A method for preparing chiral beta-hydroxypropionaldehyde glycol with high enantioselectivity

Abstract

The application provides a preparation method of high enantioselective synthesis of chiral beta-hydroxy propionaldehyde glycol, comprising the following steps: using a chiral ligand modified iridium metal catalyst to catalyze asymmetric hydrogenation of beta-ketopropanal glycol to prepare chiral beta-hydroxy propionaldehyde glycol. The method has the advantages of simple process, less amount of solvent, and shorter reaction time for obtaining beta-hydroxy propionaldehyde glycol, and can overcome the problems of the existing synthesis method, such as multiple reaction steps, large reagent consumption, and low optical purity of obtained chiral beta-hydroxy propionaldehyde glycol.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemical synthesis, more particularly to a method for preparing chiral β-hydroxypropionaldehyde glycol with high enantioselectivity. BACKGROUND

[0002] Atomoxetine is an important drug for treating attention deficit disorder (child hyperactivity syndrome, ADHD), which can selectively inhibit the pre-synaptic membrane adrenergic transporter, enhance norepinephrine function, and thus improve the symptoms of ADHD, indirectly promote the completion of cognition and concentration of attention. Fluoxetine is a selective 5-HT reuptake inhibitor (SSRI) widely used in clinical practice, which can selectively inhibit 5-HT transporter, block the pre-synaptic membrane reuptake of 5-HT, prolong and increase the effect of 5-HT, and thus produce antidepressant effect. Duloxetine is a selective 5-HT and norepinephrine (NE) reuptake inhibitor, which is used for treating depression, generalized anxiety disorder and chronic musculoskeletal pain. Tolterodine is clinically used for the treatment of symptoms such as urinary frequency, urinary urgency or urgency incontinence caused by bladder hyperactivity. The chemical structural formulas of the above drugs are as follows.

[0003]

[0004] The current preparation method of these drugs not only involves the construction of a key chiral alcohol, but also contains an important functional group that can be further modified. Through the reverse synthesis analysis of these compounds, chiral β-hydroxypropionaldehyde glycol can be used as an important intermediate for preparing the above drugs. The chemical structural formula of chiral β-hydroxypropionaldehyde glycol is as follows.

[0005]

[0006] Racemic β-hydroxypropionaldehyde glycol can be prepared by reducing β-ketopropionaldehyde glycol with a reducing agent, but there are very few methods for directly synthesizing chiral β-hydroxypropionaldehyde glycol. Paul Knochel reported in Sc(OTf)3-Catalyzed Addition of Bromomagnesium 2-VinyloxyEthoxide to Various Aldehydes Leading to Protected Aldol Products, Paul Knochel, Synlett, 2016, 27(11): 1715-1719 that Sc(OTf)3-catalyzed addition of bromomagnesium 2-vinyloxyethoxide to various aldehydes leads to protected aldol products, and then chiral β-hydroxypropionaldehyde glycol is obtained by Swern oxidation and Corey-Bakshi-Shibata reduction. However, the optical purity of chiral β-hydroxypropionaldehyde glycol obtained by this method is only 94%.

[0007] In general, there are few methods for directly preparing optically pure β-hydroxypropionaldehyde glycol, and the existing synthesis methods have the disadvantages of multiple reaction steps, large reagent consumption, and low optical purity of chiral β-hydroxypropionaldehyde glycol obtained.

[0008] Based on this, there is room for improvement in the preparation method of chiral β-hydroxypropionaldehyde glycol. SUMMARY

[0009] Therefore, the purpose of the present application is to provide a preparation method for synthesizing chiral β-hydroxypropionaldehyde glycol with high enantioselectivity, which solves the problems of existing synthesis methods, such as multiple reaction steps and large reagent consumption.

[0010] To achieve the above purpose, the technical solution provided by the present application is a preparation method for synthesizing chiral β-hydroxypropionaldehyde glycol with high enantioselectivity, which comprises: using a chiral ligand modified iridium metal catalyst to catalyze the asymmetric hydrogenation of β-ketopropionaldehyde glycol to prepare chiral β-hydroxypropionaldehyde glycol.

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

[0012]

[0013] 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;

[0014] 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.

[0015] In some embodiments, the iridium metal catalyst comprises [Ir(COD)Cl]2.

[0016] In some embodiments, the β-ketopropionaldehyde glycol is a β-ketopropionaldehyde glycol of structural formula (III),

[0017]

[0018] wherein R comprises a phenyl group, an alkyl-substituted phenyl group or an alkyl-substituted thienyl group, a halogen atom-substituted phenyl group or a halogen atom-substituted thienyl group, or a naphthyl group.

[0019] In some embodiments, the chiral β-hydroxypropionaldehyde glycol comprises a chiral β-hydroxypropionaldehyde glycol of structural formula (I) or a chiral β-hydroxypropionaldehyde glycol of structural formula (II), the chiral β-hydroxypropionaldehyde glycol is the chiral β-hydroxypropionaldehyde glycol of structural formula (I) when the chiral ligand is the chiral ligand of structural formula (IV), and the chiral β-hydroxypropionaldehyde glycol is the chiral β-hydroxypropionaldehyde glycol of structural formula (II) when the chiral ligand is the chiral ligand of structural formula (V),

[0020]

[0021] wherein R comprises a phenyl group, an alkyl-substituted phenyl group or an alkyl-substituted thienyl group, a halogen atom-substituted phenyl group or a halogen atom-substituted thienyl group, or a naphthyl group.

