A chiral α-hydroxyamide derivative, its synthesis method and application

Abstract

The present invention discloses a chiral α -hydroxyamide derivative, and its synthesis method and application. The synthesis method includes: in the presence of a chiral thiourea catalyst, an aromatic amine and α -carbonyl acylsilane undergo a catalytic asymmetric nucleophilic addition reaction under light in a solvent to form a chiral α -hydroxyamide derivative. The reaction of the present invention uses light as the driving force to achieve green synthesis; secondly, the introduction of the chiral thiourea catalyst not only significantly improves the enantioselectivity but also avoids the use of metal catalysts, which conforms to the concept of green chemistry. In addition, the reaction substrates α -carbonyl acylsilane and aromatic amine are both inexpensive and easily accessible chemicals, thereby reducing the synthesis cost and improving the feasibility and practicality of the method.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of chiral α -hydroxyamides and their derivatives, and particularly relates to a method for preparing chiral α -hydroxyamide derivatives by using a chiral thiourea catalyst, as well as the product and application thereof. Background Art

[0002] Chiral α -hydroxyamides and their derivatives are common and key synthetic building blocks for a variety of important molecules. For example, cefamandole, semagacestat, BMS-270394 (a retinoic acid receptor γ agonist, CAS No.: 262433-54-5), and D-panthenol and other molecules contain chiral α-hydroxyamide structural fragments. This fragment is widely used in the synthesis of natural products, drugs, and bioactive compounds. In the asymmetric synthesis of drugs, they can also often be used as chiral ligands. Currently, the synthetic methods for constructing chiral hydroxyamides and their derivatives mainly include enzymatic reduction, asymmetric hydrogenation, asymmetric hydroboration, asymmetric hydrosilylation, and asymmetric transfer hydrogenation. However, these methods still have many limitations in terms of reaction conditions, substrate scope, and enantioselectivity. Therefore, developing an efficient and highly enantioselective synthetic strategy is of great scientific value and practical significance for the preparation of chiral α -hydroxyamides and their derivatives.

[0003] The Brook rearrangement reaction is a typical [1,2]-migration reaction, which is characterized by the migration of a silicon group from a carbon atom to an oxygen atom, accompanied by charge transfer, converting an alkoxy species into a carbanion (Angew. Chem. Int. Ed. 2023, 62, e202217189). This reaction has been widely used in synthetic chemistry. In recent years, it has been found that α -carbonyl acylsilanes can undergo [1,3]-silyl migration under light conditions to form an oxo ketene intermediate (Angew. Chem. Int. Ed. 2021, 60, 13671-13676; Org. Chem. Front. 2024, 11, 3250-3256). Since the ketene intermediate has high electrophilicity and is prone to react with nucleophiles, we envision that under the action of a chiral catalyst, this ketene intermediate can undergo an asymmetric reaction with an aromatic amine to efficiently synthesize chiral α -hydroxyamides and their derivatives. Summary of the Invention

[0004] The present invention provides a chiral α-Hydroxyamide derivatives and their synthesis methods. Based on the Brook rearrangement strategy, the present invention proposes an asymmetric reaction of α -carbonylacylsilane with aromatic amines under the action of a chiral thiourea catalyst to synthesize chiral α -hydroxyamides and their derivatives. This method not only has high efficiency and high enantioselectivity but also has significant green chemistry characteristics. This method has the following remarkable advantages: First, the reaction uses light as the driving force to achieve green synthesis; second, the introduction of the chiral thiourea catalyst not only significantly improves the enantioselectivity (ee) but also avoids the use of metal catalysts, which conforms to the concept of green chemistry. In addition, the reaction substrates α -carbonylacylsilane and aromatic amines are both inexpensive and easily accessible chemicals, thus reducing the synthesis cost and improving the feasibility and practicality of the method. In summary, while improving the synthesis efficiency and enantioselectivity, this method has the characteristics of green chemistry, has important theoretical research value and broad application prospects, especially has great potential in the fields of drug synthesis and natural product preparation.

[0005] In a first aspect, the present invention provides a chiral α -hydroxyamide derivative having the structure shown in the following formula (I):

[0006] (I);

[0007] In formula (I):

[0008] Ar is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl, and the substituents are selected from one or more of methyl, methoxy, halogen atom, dimethylamino, and oxazolyl;

[0009] R 1 is a substituted or unsubstituted C1-C10 chain alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heterocycle having one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and the substituents are selected from one or more of hydroxyl, amino, halogen atom, nitro (-NO2), cyano (-CN), and C1-C4 alkyl;

[0010] [Si] represents a silicon group.

