal of R configuration.

[0039] The reaction of the method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity of the present invention is as follows:

[0040] or

[0041] Compared with the prior art, the method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity of the present invention uses β-ketopropionaldehyde ethylene acetal as raw material, and can synthesize β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity through chiral ligand, so that β-ketopropionaldehyde ethylene acetal can complete asymmetric selective hydrogenation reaction under normal temperature conditions to generate β-hydroxypropionaldehyde ethylene acetal with optical properties. At the same time, through the chiral ligand, in [Ir(COD)Cl] 2 and Ba(OH) 2 Under the conditions of , a small amount of solvent is used, and β-hydroxypropionaldehyde ethylene acetal is obtained in a short time. The method of the present invention can overcome the problems of the existing synthesis method, such as many reaction steps, large reagent consumption, and low optical purity of the obtained chiral β-hydroxypropionaldehyde ethylene acetal. In addition, although the reaction time of the method of the present invention is short, it still has a high yield and optical purity.

[0042] The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity of the present invention comprises the following steps: Step 1, adding an iridium metal catalyst, a chiral ligand, β-ketopropionaldehyde ethylene acetal, a solvent, and a base into an autoclave respectively; Step 2, using hydrogen to replace the air in the autoclave; Step 3, after adjusting the hydrogen pressure in the autoclave, the reaction is carried out at a set temperature for a set time to obtain a reaction product; Step 4: Separate the reaction product to obtain pure chiral β-hydroxypropionaldehyde ethylene acetal.

[0043] In some embodiments, in step 1, the molar ratio of the chiral ligand to the iridium metal catalyst is 3:1-5:1, the molar ratio of β-ketopropionaldehyde ethylene acetal to the iridium metal catalyst is 100:1-1000:1, and the molar ratio of the base to the iridium metal catalyst is 13:1-14:1.

[0044] In some embodiments, in step 1, the base is barium hydroxide.

[0045] In some embodiments, in step 1, the solvent is anhydrous ethanol.

[0046] In some embodiments, in step 2, the air in the autoclave is replaced three times with hydrogen.

[0047] In some embodiments, in step 3, the hydrogen pressure in the autoclave is adjusted to 4.0-8.0 MPa, the temperature is set to 25-50° C., and the time is set to 1-6 h.

[0048] In some embodiments, in step 3, the temperature is set to 30-40°C.

[0049] In some embodiments, in step 3, the time is set to 1-3 h.

[0050] In some embodiments, in step 4, the reaction product is separated by silica gel column chromatography.

[0051] The invention discloses a method for preparing chiral β-hydroxypropionaldehyde ethylene acetal by synthesizing it with high enantioselectivity, which comprises taking β-ketopropionaldehyde ethylene acetal as a raw material, adding a catalyst [Ir(COD)Cl] 2 、Ba(OH) 2 and a chiral ligand, anhydrous ethanol is used as a solvent, the air in the autoclave is replaced by hydrogen in the autoclave, the hydrogen pressure in the autoclave is adjusted, and chiral β-hydroxypropionaldehyde ethylene acetal is reacted under set reaction conditions to prepare chiral β-hydroxypropionaldehyde ethylene acetal.

[0052] Embodiment 1 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-phenyl-propionaldehyde acetal (288 mg, 1.50 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 1 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-phenyl-propionaldehyde acetal (colorless oil, 288 mg, yield 99%). 98.8% ee, S Configuration; [α] D 25 = - 29.4 (c = 1.00 in CHCl 3 ); 1 H NMR (600 MHz, DMSO-d 6 ) d 7.30-7.32 (m, 4H), 7.21-7.24 (m, 1H), 5.28 (d, J = 3.0 Hz, 1H), 4.84-4.86 (m, 1H), 4.65-4.67 (m, 1H), 3.86-3.89 (m, 2H), 3.74-3.77 (m, 2H), 1.93-1.96 (m, 1H), 1.72-1.76 (m, 1H); 13 C NMR (150 MHz, DMSO- d 6 ) d 146.19, 128.58,127.34, 126.21, 102.17, 69.69, 64.54 (d, J = 9.75 Hz), 44.01. HRMS (ESI) calcd.for C 11 H 14 O 3 Na [M+Na] + : 217.0841, found: 217.0840.