[0022] In some embodiments, the method for preparing a chiral β-hydroxypropionaldehyde glycol with high enantioselectivity comprises the following steps:

[0023] Step 1, adding an iridium metal catalyst, a chiral ligand, a β-ketopropionaldehyde glycol, a solvent, and a base into an autoclave, respectively;

[0024] Step 2, replacing the air in the autoclave with hydrogen gas;

[0025] 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 post-reaction product;

[0026] Step 4, the post-reaction product is separated to obtain pure chiral β-hydroxy propionaldehyde glycol.

[0027] 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 the β-keto propionaldehyde glycol 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.

[0028] In some embodiments, in step 1, the base is barium hydroxide, and the solvent is anhydrous ethanol.

[0029] In some embodiments, in step 2, the air in the autoclave is replaced with hydrogen three times.

[0030] 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℃, and the time is set to 1-6 h.

[0031] Advantages of the present application:

[0032] The preparation method of the present application for high enantioselective synthesis of chiral β-hydroxy propionaldehyde glycol uses β-keto propionaldehyde glycol as a raw material and can synthesize β-hydroxy propionaldehyde glycol with high enantioselectivity through a chiral ligand. The β-keto propionaldehyde glycol can complete asymmetric selective hydrogenation reaction at room temperature to generate β-hydroxy propionaldehyde glycol with optical properties. The method of the present application is simple, uses a small amount of solvent, and can obtain β-hydroxy propionaldehyde glycol in a short time. The method can overcome the problems of the existing synthesis methods, such as multiple reaction steps, large reagent consumption, and low optical purity of the obtained chiral β-hydroxy propionaldehyde glycol. The method provides a new approach for the synthesis of some commercial drugs. The prepared chiral β-hydroxy propionaldehyde glycol has high optical purity and chemical purity and can be further used to synthesize commercial drugs such as tomoxetine, fluoxetine, duloxetine, and tolteridine. DETAILED DESCRIPTION

[0033] To make the purpose, technical solutions and advantages of the present application clearer, the embodiments of the present application are further described in detail below.

[0034] It should be noted that all the expressions of “first” and “second” in the embodiments of the present application are used to distinguish two same-named different entities or different parameters. The “first” and “second” are only for the convenience of description and should not be understood as a limitation of the embodiments of the present application. The subsequent embodiments will not be described one by one.

[0035] The application provides a preparation method of high enantioselective synthesis of chiral beta-hydroxy propyl aldehyde glycol, which comprises the following steps: using chiral ligand modified iridium metal catalyst to catalyze asymmetric hydrogenation of beta-keto propyl aldehyde glycol to prepare chiral beta-hydroxy propyl aldehyde glycol.

[0036] In some embodiments, the chiral ligand comprises a chiral ligand of structural formula (IV) or a chiral ligand of structural formula (V).

[0037]

[0038] The chiral ligand of structural formula (IV) is (1R)-N-(2-(bis(2-methoxyphenyl)phosphine)benzyl)-1-(6-methoxyquinoline-4-yl)-1-((2R,5R)-5-vinylquinoline-2-yl)methylamine. The (1R)-N-(2-(bis(2-methoxyphenyl)phosphine)benzyl)-1-(6-methoxyquinoline-4-yl)-1-((2R,5R)-5-vinylquinoline-2-yl)methylamine has the effect of affecting the selectivity of the reaction, coordinates with metal ions as a chiral ligand to form a chiral metal complex in an asymmetric catalytic reaction of asymmetric synthesis, and can selectively catalyze the reaction as a catalyst in an asymmetric hydrogenation reaction, so that unsaturated compounds (such as olefins) are selectively hydrogenated from a certain direction to generate products with a specific stereochemical configuration; in the synthesis of chiral drugs in asymmetric synthesis, it can help to 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 drug.

[0039] The chiral ligand of structural formula (V) is (1S)-N-(2-(bis(2-methoxyphenyl)phosphoryl)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methanamine. (1S)-N-(2-(bis(2-methoxyphenyl)phosphoryl)benzyl)-1-(6-methoxyquinolin-4-yl)-1-((2R,5R)-5-vinylquinolin-2-yl)methanamine has stereoselective induction in asymmetric catalytic reactions, can coordinate with metal catalysts to form chiral metal complexes, and can provide an asymmetric environment for reaction substrates in asymmetric catalytic reactions (such as asymmetric hydrogenation, asymmetric epoxidation, etc.). For example, in asymmetric hydrogenation, when the substrate (such as an unsaturated compound) approaches the active site of the catalyst, due to the steric hindrance and electronic effect of the chiral ligand, the substrate will bind in a specific direction and manner. This makes the hydrogen atom selectively added to one side of the unsaturated bond, thereby generating a product with a specific stereochemical configuration; has enantioselective control, 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, alkylation, etc.), the chiral ligand can distinguish between enantiomers of the substrate. In addition, in reactions for synthesizing chiral drug intermediates, the chiral ligand can guide the reaction to generate a product with high optical purity, and different enantiomers of the drug intermediate can produce final drug products with different pharmacological activities or toxicities in subsequent reactions.