[0011] In some embodiments, in formula (I):

[0012] Ar is phenyl, p-tolyl, o-tolyl, m-methoxyphenyl, p-fluorophenyl, p-dimethylaminophenyl, 2-naphthyl or ;

[0013] R 1 is phenyl, p-chlorophenyl, p-fluorophenyl, p-tolyl, p-methoxyphenyl, 2-naphthyl, propyl or isobutyl;​​​​​​​​

[0014] [Si] is trimethylsilyl, triethylsilyl, dimethyl tert-butylsilyl, triisopropylsilyl (TIPS), or dimethylphenylsilyl.

[0015] In a second aspect, the present invention provides a method for synthesizing the chiral α -hydroxyamide derivative described in the first aspect, comprising: in the presence of a chiral thiourea catalyst, an aromatic amine Ar-NH2 and α -carbonyl acylsilane undergo a catalytic asymmetric nucleophilic addition reaction in a solvent under light irradiation to form the chiral α -hydroxyamide derivative;

[0016] The α -carbonyl acylsilane has the structure shown in the following formula (II):

[0017] (II).

[0018] In the above synthesis method, after the reaction is completed, the product can be separated and characterized by conventional separation and purification methods to obtain the target product.

[0019] The synthesis method of the present invention is preferably carried out in an inert atmosphere, and the inert atmosphere refers to a gas atmosphere that does not participate in the reaction, such as a nitrogen atmosphere.

[0020] In some preferred examples, the chiral thiourea catalyst includes at least one of catalyst-1, catalyst-2, catalyst-3, and catalyst-4;

[0021] Catalyst-1 (Cat-1):

[0022] ;

[0023] Catalyst-2 (Cat-2):

[0024] ;

[0025] Catalyst-3 (Cat-3):

[0026] ;

[0027] Catalyst-4 (Cat-4):

[0028] .

[0029] By using the above preferred chiral thiourea catalyst, the product yield and enantioselectivity can be further significantly improved. Among the above chiral thiourea catalysts, catalyst-4 is further preferably included, and the comprehensive product yield and enantioselectivity are the highest.

[0030] In some embodiments, the molar ratio of the aromatic amine and the α -carbonylacylsilane can be 5:1 - 25, preferably 1:1.5, which is beneficial to improving the product yield and enantioselectivity.

[0031] In some embodiments, the molar ratio of the aromatic amine and the chiral thiourea catalyst can be 1:0.001 - 0.5, preferably 1:0.05, which is beneficial to improving the product yield and enantioselectivity.

[0032] In some embodiments, the solvent may include at least one of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane (DCM), 1,2-dichloroethane, toluene, and tetrahydrofuran, preferably including dichloromethane, which is beneficial to improving the product yield and enantioselectivity.

[0033] In some embodiments, the temperature of the reaction can be -20~100 °C, preferably -10 °C, which is beneficial to improving the product yield and enantioselectivity.

[0034] In some embodiments, the reaction time can be 0.5 - 25 hours, preferably 4 hours, which is beneficial to improving the product yield and enantioselectivity.

[0035] In some embodiments, the wavelength of the light can be 360 - 800 nm, preferably 455 nm, which is beneficial to improving the product yield and enantioselectivity.

[0036] In some embodiments, the power of the light can be 1 - 100 watts, preferably 15 watts, which is beneficial to improving the product yield and enantioselectivity.

[0037] In a third aspect, the present invention provides the use of the chiral α -hydroxyamide derivative described in the first aspect or the synthesis method described in the second aspect in the preparation of drugs and natural products.

[0038] The present invention uses aromatic amine as a raw material and chiral thiourea catalyst as a chiral source to carry out an asymmetric nucleophilic addition reaction with α -carbonylacylsilane, and synthesizes a series of structurally diverse chiral α -hydroxyamide derivatives with excellent yield and enantioselectivity, and the products can be further derivatized. The chiral α -hydroxyamide derivatives synthesized by the present invention can be used as intermediates for further derivatization to prepare drugs, natural products, etc. The synthesis method of the present invention has easily available raw materials, simple operation, mild reaction conditions, and diverse functional groups.

[0039] Compared with the prior art, the beneficial effects of the present invention are:

[0040] 1) α-Oxocarboxylic acylsilanes can be prepared in large quantities by the prior art and can be used to synthesize different types and structures of α -hydroxyamide derivatives.

[0041] 2) Chiral α -hydroxyamides and their derivatives are common and key synthetic building blocks for a variety of important molecules. For example, molecules such as Cefamandole, Semagacestat, BMS-270394, D-Panthenol, and AAK1 inhibitors can be rapidly constructed through this method and the known desilylation step of tetrabutylammonium fluoride (TBAF).

