Preparation method of (R, S)-3-(dimethylamino)-1, 2-diaryl-2-N-heteroaryl ethanol

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of (R, S)-3-(dimethylamino)-1, 2-diaryl-2-N-heteroaryl ethanol. According to the invention, 1-aryl-N-heteroaryl methane and N-aryl formyl pyrrole are taken as initial raw materials, asymmetric transfer hydrogenation and diastereoselective allylation are taken as key reactions, two adjacent chiral centers are constructed, and a target product is synthesized; the method is short in route, mild in reaction condition, high in product yield, good in optical purity, simple to operate, low in equipment requirement and easy for industrial amplification.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing (R, S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol. Background Art

[0002] Tuberculosis (TB) is a fatal disease caused by infection with Mycobacterium tuberculosis (MTB). TB treatment requires extremely long medication cycles. During this period, interruptions in medication and incorrect prescriptions can lead to the emergence of drug-resistant TB, further exacerbating the threat TB poses to human health. Johnson & Johnson has developed bedaquiline, a (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol compound (structure shown below). Research has shown that bedaquiline can kill M. tuberculosis by inhibiting proton transfer in the ATP synthase of M. tuberculosis. This novel mechanism of action gives it excellent activity against TB, particularly drug-resistant TB. In 2012, the FDA approved bedaquiline for marketing in the United States, making it the first new drug approved for the treatment of TB in nearly 50 years. Based on the specific efficacy of bedaquiline against drug-resistant tuberculosis, (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol structures have been widely synthesized and studied, and some structures such as WX-81, TBAJ-587, TBAJ-876, etc. have been used in clinical studies of drug-resistant tuberculosis.

[0003]

[0004] To date, relatively few synthetic methods for (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanols have been reported, primarily focusing on the synthesis of bedaquiline. The original patent for bedaquiline (Patent Announcement No. CN101180302B) discloses a synthetic method: 6-bromo-3-benzyl-2-methoxyquinoline undergoes deprotonation at the benzylic position at low temperatures (-72°C to -78°C), followed by an addition reaction with 3-dimethylamino-1-naphthyl-1-propanone to obtain the racemic bedaquiline. The reaction mass is concentrated, treated with ethanol, and resolved using (R)-binaphthol phosphate as a chiral resolving agent to obtain (R,S)-bedaquiline in an overall yield of 7-9%. Although the material cost of this route is low, there are still many problems. For example, the reaction between 6-bromo-3-benzyl-2-methoxyquinoline and 3-dimethylamino-1-naphthyl-1-propanone needs to be carried out at -78 ° C for more than 30 hours, the raw materials cannot be completely converted, there are many side reactions, and the yield is low.

[0005]

[0006] Furthermore, the development and high efficiency of asymmetric catalysis have attracted the attention of researchers in the preparation of bedaquiline. Shibasaki (J. Am. Chem. Soc. 2010, 132, 7905-7907) used asymmetric catalytic proton transfer and diastereoselective olefination as key reactions to obtain (R,S)-bedaquiline in 12 steps, with an overall yield of only 5%.

[0007]

[0008] Chandrasekhar (Eur. J. Org. Chem. 2011, 2057-2061) and Aggarwal (Org. Lett. 2023, 25, 4281-4285) reported the preparation of (R,S)-bedaquiline using Sharpless asymmetric epoxidation and sulfonyl ide asymmetric epoxidation as key reactions, respectively. The subsequent allylation of these two routes failed to achieve stereoselectivity and involved numerous steps and high costs.

[0009]

[0010] In 2020, the Naicker group (ACS Omega 2020, 5, 3607-3611) added chiral amine ligands to the addition reaction based on the industrial route, which improved the diastereoselectivity of bedaquiline (dr=9:1). Subsequently, the chiral resolution method was still used to obtain the optically pure target product.

[0011]

[0012] In 2022, Jamison's group applied continuous flow chemistry to an industrial production route (Chem. Eur. J. 2022, e202201311). While this approach improved the yield of bedaquiline, it still failed to achieve asymmetric synthesis of the product. Zhang Wanbin's group (Sci China Chem. 2022, 10, 1968) used chiral metal catalysis to investigate the addition reaction step in the industrial route, improving the stereoselectivity of bedaquiline (ee = 99%; dr = 16:1). However, significant amounts of starting material were not fully converted, and the yield was only 22%. Therefore, developing new asymmetric synthetic methods to improve yields, reduce production costs, and achieve a simple and efficient synthesis of bedaquiline and (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol-like compounds is an urgent challenge.