[0040] In some embodiments, the iridium metal catalyst includes [Ir(COD)Cl]2, which is named (1,5-cyclooctadiene)iridium(I) chloride dimer, and is also known as dichloro 1,5-cyclooctadiene iridium dimer. [Ir(COD)Cl]2 plays a role in asymmetric hydrogenation by forming a catalytically active center and 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 will undergo ligand exchange with the chiral ligand, and the newly formed complex is the active center of the asymmetric hydrogenation reaction; has an activating effect on the substrate, and 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 the olefin coordinates with the iridium complex, the electron cloud of the double bond of the olefin will be affected by the iridium center, and the activity of the double bond will increase, making it easier to accept hydrogen addition; guides stereoselective reactions, and in asymmetric hydrogenation reactions, the chiral catalyst formed by the combination of [Ir(COD)Cl]2 and the chiral ligand can guide hydrogen atoms to selectively add from one side of the substrate, thereby highly selectively generating a product with a specific stereochemical configuration. For example, in the synthesis of intermediates for chiral drugs or natural products, such stereoselective hydrogenation can effectively control the chiral purity of the product.

[0041] In some embodiments, the β-ketopropionaldehyde glycol is a β-ketopropionaldehyde glycol of structural formula (III).

[0042]

[0043] wherein R includes a phenyl group, an alkyl-substituted phenyl group or an alkyl-substituted thienyl group, a halogen atom-substituted phenyl group or a halogen atom-substituted thienyl group, or a naphthyl group.

[0044] In some embodiments, the chiral β-hydroxypropionaldehyde glycol includes a chiral β-hydroxypropionaldehyde glycol of structural formula (I) or a chiral β-hydroxypropionaldehyde glycol of structural formula (II), the chiral β-hydroxypropionaldehyde glycol of structural formula (I) when the chiral ligand is a chiral ligand of structural formula (IV), and the chiral β-hydroxypropionaldehyde glycol of structural formula (II) when the chiral ligand is a chiral ligand of structural formula (V).

[0045]

[0046] wherein R includes a phenyl group, an alkyl-substituted phenyl group or an alkyl-substituted thienyl group, a halogen atom-substituted phenyl group or a halogen atom-substituted thienyl group, or a naphthyl group.

[0047] The chiral β-hydroxypropionaldehyde glycol of structural formula (I) is a chiral β-hydroxypropionaldehyde glycol of S configuration, and the chiral β-hydroxypropionaldehyde glycol of structural formula (II) is a chiral β-hydroxypropionaldehyde glycol of R configuration.

[0048] The reaction of the preparation method of the present application for the high enantioselective synthesis of the chiral β-hydroxypropionaldehyde glycol is shown as follows:

[0049]

[0050] or

[0051]

[0052] Compared with the prior art, the preparation method for synthesizing chiral beta-hydroxy propionaldehyde glycol with high enantioselectivity of the application can synthesize beta-hydroxy propionaldehyde glycol with high enantioselectivity by using beta-keto propionaldehyde glycol as raw material and a chiral ligand, and can complete asymmetric selective hydrogenation reaction of beta-keto propionaldehyde glycol at normal temperature to generate beta-hydroxy propionaldehyde glycol with optical properties. Meanwhile, beta-hydroxy propionaldehyde glycol can be obtained by using a small amount of solvent and reacting for a short time under the condition of [Ir(COD)Cl]2 and Ba(OH)2 through the chiral ligand. The method 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 beta-hydroxy propionaldehyde glycol. In addition, the method has a short reaction time, but still has high yield and optical purity.

[0053] The preparation method for synthesizing chiral beta-hydroxy propionaldehyde glycol with high enantioselectivity of the application comprises the following steps:

[0054] Step 1, an iridium metal catalyst, a chiral ligand, beta-keto propionaldehyde glycol, a solvent and a base are added into an autoclave respectively;

[0055] Step 2, hydrogen is used to replace the air in the autoclave;

[0056] 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 post-reaction product;

[0057] Step 4, the post-reaction product is separated to obtain pure chiral beta-hydroxy propionaldehyde glycol.

[0058] 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 beta-keto propionaldehyde glycol 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.

[0059] In some embodiments, in step 1, the base is barium hydroxide.

[0060] In some embodiments, in step 1, the solvent is anhydrous ethanol.

[0061] In some embodiments, in step 2, the air in the autoclave is replaced with hydrogen three times.

[0062] In some embodiments, in step 3, the hydrogen pressure in the autoclave is adjusted to 4.0-8.0 MPa, the set temperature is 25-50 DEG C, and the set time is 1-6 h.

[0063] In some embodiments, in step 3, the set temperature is 30-40 DEG C.

[0064] In some embodiments, in step 3, the time is set to 1-3 h.