[0042] 3) The present invention utilizes the reaction of aromatic amines with α -oxocarboxylic acylsilanes to synthesize structurally diverse chiral α -hydroxyamide derivatives with excellent enantioselectivity. The raw materials are readily available, the operation is simple, the yield of the target product is high, and further derivatization can be carried out. Detailed implementation manners

[0043] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The operation methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0044] The chemical reagents used in the following examples are all commercially available or obtained according to the prior art; α -Oxocarboxylic acylsilanes can be synthesized by referring to the methods and routes reported in the literature (such as J. Am. Chem. Soc. 2004, 126, 8618, etc.); the products are confirmed by nuclear magnetic resonance spectroscopy of hydrogen ( 1 1H NMR), nuclear magnetic resonance spectroscopy of carbon ( 13 13C NMR) and high-resolution mass spectrometry (HRMS), and the enantioselectivity is determined by high-performance liquid chromatography (HPLC) with a chiral stationary phase.

[0045] Example 1:

[0046]

[0047] Under a nitrogen atmosphere, the chiral thiourea catalyst Cat-4 (0.0075 mmol) was added to a Schlenk tube equipped with a magnetic stir bar. The tube was evacuated and backfilled with nitrogen five times. Then, anhydrous dichloromethane (3.0 mL) was added via syringe. Under a nitrogen purge, aniline 2a (13.9 mg, 0.15 mmol) and α-Carbonylacylsilane 3a (65.6 mg, 0.225 mmol) was added to a Schlenk tube in sequence, and the reaction was stirred for 4 hours at -10 °C under 455 nm light irradiation with a light intensity of 15 watts. After the reaction was complete, it was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (the eluent was petroleum ether (60 - 90 °C) / ethyl acetate: 20 / 1, v / v), to obtain the target product 1a (53.5 mg, yield 93%, 93% ee). HPLC test conditions: chromatographic column Chiralcel IC, mobile phase n-hexane / isopropanol = 97 / 3 (v / v), flow rate = 1.0 mL / min, wavelength λ = 254 nm.

[0048] Example 2:

[0049] The reaction steps and operations were the same as those in Example 1. The difference from Example 1 was that chiral thiourea catalyst Cat-1 (0.0075 mmol) was added to the reaction system to replace chiral thiourea catalyst Cat-4 (0.0075 mmol), to obtain the white solid target product 1a (55 mg, yield 96%, 36% ee).

[0050] Example 3:

[0051] The reaction steps and operations were the same as those in Example 1. The difference from Example 1 was that chiral thiourea catalyst Cat-2 (0.0075 mmol) was added to the reaction system to replace chiral thiourea catalyst Cat-4 (0.0075 mmol), to obtain the white solid target product 1a (55 mg, yield 96%, 80% ee).

[0052] Example 4:

[0053] The reaction steps and operations were the same as those in Example 1. The difference from Example 1 was that chiral thiourea catalyst Cat-3 (0.0075 mmol) was added to the reaction system to replace chiral thiourea catalyst Cat-4 (0.0075 mmol), to obtain the white solid target product 1a (55 mg, yield 96%, 80% ee).

[0054] Example 5:

[0055]

[0056] The reaction steps and operations were the same as those in Example 1. The difference from Example 1 was that p-methylaniline 2b (16.1 mg, 0.15 mmol) was added to the reaction system to replace aniline 2a (13.9 mg, 0.15 mmol), to obtain the white solid target product 1b (50.7 mg, yield 85%, 91% ee). The HPLC test conditions were the same as those in Example 1.

[0057] Example 6:

[0058]

[0059] The reaction steps and operations were the same as in Example 1. The difference from Example 1 was that m - methoxyaniline 2c (18.5 mg, 0.15 mmol) was added to the reaction system to replace aniline 2a (13.9 mg, 0.15 mmol), and the white solid target product 1c (58.3 mg, yield 94%, 93% ee) was obtained. The HPLC test conditions were the same as in Example 1.

[0060] Example 7:

[0061]

[0062] The reaction steps and operations were the same as in Example 1. The difference from Example 1 was that p - fluoroaniline 2d (16.6 mg, 0.15 mmol) was added to the reaction system to replace aniline 2a (13.9 mg, 0.15 mmol), and the white solid target product 1d (54.2 mg, yield 90%, 91% ee) was obtained. The HPLC test conditions were the same as in Example 1.