[0053] Embodiment 2 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(4-methylphenyl)-propionaldehyde acetal (124 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(4-methylphenyl)-propionaldehyde acetal (colorless oil, 112 mg, yield 90%). 99.0% ee, S Configuration; [α] D 25 = - 17.0 (c = 1.00 inCHCl 3 ); 1 H NMR (600 MHz, CDCl3 ) d 7.28 (d, J = 3.0 Hz, 2H), 7.16(d, J = 3.0 Hz, 2H),5.03-5.05 (m, 1H), 4.97-4.99 (m, 1H), 4.02-4.05 (m, 2H), 3.89-3.93 (m, 2H),3.21 (s, 1H), 2.34 (s, 3H), 2.12-2.15 (m, 1H), 2.05-2.08 (m, 1H); 13 C NMR (150MHz, DMSO- d 6 ) d 143.17, 136.33, 129.13, 126.15, 102.18, 69.49, 64.58, 43.99,21.15. HRMS (ESI) calcd. for C 12 H 16 O 3 Na [M+Na] + : 231.0997, found: 231.0994.

[0054] Embodiment 3 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(4-methoxyphenyl)-propionaldehyde acetal (333 mg, 1.50 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 1 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(4-methoxyphenyl)-propionaldehyde acetal (colorless oil, 309 mg, yield 92%). 98.6% ee, S Configuration; [α] D 25 = - 34.2 (c = 1.00 inCHCl 3 ); 1 H NMR (600 MHz, CDCl 3 ) d 7.31 (d, J = 6.0 Hz, 2H), 6.89 (d, J = 3.0 Hz, 2H),5.03-5.04 (m, 1H), 4.96-4.98 (m, 1H), 4.04-4.07 (m, 2H), 3.89-3.93 (m, 2H),3.80 (s, 3H), 3.23 (s, 1H), 2.12-2.15 (m, 1H), 2.05-2.08 (m, 1H); 13 C NMR (150MHz, CDCl 3 ) d 158.94, 136.02, 126.96, 113.79, 103.20, 69.94, 64.81, 55.28,42.34. HRMS (ESI) calcd. for C 12 H 16 O 4 Na [M+Na] + : 247.0946, found: 247.0947.

[0055] Embodiment 4 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(4-fluorophenyl)-propionaldehyde acetal (31.5 mg, 0.15 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 1 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(4-fluorophenyl)-propionaldehyde acetal (colorless oil, 25.4 mg, yield 80%). 98.0% ee, S Configuration; [α] D 25 = - 15.2 (c = 1.00 inCHCl 3 ); 1 H NMR (600 MHz, DMSO- d 6 ) d7.35-7.37 (m, 2H), 7.12-7.15 (m, 2H), 5.36(d, J = 3.0 Hz, 1H), 4.83-4.85 (m, 1H), 4.67-4.69 (m, 1H), 3.88-3.90 (m, 2H), 3.74-3.77 (m, 2H), 1.93-1.97 (m, 1H), 1.73-1.76 (m, 1H); 13 C NMR (150 MHz, CDCl 3 ) d 161.89, 160.27, 138.56, 126.36, 114.11, 102.07, 68.65, 63.83, 41.39.HRMS (ESI) calcd. for C 11 H 13 O 3 FNa [M+Na] + : 235.0746, found: 235.0740.

[0056] Embodiment 5 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-naphthyl)-propionaldehyde acetal (363 mg, 1.50 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 ° C for 1 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(2-naphthyl)-propionaldehyde acetal (colorless oil, 322 mg, yield 88%). 98.5% ee, S Configuration; [α] D 25 = - 27.6 (c = 1.00 in CHCl 3 ); 1 HNMR (600 MHz, CDCl 3 ) d7.82-7.86 (m, 4H), 7.45-7.49 (m, 3H), 5.17-5.19 (m, 1H), 5.06-5.08 (m, 1H), 4.03-4.09 (m, 2H), 3.90-3.94 (m, 2H), 3.49 (s, 1H), 2.18-2.24 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ) d 141.19, 133.30, 132.87, 128.19, 127.81(d, J = 25.5 Hz), 126.07, 125.75, 124.31, 123.96, 103.17, 70.39, 65.02, 64.85,42.29. HRMS (ESI) calcd. for C 15 H 16 O 3 Na [M+Na] + : 267.0997, found: 267.0994.