[0065] In some embodiments, in step 4, the post-reaction product is separated by silica gel column chromatography.

[0066] The preparation method of the present application for the high enantioselective synthesis of chiral β-hydroxy propionaldehyde glycol, taking β-ketopropionaldehyde glycol as raw material, adding catalyst [Ir(COD)Cl]2, Ba(OH)2 and chiral ligand, anhydrous ethanol as solvent, replacing the air in the autoclave with hydrogen gas, adjusting the hydrogen pressure in the reaction kettle and reacting under the set reaction conditions to prepare chiral β-hydroxy propionaldehyde glycol.

[0067] Example One

[0068] [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of structural formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-phenyl-propionaldehyde glycol (288 mg, 1.50 mmol) and anhydrous ethanol (2.0 mL) were added to the autoclave, the air in the autoclave was replaced with hydrogen gas three times, the hydrogen pressure in the autoclave was adjusted to 6.0 MPa, and the reaction was carried out at 35°C for 1 h. After the reaction was completed, the post-reaction product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-phenyl-propionaldehyde glycol (colorless oil, 288 mg, yield 99%). 98.8% ee, S )-3-hydroxy-3-phenyl-propionaldehyde glycol (colorless oil, 288 mg, yield 99%). 98.8% ee, S configuration; [α] D 25 = - 29.4 (c = 1.00 in CHCl3); 1 H NMR (600 MHz, DMSO- d 6) δ 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)δ 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 O3Na [M+Na] + : 217.0841, found: 217.0840.

[0069] Example 2

[0070] [Ir(COD)Cl]₂ (1.0 mg, 0.0015 mmol), (IV) chiral ligand (4.0 mg, 0.0060 mmol), Ba(OH)₂ (3.4 mg, 0.02 mmol), 3-oxo-3-(4-methylphenyl)-propanal ethylene glycol (124 mg, 0.60 mmol), and anhydrous ethanol (2.0 mL) were gradually added to an autoclave. The air inside the autoclave was replaced three times with hydrogen gas. After adjusting the hydrogen pressure inside the autoclave to 6.0 MPa, the reaction was carried out at 35 °C for 2 h. After the reaction, the product was separated by silica gel column chromatography to obtain pure [Ir(COD)Cl]₂. S 3-Hydroxy-3-(4-methylphenyl)-propionaldehyde ethylene glycol (colorless oil, 112 mg, 90% yield). 99.0% ee. S Configuration; [α] D 25 = -17.0 (c = 1.00 inCHCl3); 1 H NMR (600 MHz, CDCl3) δ 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) δ143.17, 136.33, 129.13, 126.15, 102.18, 69.49, 64.58, 43.99,21.15. HRMS (ESI) calcd. for C 12 H 16 O3Na [M+Na] + : 231.0997, found: 231.0994.

[0071] Example 3

[0072] [Ir(COD)Cl]₂ (1.0 mg, 0.0015 mmol), (IV) chiral ligand (4.0 mg, 0.0060 mmol), Ba(OH)₂ (3.4 mg, 0.02 mmol), 3-oxo-3-(4-methoxyphenyl)-propanal ethylene glycol (333 mg, 1.50 mmol), and anhydrous ethanol (2.0 mL) were gradually added to an autoclave. The air inside the autoclave was replaced three times with hydrogen gas. After adjusting the hydrogen pressure inside the autoclave to 6.0 MPa, the reaction was carried out at 35 °C for 1 h. After the reaction, the product was separated by silica gel column chromatography to obtain pure [Ir(COD)Cl]₂. S 3-Hydroxy-3-(4-methoxyphenyl)-propionaldehyde ethylene glycol (colorless oil, 309 mg, 92% yield). 98.6% ee. S Configuration; [α] D 25 = -34.2 (c = 1.00 inCHCl3); 1 H NMR (600 MHz, CDCl3) δ 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, CDCl3) δ158.94, 136.02, 126.96, 113.79, 103.20, 69.94, 64.81, 55.28,42.34. HRMS (ESI) calcd. for C 12 H 16 O4Na [M+Na] + : 247.0946, found: 247.0947.

[0073] Example 4

[0074] [Ir(COD)Cl]₂ (1.0 mg, 0.0015 mmol), (IV) chiral ligand (4.0 mg, 0.0060 mmol), Ba(OH)₂ (3.4 mg, 0.02 mmol), 3-oxo-3-(4-fluorophenyl)-propanal ethylene glycol (31.5 mg, 0.15 mmol), and anhydrous ethanol (2.0 mL) were gradually added to an autoclave. The air inside the autoclave was replaced three times with hydrogen gas. After adjusting the hydrogen pressure inside the autoclave to 6.0 MPa, the reaction was carried out at 35 °C for 1 h. After the reaction, the product was separated by silica gel column chromatography to obtain pure [Ir(COD)Cl]₂. S 3-Hydroxy-3-(4-fluorophenyl)-propionaldehyde ethylene glycol (colorless oil, 25.4 mg, 80% yield). 98.0% ee. S Configuration; [α] D 25 = -15.2 (c = 1.00 inCHCl3); 1 H NMR (600 MHz, DMSO- d 6) δ 7.35-7.37 (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, CDCl3) δ 161.89, 160.27, 138.56, 126.36, 114.11, 102.07, 68.65, 63.83, 41.39.HRMS (ESI) calcd. for C11 H 13 O3FNa [M+Na] + : 235.0746, found: 235.0740.