[0063] Example 8:

[0064]

[0065] The reaction steps and operations were the same as in Example 1. The difference from Example 1 was that β -naphthylamine 2e (21.5 mg, 0.15 mmol) was added to the reaction system to replace aniline 2a (13.9 mg, 0.15 mmol), and the white solid target product 1e (59.2 mg, yield 91%, 91% ee) was obtained. The HPLC test conditions were the same as in Example 1.

[0066] Example 9:

[0067]

[0068] The reaction steps and operations were the same as in Example 1. The difference from Example 1 was that α -carbonylacylsilane 3b (73.1 mg, 0.225 mmol) was added to the reaction system to replace α -carbonylacylsilane 3a (65.6 mg, 0.225 mmol), and the white solid target product 1f (54.5 mg, yield 87%, 94% ee) was obtained. The HPLC test conditions were the same as in Example 1.

[0069] Example 10:

[0070]

[0071] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that α -carbonylacylsilane 3c is added to replace α -carbonylacylsilane 3a (65.6 mg, 0.225 mmol), and the white solid target product 1g (56.0 mg, yield 93%, 94% ee) is obtained. The HPLC test conditions are the same as those in Example 1.

[0072] Example 11:

[0073]

[0074] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that α -carbonylacylsilane 3d (68.5 mg, 0.225 mmol) is added to replace α -carbonylacylsilane 3a (65.6 mg, 0.225 mmol), and the white solid target product 1h (53.1 mg, yield 89%, 93% ee) is obtained. The HPLC test conditions are the same as those in Example 1.

[0075] Example 12:

[0076]

[0077] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that α -carbonylacylsilane 3e (72.1 mg, 0.225 mmol) is added to replace α -carbonylacylsilane 3a (65.6 mg, 0.225 mmol), and the white solid target product 1i (53.4 mg, yield 86%, 94% ee) is obtained. The HPLC test conditions are the same as those in Example 1.

[0078] Example 13:

[0079]

[0080] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that α -carbonylacylsilane 3f (76.6 mg, 0.225 mmol) is added to replace α-Carbonyl acylsilane 3a (65.6 mg, 0.225 mmol) was added to afford the desired product 1j (58.5 mg, 90% yield, 92% ee) as a white solid. HPLC analysis conditions were the same as in Example 1.

[0081] Example 14:

[0082]

[0083] The reaction steps and operations are the same as those in Example 1, except that α -Carbonyl acylsilane 3g (57.7 mg, 0.225 mmol) was substituted α -Carbonyl acylsilane 3a (65.6 mg, 0.225 mmol) afforded the desired product 1k (50.3 mg, 97% yield, 97% ee) as a white solid. HPLC conditions: Chiralcel IA column, mobile phase: n-hexane / isopropanol = 95 / 5 (v / v), flow rate = 1.0 mL / min, wavelength = 254 nm.

[0084] Example 15:

[0085]

[0086] The reaction steps and operations are the same as those in Example 1, except that α -Carbonyl acylsilane 3h (60.8 mg, 0.225 mmol) was substituted α -carbonyl acylsilane 3a (65.6 mg, 0.225 mmol) was added to afford the desired product 11 (49.1 mg, 90% yield, 96% ee) as a white solid. HPLC analysis conditions were the same as in Example 14.

[0087] Example 16:

[0088] Adapter-associated kinase 1 (AAK1) plays a key role in pain signal transduction, viral entry into cells, and receptor function regulation. Its inhibitors have significant potential in treating neuropathic pain, antiviral infections, and related diseases. The present invention can more efficiently and conveniently synthesize AAK1 inhibitors through the reaction of alkyl acylsilanes with amine compounds, which has important synthetic significance and application value.

[0089] Synthetic compound 6 (AAK1 inhibitor, see patent specification with publication number WO2015006100A1):

[0090]

[0091] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that α -carbonylacylsilane 3h (60.9 mg, 0.225 mmol) was added instead of α -carbonylacylsilane 3a (65.6 mg, 0.225 mmol), and starting material 2f (0.15 mmol) was added instead of aniline 2a (13.9 mg, 0.15 mmol), to obtain the white solid target product 4 (44.9 mg, yield 65%, 97% ee). HPLC test conditions: chromatographic column Chiralcel IA, mobile phase n-hexane / isopropanol = 85 / 15 (v / v), flow rate = 1.0 mL / min, wavelength λ = 254 nm.

[0092] Under a nitrogen atmosphere, product 4 (44.9 mg, 0.146 mmol) was added to a Schlenk tube equipped with a magnetic stir bar. The tube was evacuated and backfilled with nitrogen five times. Then anhydrous tetrahydrofuran (THF, 3.0 mL) was added via syringe. Under a nitrogen purge, tetrabutylammonium fluoride (76.5 mg, 0.293 mmol) was added to the Schlenk tube, and the reaction was stirred at 0 °C for 2 hours. After the reaction was complete, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether (60 - 90 °C) / ethyl acetate: 10 / 1, v / v) to obtain the target product 5 (39.6 mg, yield 89%, 97% ee). The HPLC test conditions were the same as those in Example 14.