[0057] Embodiment 6 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-trifluoromethylphenyl)-propionaldehyde acetal (390 mg, 1.50 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 ° C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(2-trifluoromethylphenyl)-propionaldehyde acetal (colorless oil, 346 mg, yield 88%). 99.0% ee, S Configuration; [α] D 25 = -25.7 (c = 1.00in CHCl 3 ); 1 H NMR (600 MHz, DMSO- d 6 ) d 7.84 (d,J = 3.0 Hz, 1H), 7.68-7.70 (m, 1H),7.65 (d, J = 3.0 Hz, 1H), 7.44-7.47 (m, 1H), 5.58 (d, J = 1.5 Hz, 1H), 5.09 (d, J =6.0 Hz, 1H), 5.04-5.06 (m, 1H), 3.85-3.90 (m, 2H), 3.74-3.82 (m, 2H), 1.91-1.96 (m, 1H), 1.63-1.66 (m, 1H). HRMS (ESI) calcd. for C 12 H 13 O 3 F 3 Na [M+Na] + :285.0714, found: 285.0718.

[0058] Embodiment 7 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(3,5-di(trifluoromethyl)phenyl)-propionaldehyde acetal (492 mg, 1.50 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(3,5-bis(trifluoromethyl)phenyl)-propionaldehyde acetal (colorless oil, 396 mg, yield 80%). 99.0% ee, S Configuration; [α] D 25 = -15.8 (c = 1.00 in CHCl 3 ); 1 H NMR (600 MHz, DMSO- d 6 ) d8.02 (s, 2H), 7.98 (s, 1H), 5.77 (s, 1H), 4.92-4.96 (m, 2H), 3.85-3.92 (m, 2H), 3.75-3.80 (m, 2H), 1.99-2.03 (m, 1H), 1.88-1.92 (m, 1H); 13 C NMR (150 MHz, CDCl 3 ) d 197.89, 137.75,137.20, 132.31, 130.72, 130.46, 127.40, 101.16, 65.04, 47.58. HRMS (ESI)calcd. for C 13 H 12 O 3 F 6 Na [M+Na] + : 353.0588, found: 353.0584.

[0059] Embodiment 8 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2,4-dichlorophenyl)-propionaldehyde acetal (78 mg, 0.30 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 3 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(2,4-dichlorophenyl)-propionaldehyde acetal (colorless oil, 74 mg, yield 94%). 97.7% ee, S Configuration; [α] D 25 = - 54.9 (c = 1.00 inCHCl 3 ); 1 H NMR (600 MHz, DMSO- d 6 ) d 7.61(d, J = 6.0 Hz, 1H), 7.53(s, 1H), 7.45 (d,J = 3.0 Hz, 1H), 5.58 (d, J = 3.0 Hz, 1H), 5.03-5.06 (m, 1H), 4.99-5.01 (m, 1H), 3.85-3.93 (m, 2H), 3.74-3.82 (m, 2H), 1.75-1.85 (m, 2H); 13 C NMR (150 MHz, DMSO- d 6 ) d 142.66, 132.48, 131.77, 129.49, 128.78, 128.00, 101.88, 65.91, 64.55(d, J = 6.75 Hz), 42.11. HRMS (ESI) calcd. for C 11 H 12 O 3 Cl 2 Na [M+Na] + : 285.0061,found: 285.0060.

[0060] Embodiment 9 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-thienyl)-propionaldehyde acetal (29.7 mg, 0.15 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 1 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(2-thienyl)-propionaldehyde acetal (yellow oil, 29.1 mg, yield 97%). 98.8% ee, S Configuration; [α] D 25 = -29.4 (c = 1.00 in CHCl 3 ); 1 HNMR (600 MHz, CDCl 3 ) d 7.24 (d, J= 3.0 Hz, 1H), 6.95-6.97 (m, 2H), 5.27(d, J = 6.0Hz, 1H), 5.07-5.08 (m, 1H), 4.02-4.07 (m, 2H), 3.87-3.93 (m, 2H), 3.50 (s,1H), 2.19-2.28 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ) d 147.79, 126.61, 124.45,123.24, 102.82, 66.57, 64.99, 64.85, 42.42. HRMS (ESI) calcd. for C 9 H 12 O 3 SNa[M+Na] + : 223.0405, found: 223.0403.