[0075] Example 5

[0076] [Ir(COD)Cl]₂ (1.0 mg, 0.0015 mmol), (IV) chiral ligand (4.0 mg, 0.0060 mmol), Ba(OH)₂ (3.4 mg, 0.02 mmol), 3-oxo-3-(2-naphthyl)-propionaldehyde ethylene glycol (363 mg, 1.50 mmol), and anhydrous ethanol (2.0 mL) were gradually added to an autoclave. The air inside the autoclave was replaced three times with hydrogen gas. After adjusting the hydrogen pressure inside the autoclave to 6.0 MPa, the reaction was carried out at 35 °C for 1 h. After the reaction, the product was separated by silica gel column chromatography to obtain pure [Ir(COD)Cl]₂. S 3-Hydroxy-3-(2-naphthyl)-propionaldehyde ethylene glycol (colorless oil, 322 mg, 88% yield). 98.5% ee. S Configuration; [α] D 25 = -27.6 (c = 1.00 in CHCl3); 1 HNMR (600 MHz, CDCl3) δ 7.82-7.86 (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, CDCl3) δ 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 O3Na [M+Na] + : 267.0997, found: 267.0994.

[0077] Example 6

[0078] [Ir(COD)Cl]₂ (1.0 mg, 0.0015 mmol), (IV) chiral ligand (4.0 mg, 0.0060 mmol), Ba(OH)₂ (3.4 mg, 0.02 mmol), 3-oxo-3-(2-trifluoromethylphenyl)-propanal ethylene glycol (390 mg, 1.50 mmol), and anhydrous ethanol (2.0 mL) were gradually added to an autoclave. The air inside the autoclave was replaced three times with hydrogen gas. After adjusting the hydrogen pressure inside the autoclave to 6.0 MPa, the reaction was carried out at 35 °C for 2 h. After the reaction, the product was separated by silica gel column chromatography to obtain pure [Ir(COD)Cl]₂. S 3-Hydroxy-3-(2-trifluoromethylphenyl)-propionaldehyde ethylene glycol (colorless oil, 346 mg, 88% yield). 99.0% ee. S Configuration; [α] D 25 = -25.7 (c = 1.00in CHCl3); 1 H NMR (600 MHz, DMSO- d 6) δ 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 O3F3Na [M+Na] + :285.0714, found: 285.0718.

[0079] Example 7

[0080] [Ir(COD)Cl]₂ (1.0 mg, 0.0015 mmol), (IV) chiral ligand (4.0 mg, 0.0060 mmol), Ba(OH)₂ (3.4 mg, 0.02 mmol), 3-oxo-3-(3,5-bis(trifluoromethyl)phenyl)-propanal ethylene glycol (492 mg, 1.50 mmol), and anhydrous ethanol (2.0 mL) were gradually added to an autoclave. The air inside the autoclave was replaced three times with hydrogen gas. After adjusting the hydrogen pressure inside the autoclave to 6.0 MPa, the reaction was carried out at 35 °C for 2 h. After the reaction, the product was separated by silica gel column chromatography to obtain pure [Ir(COD)Cl]₂. S 3-Hydroxy-3-(3,5-bis(trifluoromethyl)phenyl)-propionaldehyde ethylene glycol (colorless oil, 396 mg, 80% yield). 99.0% ee. S Configuration; [α] D 25 = -15.8 (c = 1.00 in CHCl3); 1 H NMR (600 MHz, DMSO- d 6) δ 8.02 (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, CDCl3) δ 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 O3F6Na [M+Na] + : 353.0588, found: 353.0584.

[0081] Example 8

[0082] To a pressure vessel was added [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of structural formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(2,4-dichlorophenyl)-propanal acetonide (78 mg, 0.30 mmol), and anhydrous ethanol (2.0 mL). The air in the pressure vessel was replaced with hydrogen three times, and the pressure of hydrogen in the pressure vessel was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 3 h. After the reaction was completed, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(2,4-dichlorophenyl)-propanal acetonide (colorless oil, 74 mg, yield 94%). 97.7% ee, [a] S = -54.9 (c = 1.00 in CHCl3); S = -54.9 (c = 1.00 in CHCl3); D 25 = -54.9 (c = 1.00 in CHCl3); 1 H NMR (600 MHz, DMSO- d 6) δ 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) δ 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 O3Cl2Na [M+Na] + : 285.0061,found: 285.0060.