[0093] Under a nitrogen atmosphere, the product 5 (39.6 mg, 0.130 mmol) was added to a Schlenk tube equipped with a magnetic stir bar. The tube was evacuated and backfilled with nitrogen five times. Then, anhydrous tetrahydrofuran (3.0 mL) was added via syringe. Methanesulfonyl chloride (MeSO2Cl, 17.2 mg, 0.150 mmol) and triethylamine (NEt3, 15.2 mg, 0.150 mmol) were added to the Schlenk tube under a nitrogen purge, and the reaction was stirred at 0 °C for 1 hour. After the reaction was complete, it was concentrated under reduced pressure. The crude product was added to anhydrous N,N-dimethylformamide (DMF, 3.0 mL), sodium azide (NaN3, 19.5 mg, 0.300 mmol) was added, and the reaction was stirred at 0 °C for 1 hour. After the reaction was complete, it was quenched with saturated aqueous sodium bicarbonate, and the organic phases were combined after extraction and concentrated under reduced pressure. The crude product was added to anhydrous methanol (MeOH, 3.0 mL), palladium on carbon (Pd / C, 2 mg, 10 wt% aqueous dispersion) was added, and the reaction was stirred at room temperature under a hydrogen (H2) atmosphere for 2 hours. After the reaction was complete, it was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether (60 - 90 °C) / ethyl acetate: 10 / 1, v / v) to obtain the target product 6 (37.5 mg, yield 95%, 97% ee). The HPLC test conditions were the same as in Example 14.

[0094] Characterization data of typical compounds:

[0095] α -Hydroxyamide derivative 1a, white solid. 1 H NMR(600 MHz, CDCl3) δ 8.77 (s, 1H),7.58 – 7.53 (m, 4H), 7.38 – 7.34 (m, 2H), 7.34 – 7.29 (m, 3H), 7.11 (td, J =7.4, 1.2 Hz, 1H), 5.28 (s, 1H), 1.20 (dp, J = 8.4, 7.3 Hz, 3H), 1.08 (dd, J =19.1, 7.5 Hz, 18H); 13 C NMR(151 MHz, CDCl3) δ 170.28, 139.74, 137.48, 129.18,128.51, 128.36, 126.26, 124.45, 119.43, 76.39, 18.01, 17.95, 12.14;HRMS(ESI-TOF, m / z): calcd for C 23H 33 NO2Si [M+H] + : 384.2353, found: 384.2355。

[0096] α -Hydroxyamide derivative 1b, white solid. 1 H NMR(600 MHz, CDCl3) δ 8.71 (s, 1H),7.56 – 7.53 (m, 2H), 7.46 – 7.43 (m, 2H), 7.38 – 7.34 (m, 2H), 7.32 – 7.29(m, 1H), 7.13 (d, J = 8.1 Hz, 2H), 5.27 (s, 1H), 2.31 (s, 3H), 1.22 – 1.18 (m,3H), 1.08 (dd, J = 18.8, 7.5 Hz, 18H); 13 CNMR(151 MHz, CDCl3) δ 170.11, 139.82,134.95, 134.04, 129.63, 128.47, 128.30, 126.25, 119.42, 76.36, 20.96, 18.00,17.94, 12.13;HRMS(ESI-TOF, m / z): calcd for C 24 H 35 NO2Si [M+H] + : 398.2510, found:398.2511。

[0097] α -Hydroxyamide derivative 1c, white solid. 1 H NMR(600 MHz, CDCl 3 ) δ 8.77 (s, 1H),7.56 – 7.51 (m, 2H), 7.40 (t, J = 2.3 Hz, 1H), 7.36 (dd, J = 8.3, 6.6 Hz, 2H),7.33 – 7.29 (m, 1H), 7.21 (t, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.0, 2.0 Hz, 1H),6.66 (dd, J= 8.3, 2.5 Hz, 1H), 5.26 (s, 1H), 3.78 (s, 3H), 1.22 – 1.17 (m,3H), 1.07 (dd, J = 19.3, 7.5 Hz, 18H); 13 C NMR (151 MHz, CDCl3) δ 170.31, 160.36,139.71, 138.72, 129.81, 128.54, 128.41, 126.31, 111.50, 110.49, 105.03,76.41, 55.41, 18.01, 17.94, 12.14;HRMS(ESI-TOF, m / z): calcd for C 24 H 35 NO3Si [M+H] + : 414.2459, found: 414.2463。