[0061] Embodiment 10 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(5-chloro-2-thienyl)-propionaldehyde acetal (70 mg, 0.30 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 1 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( S )-3-Hydroxy-3-(5-chloro-2-thienyl)-propionaldehyde acetal (yellow oil, 70 mg, yield 99%). 97.3% ee, S Configuration; [α] D 25 = - 1.8 (c = 1.00 inCHCl 3 ); 1 H NMR (600 MHz, CDCl 3 ) d 6.76 (d, J = 3.0 Hz, 1H), 6.72 (d, J= 3.0 Hz, 1H),5.15-5.17 (m, 1H), 5.06-5.07 (m, 1H), 4.03-4.06 (m, 2H), 3.89-3.92 (m, 2H),3.53 (s, 1H), 2.17-2.19 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ) d 146.52, 128.93,125.54, 122.31, 102.66, 66.70, 64.94 (d, J = 9.75 Hz), 42.00. HRMS (ESI) calcd.for C 9 H 11 O 3 SClNa [M+Na] + : 257.0015, found: 257.0012.

[0062] Embodiment 11 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(4-methylphenyl)-propionaldehyde acetal (124 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(4-methylphenyl)-propionaldehyde acetal (colorless oil, 120 mg, yield 96%). 97.7% ee, R Configuration; [α] D 25 = + 22.2 (c = 1.00 inCHCl 3 ). 1 H NMR (600 MHz, CDCl 3 ) d 7.28 (d, J = 3.0 Hz, 2H), 7.16(d, J= 3.0 Hz, 2H),5.03-5.05 (m, 1H), 4.97-4.99 (m, 1H), 4.02-4.05 (m, 2H), 3.89-3.93 (m, 2H),3.21 (s, 1H), 2.34 (s, 3H), 2.12-2.15 (m, 1H), 2.05-2.08 (m, 1H); 13 C NMR (150MHz, DMSO- d 6 ) d 143.17, 136.33, 129.13, 126.15, 102.18, 69.49, 64.58, 43.99,21.15. HRMS (ESI) calcd. for C 12 H 16 O 3 Na [M+Na] + : 231.0997, found: 231.0994.

[0063] Embodiment 12 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(4-chlorophenyl)-propionaldehyde acetal (136 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(4-chlorophenyl)-propionaldehyde acetal (colorless oil, 109 mg, yield 80%). 94.2% ee, R Configuration; [α] D 25 = + 18.5 (c = 1.00 in CHCl 3 ). 1 HNMR (600 MHz, DMSO- d 6 ) d7.34-7.38 (m, 4H), 5.41 (s, 1H), 4.84-4.86 (m, 1H), 4.67-4.69 (m, 1H), 3.87-3.89 (m, 2H), 3.74-3.77 (m, 2H), 1.92-1.96 (m, 1H),1.73-1.76 (m, 1H); 13 C NMR (150 MHz, CDCl 3 ) d 141.37, 132.01, 127.52, 126.09,102.05, 68.61, 63.85, 41.33. HRMS (ESI) calcd. for C 11 H 13 ClNaO 3 [M+Na] + :251.0445, found: 251.0446.

[0064] Embodiment 13 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(4-bromophenyl)-propionaldehyde acetal (162 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(4-bromophenyl)-propionaldehyde acetal (colorless oil, 145 mg, yield 89%). 98.3% ee, R Configuration; [α] D 25 = + 15.0 (c = 1.00 in CHCl 3 ). 1 HNMR (600 MHz, DMSO- d 6 ) δ 7.51(d, J = 3.0 Hz, 2H), 7.29 (d, J = 6.0 Hz, 2H), 5.41(d, J= 1.5 Hz, 1H), 4.84-4.85 (m, 1H), 4.64-4.68 (m, 1H), 3.85-3.89 (m, 2H), 3.73-3.78 (m, 2H), 1.92-1.95 (m, 1H), 1.72-1.76 (m, 1H); 13 C NMR (150 MHz, DMSO- d 6 ) δ 141.90, 130.47, 126.45, 120.11, 102.03, 68.65, 63.94, 41.28. HRMS(ESI) calcd. for C 11 H 13 BrNaO 3 [M+Na] + : 294.9940, found: 294.9947.