[0083] Example Nine

[0084] To a pressure vessel was added [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of structural formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(2-thienyl)-propanal acetonide (29.7 mg, 0.15 mmol), and absolute ethanol (2.0 mL). The air in the pressure vessel was replaced with hydrogen three times, and the reaction was carried out at 35 °C for 1 h after the pressure of hydrogen in the pressure vessel was adjusted to 6.0 MPa. The pure (R)-3-hydroxy-3-(2-thienyl)-propanal acetonide (yellow oil, 29.1 mg, 97% yield) was obtained by silica gel column chromatography after the reaction was completed. S 98.8% ee, S configuration; [a] D 25 = -29.4 (c = 1.00 in CHCl3); 1 HNMR (600 MHz, CDCl3) δ 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, CDCl3) δ 147.79, 126.61, 124.45,123.24, 102.82, 66.57, 64.99, 64.85, 42.42. HRMS (ESI) calcd. for C9H 12 O3SNa[M+Na] + : 223.0405, found: 223.0403.

[0085] Example Ten

[0086] To the autoclave was added [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of structural formula (IV) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(5-chloro-2-thienyl)-propanal acetonide (70 mg, 0.30 mmol) and absolute ethanol (2.0 mL). The autoclave was purged with hydrogen three times and the pressure was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 1 h. The product was isolated by silica gel column chromatography to give pure (R)-3-hydroxy-3-(5-chloro-2-thienyl)-propanal acetonide (yellow oil, 70 mg, 99% yield). 97.3% ee, [a] S = -1.8 (c = 1.00 in CHCl3); S = -1.8 (c = 1.00 in CHCl3); D 25 = -1.8 (c = 1.00 in CHCl3); 1 H NMR (600 MHz, CDCl3) δ 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, CDCl3) δ 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 C9H 11 O3SClNa [M+Na] + : 257.0015, found: 257.0012.

[0087] Example Eleven

[0088] To a high-pressure vessel, [Ir(COD)Cl]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)-propanal acetonide (124 mg, 0.60 mmol) and anhydrous ethanol (2.0 mL) were added step by step, the air in the high-pressure vessel was replaced with hydrogen for three times, after adjusting the hydrogen pressure in the high-pressure vessel to 6.0 MPa, the reaction was carried out at 35 ℃ for 2 h, after the reaction was completed, the post-reaction product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(4-methylphenyl)-propanal acetonide (colorless oil, 120 mg, yield 96%, 97.7% ee, [α] R = +22.2 (c = 1.00 in CHCl3). R = +22.2 (c = 1.00 in CHCl3). D 25 = +22.2 (c = 1.00 in CHCl3). 1 H NMR (600 MHz, CDCl3) δ 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) δ 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 O3Na [M+Na] + : 231.0997, found: 231.0994.

[0089] Example Twelve

[0090] To the autoclave was added [Ir(COD)Cl]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)-propanal acetonide (136 mg, 0.60 mmol) and absolute ethanol (2.0 mL). The air in the autoclave was replaced with hydrogen three times and the hydrogen pressure was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 2 h. After the reaction was completed, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(4-chlorophenyl)-propanal acetonide (colorless oil, 109 mg, yield 80%, 94.2% ee, [a]D= +18.5 (c = 1.00 in CHCl3). R R = + 18.5 (c = 1.00 in CHCl3). D 25 = + 18.5 (c = 1.00 in CHCl3). 1 HNMR (600 MHz, DMSO- d 6) δ 7.34-7.38 (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, CDCl3) δ 141.37, 132.01, 127.52, 126.09,102.05, 68.61, 63.85, 41.33. HRMS (ESI) calcd. for C 11 H 13 ClNaO3[M+Na] + :251.0445, found: 251.0446.

[0091] Example XIII

[0092] ​To a pressure vessel was added [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of formula (V) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(4-bromophenyl)-propanal acetonide (162 mg, 0.60 mmol) and absolute ethanol (2.0 mL). The air in the pressure vessel was replaced with hydrogen three times and the pressure was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 2 h. The product was isolated by silica gel column chromatography to give pure (R)-3-hydroxy-3-(4-bromophenyl)-propanal acetonide (colorless oil, 145 mg, 89% yield). 98.3% ee, [a] R = + 15.0 (c = 1.00 in CHCl3). R = + 15.0 (c = 1.00 in CHCl3). D 25 = + 15.0 (c = 1.00 in CHCl3). 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 BrNaO3[M+Na] + : 294.9940, found: 294.9947.

[0093] Example Fourteen

[0094] To the autoclave was added [Ir(COD)Cl]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)-propanal acetonide (62 mg, 0.30 mmol) and absolute ethanol (2.0 mL). The autoclave was purged with hydrogen three times to remove air. After the pressure of hydrogen was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 3 h. After the reaction was completed, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(2-methylphenyl)-propanal acetonide (colorless oil, 52 mg, yield 84%, 99.3% ee, [a]D= + 46.7 (c = 1.00 in CHCl3). R = + 46.7 (c = 1.00 in CHCl3). R = + 46.7 (c = 1.00 in CHCl3). D 25 = + 46.7 (c = 1.00 in CHCl3). 1 HNMR (600 MHz, CDCl3) δ 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, CDCl3) δ 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 NaO3[M+Na] + :231.0992, found: 231.0992.