[0098] α -Hydroxyamide derivative 1d, white solid. 1 H NMR(600 MHz, CDCl3) δ 8.74 (s, 1H),7.56 – 7.49 (m, 4H), 7.36 (dd, J = 8.4, 6.8 Hz, 2H), 7.33 – 7.29 (m, 1H), 7.03– 6.98 (m, 2H), 5.27 (s, 1H), 1.23 – 1.17 (m, 3H), 1.07 (dd, J = 19.3, 7.5 Hz,18H).; 13 C NMR(151 MHz, CDCl3) δ 170.25, 160.28, 158.67, 139.63, 133.54,133.52, 128.54, 128.42, 126.22, 121.12, 121.07, 115.88, 115.73, 76.32, 18.00,17.93, 12.13.;HRMS(ESI-TOF, m / z): calcd for C 23 H 32 FNO2Si [M+H] + : 402.2259,found: 402.2265。

[0099] α -Hydroxyamide derivative 1e, white solid.1 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.29 (d, J J = 2.1 Hz, 1H), 7.83 – 7.75 (m, 3H), 7.60 (d, J J = 7.2 Hz, 2H), 7.46 (ddd, J J = 12.9, 8.3, 1.8 Hz, 2H), 7.40 (dt, J J = 11.5, 4.3 Hz, 3H), 7.33 (t, J J = 7.1 Hz, 1H), 5.35 (s, 1H), 1.28 – 1.20 (m, 3H), 1.11 (dd, J J = 12.5, 7.4 Hz, 18H); 13 13C NMR (101 MHz, CDCl3) δ 170.53, 139.70, 134.82, 133.97, 130.78, 128.97, 128.55, 128.41, 127.77, 127.65, 126.66, 126.25, 125.12, 119.45, 116.24, 76.44, 18.03, 17.97, 12.16; HRMS (ESI-TOF, m / z): calcd for C 27 H 35 NO2Si [M+H] + : 434.2510, found: 434.2509。

[0100] α -Hydroxyamide derivative 1f, white solid. 1 1H NMR (600 MHz, CDCl3) δ 8.71 (s, 1H), 7.55 – 7.52 (m, 2H), 7.51 – 7.48 (m, 2H), 7.35 – 7.31 (m, 4H), 7.11 (tt, J J = 7.4, 1.2 Hz, 1H), 5.25 (s, 1H), 1.22 – 1.18 (m, 3H), 1.07 (dd, J J = 15.9, 7.5 Hz, 18H); 1313C NMR (151 MHz, CDCl3) δ 169.81, 138.28, 137.28, 134.24, 129.23, 128.73, 127.58, 124.64, 119.46, 75.71, 18.00, 17.96, 12.11; HRMS (ESI-TOF, m / z): calcd for C 23 H 32 ClNO2Si [M+H] + : 418.1964, found: 418.1956。

[0101] α -Hydroxyamide derivative 1g, white solid. 1 1H NMR (600 MHz, CDCl3) δ 8.74 (s, 1H), 7.55 – 7.50 (m, 4H), 7.34 – 7.30 (m, 2H), 7.11 (td, J J = 7.4, 1.2 Hz, 1H), 7.07 – 7.02 (m, 2H), 5.25 (s, 1H), 1.19 (qd, J J = 7.4, 1.2 Hz, 3H), 1.07 (dd, J J = 17.5, 7.4 Hz, 18H); 13 13C NMR (151 MHz, CDCl3) δ 170.09, 163.64, 162.00, 137.34, 135.62, 135.60, 129.23, 127.99, 127.94, 124.61, 119.47, 115.54, 115.40, 75.71, 18.00, 17.95, 12.12; HRMS (ESI-TOF, m / z): calcd for C 23 H 32 FNO2Si [M+H] + : 402.2259, found: 402.2260。

[0102] α -Hydroxyamide derivative 1h, white solid. 1 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.56 (d, J J = 8.0 Hz, 2H), 7.43 (d, J= 7.8 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.16(d, J = 7.8 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 5.25 (s, 1H), 2.34 (s, 3H), 1.23 –1.16 (m, 3H), 1.08 (dd, J = 12.0, 7.3 Hz, 18H); 13 C NMR(101 MHz, CDCl3) δ 170.49,138.05, 137.55, 136.79, 129.20, 129.15, 126.16, 124.38, 119.42, 76.28, 21.29,18.03, 17.97, 12.15.;HRMS(ESI-TOF, m / z): calcd for C 24 H 35 NO2Si [M+H] + :398.2510, found: 398.2504。