[0065] Embodiment 14 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-methylphenyl)-propionaldehyde acetal (62 mg, 0.30 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 3 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(2-methylphenyl)-propionaldehyde acetal (colorless oil, 52 mg, yield 84%). 99.3% ee, R Configuration; [α] D 25 = + 46.7 (c = 1.00 in CHCl 3 ). 1 HNMR (600 MHz, CDCl 3 ) d 7.54 (d, J = 6.0 Hz, 1H), 7.21-7.24 (m, 1H), 7.15-7.18 (m,1H), 7.12 (d, J = 6.0 Hz, 1H), 5.23 (d,J = 6.0 Hz, 1H), 5.07-5.08 (m, 1H), 4.05-4.07 (m, 2H), 3.89-3.92 (m, 2H), 3.28(s, 1H), 2.33 (s, 3H), 2.04-2.07 (m,2H); 13 C NMR (150 MHz, CDCl 3 ) d 140.82, 133.01, 129.26, 126.10, 125.22, 124.22,102.25, 65.68, 64.01, 40.08, 17.87. HRMS (ESI) calcd. for C 12 H 16 NaO 3 [M+Na] + :231.0992, found: 231.0992.

[0066] Embodiment 15 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-fluorophenyl)-propionaldehyde acetal (126 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 1 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(2-fluorophenyl)-propionaldehyde acetal (yellow oil, 112 mg, yield 88%). 96.7% ee, R Configuration; [α] D 25 = + 49.2 (c = 1.00 in CHCl 3 ). 1 HNMR (600 MHz, DMSO- d 6 ) d 7.51-7.53 (m, 1H), 7.28-7.31 (m, 1H), 7.19-7.21 (m,1H), 7.10-7.14 (m, 1H), 5.44 (d,J = 3.0 Hz, 1H), 5.00-5.02 (m, 1H), 4.93-4.94(m, 1H), 3.85-3.90 (m, 2H), 3.75-3.80 (m, 2H), 1.94-1.98 (m, 1H), 1.76-1.79(m, 1H); 13 C NMR (150 MHz, CDCl 3 ) d 160.32, 158.69, 130.89, 128.78, 127.34,124.24, 115.25, 103.23, 64.81(d, J = 33.0 Hz), 40.98. HRMS (ESI) calcd. forC 11 H 13 FNaO 3 [M+Na] + : 235.0741, found: 235.0745.

[0067] Embodiment 16 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-trifluoromethylphenyl)-propionaldehyde acetal (156 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 ° C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(2-trifluoromethylphenyl)-propionaldehyde acetal (yellow oil, 138 mg, yield 88%). 99.0% ee, R Configuration; [α] D 25 = + 26.3 (c = 1.00in CHCl 3 ). 1 H NMR (600 MHz, DMSO- d 6 ) d 7.84 (d, J= 3.0 Hz, 1H), 7.68-7.70 (m, 1H),7.65 (d, J = 3.0 Hz, 1H), 7.44-7.47 (m, 1H), 5.58 (d, J = 1.5 Hz, 1H), 5.09 (d, J =6.0 Hz, 1H), 5.04-5.06 (m, 1H), 3.85-3.90 (m, 2H), 3.74-3.82 (m, 2H), 1.91-1.96 (m, 1H), 1.63-1.66 (m, 1H). HRMS (ESI) calcd. for C 12 H 13 O 3 F 3 Na [M+Na] + :285.0714, found: 285.0718.

[0068] Embodiment 17 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-chlorophenyl)-propionaldehyde acetal (68 mg, 0.30 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 3 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(2-chlorophenyl)-propionaldehyde acetal (colorless oil, 57 mg, yield 84%). 97.6% ee, R Configuration; [α] D 25 = + 50.2 (c = 1.00 in CHCl 3 ). 1 H NMR (600 MHz, CDCl 3 ) d 7.66 (d, J = 3.0 Hz, 1H), 7.29-7.32 (m, 2H), 7.19-7.21 (m,1H), 5.39 (d, J= 6.0 Hz, 1H), 5.10-5.11 (m, 1H), 4.04-4.11 (m, 2H), 3.89-3.96(m, 2H), 3.63 (s, 1H), 2.23 (d, J = 6.0 Hz, 1H), 1.95-2.00 (m, 1H); 13 C NMR (150MHz, CDCl 3 ) d 140.05, 130.30, 128.28, 127.34, 126.04, 102.28, 66.05, 64.02,63.78, 39.34. HRMS (ESI) calcd. for C 11 H 13 ClNaO 3 [M+Na] + : 251.0445, found:251.0453.