[0013] Summary of the Invention

[0014] The purpose of the present invention is to provide a method for preparing a (R, S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol structure compound with cheap and readily available raw materials, simple operation and environmental friendliness in response to the problems of the prior art.

[0015] The present invention provides a method for preparing (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol, which uses 1-aryl-N-heteroarylmethane and N-arylformylpyrrole as starting materials, asymmetric transfer hydrogenation and diastereoselective allylation as key reactions, constructs two adjacent chiral centers, and synthesizes the target product (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol. The specific route is as follows:

[0016]

[0017] In the formula, substituents R1, R2, R3 are halogen, aromatic ring, methoxy, acetoxy, trifluoromethyl, etc.; substituent R' is halogen, aromatic ring, methoxy, trifluoromethyl, etc.; substituents Ar, Ar1 are benzene ring, naphthalene ring, substituted aromatic ring, etc.

[0018]

[0019] The specific steps of the present invention are as follows:

[0020] (1) Under alkaline conditions, 1-aryl-N-heteroarylmethane (5) and N-arylformylpyrrole (6) undergo an aromatic acylation reaction in an organic solvent to obtain 1,2-diaryl-2-N-heteroarylethyl ketone (7);

[0021] The ratio of the 1-aryl-N-heteroarylmethane (5), N-arylformylpyrrole (6) and the base is 1:1:2 to 1:1.5:4;

[0022] The organic base is selected from non-nucleophilic bases such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, etc.

[0023] The reaction temperature is 30°C-70°C; the reaction time is 6-18 hours; one or more of tetrahydrofuran, dimethyltetrahydrofuran, dioxane, etc. are selected as the organic solvent;

[0024] The optimal reaction conditions for step (1) are: lithium hexamethyldisilazide is used as the base, the ratio of 1-aryl-N-heteroarylmethane (5), N-arylformylpyrrole (6) to the base is 1:1.2:4; tetrahydrofuran is used as the solvent, and the reaction is carried out at 50°C for 12 hours.

[0025] (2) In an inert gas atmosphere, 1,2-diaryl-2-N-heteroaryl ethyl ketone (7) is used as a substrate, rhodium metal is used as a chiral catalyst, and formate is used as a hydrogen source. Asymmetric transfer hydrogenation is carried out in an organic solvent to obtain (R,S)-1,2-diaryl-2-N-heteroaryl ethanol (8);

[0026] The ratio of the rhodium metal, 1,2-diaryl-2-N-heteroaryl ethyl ketone (7), and formate is 0.02:1:5 to 0.1:1:15;

[0027] The formate is selected from sodium formate, potassium formate, ammonium formate, HCOOH / Et3N, etc.

[0028] The reaction temperature is 40°C-70°C; the reaction time is 18-36 hours; one or more of tetrahydrofuran, ethyl acetate, dioxane, toluene, etc. are selected as the organic solvent;

[0029] Step (2) Optimal reaction conditions: Cat14g was selected as the catalyst, potassium formate was used as the hydrogen source, ethyl acetate was used as the solvent, and the amount ratio of rhodium metal, 1,2-diaryl-2-N-heteroaryl ethyl ketone (7), and formate was 0.05:1:10, and the reaction was carried out at 60°C for 24 hours.

[0030] (3) (R,S)-1,2-diaryl-2-N-heteroarylethanol (8) and Dess-Martin reagent react in dichloromethane solvent at room temperature for 3-6 hours to obtain 1,2-diaryl-2-N-heteroarylethyl ketone (9) with R configuration at the α position;

[0031] (4) Under low temperature conditions, (R)-1,2-diaryl-2-N-heteroaryl ethyl ketone (9) is used as a substrate, allyl magnesium chloride is used as a nucleophilic reagent, and TADDOL is used as a chiral reagent to carry out an asymmetric allylation reaction in an organic solvent to obtain (R,S)-1-allyl-1,2-diaryl-2-N-heteroaryl ethanol (10);

[0032] The ratio of the (R)-1,2-diaryl-2-N-heteroarylethanone (9), chiral reagent and allylmagnesium chloride is 1:1:3 to 1:5:15;

[0033] The reaction temperature is -80°C to 0°C; the reaction time is 4 to 16 hours; one or more of dichloromethane, ether, chloroform, etc. are selected as the organic solvent;

[0034] Optimal reaction conditions for step (4): A chiral reagent in which Ar1 is substituted with a phenyl group is selected, the ratio of (R)-1,2-diaryl-2-N-heteroarylethanone (9), chiral reagent, and allylmagnesium chloride is 1:3:9, and the reaction is carried out at -78°C for 12 hours using dichloromethane as solvent.