[0103] α -Hydroxyamide derivative 1i, white solid. 1 H NMR(600 MHz, CDCl3) δ 8.77 (s, 1H),7.58 – 7.53 (m, 2H), 7.47 – 7.43 (m, 2H), 7.34 – 7.30 (m, 2H), 7.10 (td, J =7.4, 1.2 Hz, 1H), 6.91 – 6.87 (m, 2H), 5.22 (s, 1H), 3.79 (s, 3H), 1.21 –1.16 (m, 3H), 1.07 (dd, J = 18.0, 7.4 Hz, 18H).; 13 C NMR(151 MHz, CDCl3) δ170.56, 159.68, 137.54, 131.98, 129.17, 127.49, 124.40, 119.41, 113.94,75.98, 55.36, 18.03, 17.96, 12.14;HRMS(ESI-TOF, m / z): calcd for C 24 H 35 NO3Si [M+H]+ : 414.2459, found: 414.2460。

[0104] α -Hydroxyamide derivative 1j, white solid. 1 H NMR(400 MHz, CDCl3) δ 8.85 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.91 – 7.82 (m, 3H), 7.71 (dd, J = 8.5, 1.8 Hz, 1H), 7.61 – 7.56 (m, 2H), 7.49 (hept, J = 4.9 Hz, 2H), 7.37 – 7.30 (m, 2H), 7.15 – 7.09 (m, 1H), 5.48 (s, 1H), 1.25 (qd, J = 7.2, 1.6 Hz, 3H), 1.11 (dd, J = 14.8, 7.3 Hz, 18H).; 13 C NMR(101 MHz, CDCl3) δ 170.20, 137.45, 137.16, 133.43, 133.21, 129.18, 128.41, 128.27, 127.82, 126.26, 126.21, 125.48, 124.49, 123.91, 119.48, 76.55, 18.04, 17.99, 12.17; HRMS(ESI-TOF, m / z): calcd for C 27 H 35 NO2Si [M+H] + : 434.2510, found: 434.2510。

[0105] α -Hydroxyamide derivative 1k, white solid. 1 H NMR(400 MHz, CDCl3) δ 8.56 (s, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.37–7.31 (m, 2H), 7.16–7.08 (m, 1H), 4.43 (dd, J= 5.5, 3.6 Hz, 1H), 2.01–1.91 (m, 1H), 1.77–1.70 (m, 1H), 1.62–1.50 (m, 1H), 1.36–1.28 (m, 1H), 1.21–1.15 (m, 3H), 1.12 (dd, J = 6.5, 3.8 Hz, 18H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR(101 MHz, CDCl3) δ 171.93, 137.47, 129.23, 124.40, 119.43, 74.00, 37.69, 18.13, 18.09, 16.79, 14.24, 12.30; HRMS(ESI-TOF, m / z): calcd for C 20 H 35 NO2Si [M+H] + : 350.2510, found: 350.2509。

[0106] α -Hydroxyamide derivative 1l, white solid. 1 H NMR(400 MHz, CDCl3) δ 8.53 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.34 (m, J = 7.7 Hz, 2H), 7.12 (m, J = 7.4 Hz, 1H), 4.40(t, J = 5.7 Hz, 1H), 1.91 (m, J = 13.3, 6.7 Hz, 1H), 1.80–1.67 (m, 2H), 1.21–1.15(m, 3H), 1.12 (q, J = 4.5 Hz, 18H), 0.96 (dd, J = 6.6, 4.0 Hz, 6H); 13 C NMR(101MHz, CDCl3) δ 172.22, 137.58, 129.24, 124.35, 119.38, 73.43, 45.01, 24.10, 23.77, 22.97, 18.15, 18.11, 12.34; HRMS(ESI-TOF, m / z): calcd for C 21H 37 NO2Si [M+H] + : 364.2666, found: 364.2665。

[0107] Product 4, white solid. 1 H NMR(400 MHz, CDCl3) δ 8.63 (s, 1H), 7.89 (s, 1H),7.79 (d, J J = 1.9 Hz, 1H), 7.70 (d, J J = 8.4 Hz, 1H), 7.53 (s, 1H), 6.89–6.82 (m,1H), 4.44–4.38 (m, 1H), 3.99 (s, 3H), 1.92 (dt, J J = 13.3, 6.7 Hz, 1H), 1.79–1.68 (m, 2H), 1.21–1.15 (m, 3H), 1.13 (dd, J J = 6.6, 3.3 Hz, 18H), 0.97 (dd, J J =6.6, 3.1 Hz, 6H); 13 C NMR(101 MHz, CDCl3) δ 172.48, 156.59, 149.33, 147.99,138.82, 126.51, 124.79, 113.26, 111.02, 102.50, 73.52, 55.73, 45.16, 24.17,23.71, 22.90, 18.15, 18.11, 12.39.;HRMS(ESI-TOF, m / z): calcd for C 25 H 41 N2O4Si[M+H] + : 461.2757, found: 461.2757。