[0069] Embodiment 18 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(3,4-dichlorophenyl)-propionaldehyde acetal (78 mg, 0.30 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 3 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(3,4-dichlorophenyl)-propionaldehyde acetal (colorless oil, 47 mg, yield 60%). 91.3% ee, R Configuration; [α] D 25 = + 10.4 (c = 1.00 inCHCl 3 ) . 1 H NMR (600 MHz, CDCl 3 ) d 7.51 (d, J = 3.0 Hz, 1H), 7.41 (d, J= 3.0 Hz,1H), 7.19-7.21 (m, 1H), 5.03-5.05 (m, 1H), 4.98-5.00 (m, 1H), 4.05-4.09 (m,2H), 3.89-3.94 (m, 2H), 3.60 (s, 1H), 2.050-2.07 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ) d 144.14, 132.46, 131.10, 130.34, 127.81, 125.07, 102.91, 69.05, 64.99,42.11. HRMS (ESI) calcd. for C 11 H 12 Cl 2 NaO 3 [M+Na] + : 285.0056, found: 285.0054.

[0070] Embodiment 19 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(2-thienyl)-propionaldehyde acetal (119 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 ° C for 6 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-Hydroxy-3-(2-thienyl)-propionaldehyde acetal (yellow oil, 103 mg, yield 86%). 95.0% ee, R Configuration; [α] D 25 = + 18.0 (c = 1.00 in CHCl 3 ) . 1 H NMR (600 MHz, CDCl 3 ) δ 7.24 (d, J = 3.0 Hz, 1H), 6.95-6.97 (m, 2H), 5.27(d, J=6.0 Hz, 1H), 5.07-5.08 (m, 1H), 4.02-4.07 (m, 2H), 3.87-3.93 (m, 2H), 3.50(s, 1H), 2.19-2.28 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ) δ 147.79, 126.61, 124.45,123.24, 102.82, 66.57, 64.92, 42.42. HRMS (ESI) calcd. for C 9 H 12 O 3 SNa [M+Na] + :223.0405, found: 223.0403.

[0071] Embodiment 20 [Ir(COD)Cl] was gradually added to the autoclave. 2 (1.0 mg, 0.0015 mmol), chiral ligand of structural formula (V) (4.0 mg, 0.0060 mmol), Ba(OH) 2 (3.4 mg, 0.02 mmol), 3-oxo-3-(5-methyl-2-thienyl)-propionaldehyde acetal (64 mg, 0.30 mmol) and anhydrous ethanol (2.0 mL), the air in the autoclave was replaced three times with hydrogen, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, the reaction was carried out at 35 ° C for 2 h, and after the reaction was completed, the reaction product was separated by silica gel column chromatography to obtain pure ( R )-3-hydroxy-3-(5-methyl-2-thienyl)-propionaldehyde acetal (yellow oil, 52 mg, yield 81%). 93.7% ee, R Configuration; [α] D 25 = + 5.0 (c = 1.00 inCHCl 3 ) . 1 H NMR (600 MHz, CDCl 3 ) δ 6.76 (d, J = 3.0 Hz, 1H), 6.60 (d, J= 3.0 Hz,1H), 5.16-5.18 (m, 1H), 5.06-5.07 (m, 1H), 4.02-4.06 (m, 2H), 3.87-3.92 (m,2H), 3.32 (s, 1H), 2.46 (s, 3H), 2.16-2.23 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ) δ145.19, 139.13, 124.55, 123.30, 102.87, 66.68, 64.92, 42.26, 15.38. HRMS(ESI) calcd. for C 10 H 14 NaO 3 S [M+Na] + : 237.0556, found: 237.0562.

[0072] The invention discloses a method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity, which utilizes iridium metal catalysts modified with chiral ligands of different configurations to catalyze the hydrogenation of β-ketopropionaldehyde ethylene acetal to synthesize chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity, has a simple process, a high yield of the obtained product, and high optical purity and chemical purity. The method of the invention uses β-ketopropionaldehyde ethylene acetal as a reaction substrate, and under a pressure of 4.0-8.0 MPa, a temperature of 25-50° C., and anhydrous ethanol as a solvent, adds [Ir(COD)Cl] 2 , Ba(OH) 2 Under the conditions of a chiral catalyst, the yield of synthesized β-hydroxypropionaldehyde ethylene acetal derivatives other than (R)-3-hydroxy-3-(3,4-dichlorophenyl)-propionaldehyde ethylene acetal can reach up to 99%, and the ee value is 90%-99%. The method of the present invention can be widely used in this field.