[0035] (5) At room temperature, (R,S)-1-allyl-1,2-diaryl-2-N-heteroarylethanol (10), dioxane, water, 2,6-lutidine, K2OsO4·H2O, and NaIO4 were added to the reaction flask in sequence and stirred for 3-6 hours. The crude product (11) was treated with CH3COOH, dimethylamine, and NaBH(OAc)3 and stirred in THF solvent under an inert gas atmosphere at room temperature for 6-12 hours to obtain the target product (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol (12).

[0036] Beneficial effects

[0037] The present invention obtains the target product (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol structural compound with a total yield of 18%-40%. Compared with previous synthetic routes, this method has the advantages of high yield, good optical purity, simple operation, easy product separation, and low environmental pollution, and has the potential for industrial application. DETAILED DESCRIPTION

[0038] In order to explain the technical content, purpose and effect of the technical solution of the present invention in detail, the following is further described in conjunction with specific embodiments. This embodiment is implemented under the premise of the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the scope of protection of the present invention is not limited to the following embodiments.

[0039] 1-Aryl-N-heteroarylmethane was synthesized according to the literature (Chem. Eur. J. 2022, e202201311), and N-arylformylpyrrole was synthesized according to the literature (Org. Biomol. Chem. 2020, 18, 500-513). Unless otherwise stated, other raw materials and reagents used were commercially available products and used directly.

[0040] Example 1, preparation of bedaquiline.

[0041] A: Under N2 atmosphere, 3-benzyl-6-bromo-2-methoxyquinoline (3.27 g, 10 mmol, 1.0 equiv), naphthalen-1-yl(1H-pyrrol-1-yl)methanone (2.65 g, 12 mmol, 1.2 equiv) and THF (60 mL) were added to a flask. LiN(SiMe3)2 (40 mL, 1 Min THF) was slowly added dropwise while stirring. The reaction mixture was stirred at 50°C for 12 hours. TLC indicated that the reaction was complete and the reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL). The organic layer was separated and the aqueous phase was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and slurried with methanol to give 2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phenylethan-1-one as a white solid (yield: 91%).

[0042] Structural characterization data: 1 H NMR (400MHz, CDCl3): δ8.56(d,J=8.4Hz,1H),8.04(d,J=7.2Hz,1H),7.94(d,J=8.3Hz,1H),7.84(d,J=7.6Hz,1H),7.73 (d,J=2.1Hz,1H),7.71(d,J=8.9Hz,1H),7.63(dd,J1=8.9,J2=2.1Hz,1H),7.56-7.35(m,9H),6.24(s,1H),3.97(s,3H). 13 C NMR (100MHz, CDCl3): δ201.0,160.0,144.5,136.9,136.1,135.5,134.0,132.7,132.4,130.6,129.7,129.6,129.4,1 28.6,128.4,128.0,127.9,127.7,126.9,126.5,125.8,124.3,117.1,57.3,54.0.IR:1685,1620,1487,1263,1057cm -1 .HR-MS:Calcd forC 28 H 20 BrNO2Na[M+Na] + 504.0570,found504.0568,MP168.1℃-169.5℃.

[0043] B: Under N2 atmosphere, 2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phenylethan-1-one (1.45 g, 3.0 mmol, 1.0 eq), HCOOK (2.49 g, 30 mmol, 10.0 eq), cat. 14 g (134 mg, 0.15 mmol, 5 mol%), and EA (30 mL) were added sequentially to a sealed tube (10 mL) equipped with a magnetic stirrer. The mixture was then stirred at 60°C for 24 h. After completion, the reaction solution was concentrated and the crude product was purified by silica gel column chromatography (PE:DCM=2:3, Rf=0.25) to give (1S,2R)-2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phenylethan-1-ol as a white solid (yield: 81%, ee 96%).