[0108] Product 5, white solid. 1 H NMR(400 MHz, d 6 -DMSO) δ 9.83 (s, 1H), 8.36 (s, 1H),7.70 – 7.58 (m, 2H), 7.51 (dd, J J = 8.6, 1.8 Hz, 1H), 7.44 (s, 1H), 5.75 (d, J J =5.5 Hz, 1H), 4.05 (q,J = 6.2 Hz, 1H), 3.90 (s, 3H), 1.83 (m, J = 6.8 Hz, 1H),1.51 (t, J = 6.9 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H); 13 C NMR(101 MHz, d 6 -DMSO) δ173.87, 155.52, 150.38, 147.12, 140.14, 125.65, 123.81, 111.58, 111.34,102.83, 70.30, 55.51, 43.27, 23.97, 23.32, 21.59;HRMS(ESI-TOF, m / z): calcdfor C 16 H 21 N2O4 [M+H] + : 305.1423, found: 305.1422。

[0109] AAK1 inhibitor 6, white solid. 1 H NMR(400 MHz, MeOD) δ 8.10 (s, 1H), 7.62 (d, J =8.5 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.37 (s, 1H), 7.13 (dd, J = 8.5, 2.0 Hz,1H), 3.89 (s, 3H), 3.40 (dd, J = 8.3, 6.0 Hz, 1H), 3.25 (s, 2H), 1.67 (dq, J =13.4, 6.7 Hz, 1H), 1.54 (ddd, J = 13.8, 7.9, 6.1 Hz, 1H), 1.39 (ddd, J = 13.8,8.3, 6.2 Hz, 1H), 0.89 (dd, J = 7.9, 6.5 Hz, 6H).

[0110] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A chiral α -hydroxyamide derivative synthesis method, characterized in that The chiral α -hydroxyamide derivative has the structure shown in the following formula (I): （I）； In formula (I): Ar is a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group, wherein the substituents are selected from one or more of methyl, methoxy, halogen atom, dimethylamino, and oxazolyl; R 1 is a substituted or unsubstituted C1-C10 alkyl, phenyl, p-chlorophenyl, p-fluorophenyl, p-tolyl, p-methoxyphenyl or 2-naphthyl, wherein the substituent is selected from one or more of a hydroxyl group, an amino group, a halogen atom, a nitro group, a cyano group, and a C1-C4 alkyl group; [Si] is trimethylsilyl, triethylsilyl, dimethyl tert-butylsilyl, triisopropylsilyl, or dimethylphenylsilyl; The chiral α -hydroxyamide derivative synthesis method includes: in the presence of a chiral thiourea catalyst, an aromatic amine Ar-NH2 and α -carbonyl acylsilane undergo a catalytic asymmetric nucleophilic addition reaction under light in a solvent to form the chiral α -hydroxyamide derivative; The said α -carbonylacylsilane has a structure shown in the following formula (II): (II); The chiral thiourea catalyst is: 。 2. The synthesis method according to claim 1, characterized in that, In formula (I): Ar is phenyl, p-tolyl, o-tolyl, m-methoxyphenyl, p-fluorophenyl, p-dimethylaminophenyl, 2-naphthyl or ； R 1 is phenyl, p-chlorophenyl, p-fluorophenyl, p-tolyl, p-methoxyphenyl, 2-naphthyl, propyl or isobutyl; [Si] is trimethylsilyl, triethylsilyl, dimethyl tert-butylsilyl, triisopropylsilyl, or dimethylphenylsilyl.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of the aromatic amine and the α -carbonylacylsilane is 5:1 to 25; The molar ratio of the aromatic amine to the chiral thiourea catalyst is 1:0.001 - 0.

5.

4. The synthesis method according to claim 1, characterized in that, The solvent is at least one of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane, 1,2-dichloroethane, toluene, and tetrahydrofuran.

5. The synthesis method according to claim 1, characterized in that, The temperature of the reaction is -20~100 °C, and the time of the reaction is 0.5 - 25 hours.

6. The synthesis method according to claim 1, characterized in that, The wavelength of the light irradiation is 360 - 800 nm.

7. The synthesis method according to claim 1, characterized in that, The power of the light irradiation is 1 - 100 watts.

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