[0073] The β-ketopropionaldehyde ethylene acetal raw materials containing different substituents in Examples 1 to 20 are subjected to asymmetric catalytic hydrogenation using a chiral catalyst having a chiral ligand of structural formula (IV) or a chiral ligand of structural formula (V) to obtain β-hydroxypropionaldehyde ethylene acetal products with different substituents. These merely represent the results that have been actually synthesized. β-ketopropionaldehyde ethylene acetal raw materials containing other substituents and their products should also fall within the scope of protection of the present invention, and the scope of protection of the present invention should not be limited to the examples listed.

[0074] The invention discloses a method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity, which utilizes an iridium metal catalyst system to catalyze the asymmetric hydrogenation of β-ketopropionaldehyde ethylene acetal to prepare chiral β-hydroxypropionaldehyde ethylene acetal with high optical purity, and provides a new approach for the synthesis of some existing commercial drugs; the process is simple, and the obtained product has high optical purity and chemical purity; the prepared chiral β-hydroxypropionaldehyde ethylene acetal can be further used for synthesizing commercial drugs such as atomoxetine, fluoxetine, duloxetine, tolterodine, etc.

[0075] The technical features of the above embodiments may be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0076] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. A method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity, characterized in that: include: Chiral β-hydroxypropionaldehyde ethylene acetal was prepared by asymmetric hydrogenation of β-ketopropionaldehyde ethylene acetal over iridium metal catalyst modified with chiral ligand.

2. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 1, characterized in that: The chiral ligand includes a chiral ligand of structural formula (IV) or a chiral ligand of structural formula (V), The chiral ligand of structural formula (IV) is (1R)-N-(2-(bis(2-methoxyphenyl)phosphinoyl)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methanamine; The chiral ligand of structural formula (V) is (1S)-N-(2-(bis(2-methoxyphenyl)phosphinoyl)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R, 5R)-5-vinylquinolin-2-yl)methanamine.

3. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 2, characterized in that: The iridium metal catalyst includes [Ir(COD)Cl]2.

4. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 3, characterized in that: The β-ketopropionaldehyde ethylene acetal is β-ketopropionaldehyde ethylene acetal of structural formula (III), Wherein R includes phenyl, alkyl-substituted phenyl or alkyl-substituted thienyl, halogen-substituted phenyl or halogen-substituted thienyl, or naphthyl.

5. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 4, characterized in that: The chiral β-hydroxypropionaldehyde ethylene acetal includes the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (I) or the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (II). When the chiral ligand is the chiral ligand of structural formula (IV), the chiral β-hydroxypropionaldehyde ethylene acetal is the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (I). When the chiral ligand is the chiral ligand of structural formula (V), the chiral β-hydroxypropionaldehyde ethylene acetal is the chiral β-hydroxypropionaldehyde ethylene acetal of structural formula (II). Wherein R includes phenyl, alkyl-substituted phenyl or alkyl-substituted thienyl, halogen-substituted phenyl or halogen-substituted thienyl, or naphthyl.

6. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to any one of claims 1 to 5, characterized in that: The following steps are involved: Step 1, adding the iridium metal catalyst, chiral ligand, β-ketopropionaldehyde ethylene acetal, solvent and base into an autoclave respectively; Step 2, replacing the air in the autoclave with hydrogen; Step 3, after adjusting the hydrogen pressure in the autoclave, reacting at a set temperature for a set time to obtain a reaction product; Step 4: separating the reaction product to obtain pure chiral β-hydroxypropionaldehyde ethylene acetal.

7. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 6, characterized in that: In step 1, the molar ratio of the chiral ligand to the iridium metal catalyst is 3:1-5:1, the molar ratio of the β-ketopropionaldehyde ethylene acetal to the iridium metal catalyst is 100:1-1000:1, and the molar ratio of the base to the iridium metal catalyst is 13:1-14:

1.

8. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 6, characterized in that: In the step 1, the base is barium hydroxide, and the solvent is anhydrous ethanol.

9. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 6, characterized in that: In the step 2, the air in the autoclave is replaced three times with the hydrogen.

10. The method for preparing chiral β-hydroxypropionaldehyde ethylene acetal with high enantioselectivity according to claim 6, characterized in that: In the step 3, the hydrogen pressure in the autoclave is adjusted to 4.0-8.0 MPa, the set temperature is 25-50° C., and the set time is 1-6 h.

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