[0095] Example Fifteen

[0096] To a pressure vessel was added [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of formula (V) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(2-fluorophenyl)-propanal acetonide (126 mg, 0.60 mmol) and absolute ethanol (2.0 mL). The air in the pressure vessel was replaced with hydrogen three times and the reaction was carried out at 35 °C for 1 h under 6.0 MPa of hydrogen pressure. The product was isolated by silica gel column chromatography to give pure (R)-3-hydroxy-3-(2-fluorophenyl)-propanal acetonide (yellow oil, 112 mg, 88% yield). 96.7% ee, [a] R = +49.2 (c = 1.00 in CHCl3). R = +49.2 (c = 1.00 in CHCl3). D 25 = +49.2 (c = 1.00 in CHCl3). 1 HNMR (600 MHz, DMSO- d 6) δ 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, CDCl3) δ 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 FNaO3[M+Na] + : 235.0741, found: 235.0745.

[0097] Example Sixteen

[0098] To a 100 mL autoclave, [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of formula (V) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(2-trifluoromethylphenyl)-propanal acetonide (156 mg, 0.60 mmol) and absolute ethanol (2.0 mL) were added in sequence. The autoclave was purged with hydrogen three times and the pressure was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 2 h. After the reaction was completed, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(2-trifluoromethylphenyl)-propanal acetonide (yellow oil, 138 mg, 88% yield). 99.0% ee, [a] R ]D35 = + 26.3 (c = 1.00 in CHCl3). R D 25 1 H NMR (600 MHz, DMSO- d 6) δ 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 O3F3Na [M+Na] + :285.0714, found: 285.0718.

[0099] Example Seventeen

[0100] ​​To a high-pressure vessel was added [Ir(COD)Cl]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)-propanal acetonide (68 mg, 0.30 mmol), and absolute ethanol (2.0 mL). The air in the high-pressure vessel was replaced with hydrogen three times, and the hydrogen pressure in the high-pressure vessel was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 3 h. After the reaction was completed, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(2-chlorophenyl)-propanal acetonide (colorless oil, 57 mg, yield 84%, 97.6% ee, [a]D= + 50.2 (c = 1.00 in CHCl3). R R = + 50.2 (c = 1.00 in CHCl3). D 25 = + 50.2 (c = 1.00 in CHCl3). 1 H NMR (600 MHz, CDCl3) δ 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, CDCl3) δ 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 ClNaO3[M+Na] + : 251.0445, found:251.0453.

[0101] Example Eighteen

[0102] ​To a 100 mL autoclave, [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of formula (V) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(3,4-dichlorophenyl)-propanal acetonide (78 mg, 0.30 mmol) and absolute ethanol (2.0 mL) were added in sequence. The air in the autoclave was replaced with hydrogen three times and the hydrogen pressure was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 3 h. After the reaction, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(3,4-dichlorophenyl)-propanal acetonide (colorless oil, 47 mg, yield 60%, 91.3% ee, [a]D= +10.4 (c = 1.00 in CHCl3). R R = + 10.4 (c = 1.00 inCHCl3). D 25 = + 10.4 (c = 1.00 inCHCl3). 1 H NMR (600 MHz, CDCl3) δ 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,CDCl3) δ 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 Cl2NaO3[M+Na] + : 285.0056, found: 285.0054.

[0103] Example Nineteen

[0104] ​To a 100 mL Schlenk flask, [Ir(COD)Cl]2(1.0 mg, 0.0015 mmol), chiral ligand of formula (V) (4.0 mg, 0.0060 mmol), Ba(OH)2(3.4 mg, 0.02 mmol), 3-oxo-3-(2-thienyl)-propanal acetonide (119 mg, 0.60 mmol) and absolute ethanol (2.0 mL) were added successively. The air in the Schlenk flask was replaced by hydrogen for three times. After the pressure of hydrogen was adjusted to 6.0 MPa, the reaction was carried out at 35 °C for 6 h. After the reaction was completed, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(2-thienyl)-propanal acetonide (yellow oil, 103 mg, yield 86%, 95.0% ee, [a]D= + 18.0 (c = 1.00 in CHCl3). R R = + 18.0 (c = 1.00 in CHCl3). D 25 = + 18.0 (c = 1.00 in CHCl3). 1 H NMR (600 MHz, CDCl3) 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, CDCl3) δ 147.79, 126.61, 124.45,123.24, 102.82, 66.57, 64.92, 42.42. HRMS (ESI) calcd. for C9H 12 O3SNa [M+Na] + :223.0405, found: 223.0403.

[0105] Example Twenty

[0106] ​To the autoclave was added [Ir(COD)Cl]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)-propanal acetonide (64 mg, 0.30 mmol) and absolute ethanol (2.0 mL). The air in the autoclave was replaced with hydrogen three times and the hydrogen pressure was adjusted to 6.0 MPa. The reaction was carried out at 35 °C for 2 h. After the reaction was completed, the product was separated by silica gel column chromatography to obtain pure (R)-3-hydroxy-3-(5-methyl-2-thienyl)-propanal acetonide (yellow oil, 52 mg, yield 81%). 93.7% ee, [a] R ]D35 = + 5.0 (c = 1.00 in CHCl3). R D 25 = + 5.0 (c = 1.00 in CHCl3). 1 H NMR (600 MHz, CDCl3) 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, CDCl3) δ 145.19, 139.13, 124.55, 123.30, 102.87, 66.68, 64.92, 42.26, 15.38. HRMS (ESI) calcd. for C 10 H 14 NaO3S [M+Na] + : 237.0556, found: 237.0562.

[0107] ​The preparation method of the high enantioselective synthesis of chiral beta-hydroxy propionaldehyde glycol of the application uses different configuration chiral ligand modified iridium metal catalyst to catalyze beta-keto propionaldehyde glycol hydrogenation to synthesize chiral beta-hydroxy propionaldehyde glycol, which is simple in process, high in yield of obtained product, and high in optical purity and chemical purity.

[0108] The beta-keto propionaldehyde glycol raw material containing different substituents in the examples one to twenty is subjected to asymmetric catalytic hydrogenation by the chiral catalyst of the chiral ligand of structural formula (IV) or the chiral ligand of structural formula (V) to obtain beta-hydroxy propionaldehyde glycol products containing different substituents, which only represent the results of actual synthesis, and the beta-keto propionaldehyde glycol raw material containing other substituents and its product should also belong to the protection scope of the application, and the protection scope of the application should not be limited to the listed examples.

[0109] The preparation method of the high enantioselective synthesis of chiral beta-hydroxy propionaldehyde glycol of the application uses iridium metal catalytic system to catalyze asymmetric hydrogenation of beta-keto propionaldehyde glycol to prepare chiral beta-hydroxy propionaldehyde glycol with high optical purity, which provides a new way for synthesis of some commercial drugs; the process is simple, the obtained product has high optical purity and chemical purity, and the prepared chiral beta-hydroxy propionaldehyde glycol can be further used for synthesis of commercial drugs such as tomoxetine, fluoxetine, duloxetine, and tolteridine.

[0110] The technical features of the above examples can be combined arbitrarily, and for the sake of brevity, all possible combinations of the technical features in the above examples are not described, however, as long as the combination of the technical features does not exist contradictory, it should be considered as the scope of the description.

[0111] The above examples only express several embodiments of the application, which are described in detail and specifically, but should not be understood as the limitation of the scope of the patent. It should be pointed out that for ordinary skilled in the art, without departing from the concept of the application, several modifications and improvements can be made, which are within the protection scope of the application.

Claims

1. A process for the preparation of a chiral β-hydroxypropionaldehyde glycol acetal, characterized in that, The application relates to a method for preparing chiral beta-hydroxy propionaldehyde glycol by asymmetric hydrogenation of beta-keto propionaldehyde glycol using an iridium metal catalyst modified by a chiral ligand. The chiral ligand is selected from a chiral ligand of structural formula (IV) or a chiral ligand of structural formula (V). The iridium metal catalyst is selected from [Ir(COD)Cl]2. The beta-keto propionaldehyde glycol is beta-keto propionaldehyde glycol of structural formula (III).

2. The process for the preparation of a chiral β-hydroxypropionaldehyde glycol acetal according to claim 1, characterized in that, R is selected from a phenyl group, an alkyl-substituted phenyl group or an alkyl-substituted thienyl group, a halogen atom-substituted phenyl group or a halogen atom-substituted thienyl group, or a naphthyl group. The chiral beta-hydroxy propionaldehyde glycol is selected from chiral beta-hydroxy propionaldehyde glycol of structural formula (I) or chiral beta-hydroxy propionaldehyde glycol of structural formula (II).

3. Process for the preparation of chiral β-hydroxypropionaldehyde glycol acetal according to claim 2, characterized in that, R is selected from a phenyl group, an alkyl-substituted phenyl group or an alkyl-substituted thienyl group, a halogen atom-substituted phenyl group or a halogen atom-substituted thienyl group, or a naphthyl group. The method comprises the following steps:

4. Process for the preparation of a synthetic chiral β-hydroxypropionaldehyde glycol according to any one of claims 1 to 3, characterized in that, Step 1, adding the iridium metal catalyst, the chiral ligand, the beta-keto propionaldehyde glycol, a solvent and a base into an autoclave respectively; Step 2, replacing the air in the autoclave with hydrogen; Step 3, adjusting the hydrogen pressure in the autoclave, and then reacting at a set temperature for a set time to obtain a post-reaction product; Step 4, separating the post-reaction product to obtain pure chiral beta-hydroxy propionaldehyde glycol. 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 beta-keto propionaldehyde glycol 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.

5. The process for the preparation of a chiral β-hydroxypropionaldehyde glycol acetal according to claim 4, characterized in that, In step 1, the base is barium hydroxide, and the solvent is anhydrous ethanol.

6. The process for the preparation of synthetic chiral β-hydroxypropionaldehyde glycol acetal according to claim 4, characterized in that, In step 2, the air in the autoclave is replaced with hydrogen three times.

7. The process for the synthesis of chiral β-hydroxypropionaldehyde glycol acetal according to claim 4, characterized in that, In step 3, the hydrogen pressure in the autoclave is adjusted to 4.0-8.0 MPa, the set temperature is 25-50 DEG C, and the set time is 1-6 h.

8. The process for the preparation of a chiral β-hydroxypropionaldehyde glycol acetal according to claim 4, characterized in that, ​

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