[0044] Structural characterization data: 1 H NMR (400MHz, CDCl3): δ8.15(d,J=5.6Hz,2H),7.81-7.77(m,2H),7.66(d,J=8.0Hz,1H),7.58-7.52(m,2H),7.49-7.41 (m,2H),7.23-7.17(m,5H),7.13-7.10(m,2H),6.21(d,J=2.4Hz,1H),4.95(d,J=5.2Hz,1H),3.79(s,3H),2.12(s,1H). 13 CNMR (100MHz, CDCl3): δ160.4,143.9,141.1,138.1,137.6,135.8,133.8,132.2,130.6,129.9,129.5,129.1,128.4,128.3, 128.2,128.1,127.2,126.5,126.2,125.5,125.0,124.4,123.1,117.2,72.4,53.7,50.5.IR:υ3218,1637,1397,1252,1062cm -1 .HR-MS(m / z):Calcd for C 28 H 23 BrNO2[M+H] + 484.0907,found 484.0910,MP139.7℃-140.3℃,[α] 25 D = -22.3 (c 0.5, CHCl3).

[0045] C: Under N₂ atmosphere, (1S,2R)-2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phenylethan-1-ol (482 mg, 1.0 mmol, 1.0 equiv), Dess-Martin sodium periodate (DMP) (635 mg, 1.5 mmol, 1.5 equiv), and DCM (7 mL) were added to a Schleck tube equipped with a magnetic stirrer. After stirring at room temperature for 4 h, saturated aqueous Na₂S₂O₃ was added and the mixture was stirred for 10 min. The organic phase was washed with saturated NaHCO₃, brine, dried over Na₂SO₄, and concentrated. The crude product was slurried in MeOH to afford (R)-2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phenylethan-1-one as a white solid (yield: 93%, ee: 96%).

[0046] Structural characterization data: 1 H NMR (400MHz, CDCl3): δ8.56(d,J=8.4Hz,1H),8.04(d,J=7.2Hz,1H),7.94(d,J=8.3Hz,1H),7.84(d,J=7.6Hz,1H),7.73 (d,J=2.1Hz,1H),7.71(d,J=8.9Hz,1H),7.63(dd,J1=8.9,J2=2.1Hz,1H),7.56-7.35(m,9H),6.24(s,1H),3.97(s,3H). 13 C NMR (100MHz, CDCl3): δ201.0,160.0,144.5,136.9,136.1,135.5,134.0,132.7,132.4,130.6,129.7,129.6,129.4,1 28.6,128.4,128.0,127.9,127.7,126.9,126.5,125.8,124.3,117.1,57.3,54.0.IR:1685,1620,1487,1263,1057cm -1 .HR-MS:Calcd forC 28 H 20 BrNO2Na[M+Na] + 504.0570,found504.0568,MP168.1℃-169.5℃,[α] 25D =218.1(c0.5,CHCl3).

[0047] D: Under N₂ atmosphere, TADDOL (699 mg, 1.5 mmol, 3.0 equiv) was dissolved in anhydrous DCM (5 mL) in a dry Schleck tube and cooled to -78°C. Allylmagnesium chloride (2.25 mL, 4.5 mmol, 9.0 equiv of 2.0 M in THF) was quickly added via syringe to the colorless solution, and the mixture was stirred for 10 minutes. (R)-2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phenylethan-1-one (241 mg, 0.5 mmol, 1.0 equiv) was dissolved in anhydrous DCM (3 mL) and added via syringe. Stirring was continued at -78°C for 8 hours. The reaction mixture was then quenched with saturated aqueous NH₄Cl and extracted twice with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel column chromatography to give (R,S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(naphthalen-1-yl)-1-phenylpent-4-en-2-ol as a white solid.

[0048] Structural characterization data: 1 H NMR (400MHz, CDCl3): δ8.70-8.66(m,2H),7.98(d,J=1.9Hz,1H),7.87(d,J=7.8Hz,1H),7.73(d,J= 8.8Hz,1H),7.66(dd,J1=8.8Hz,J2=1.9Hz,3H),7.58(dd,J1=7.6Hz,J2=0.8Hz,1H),7.52-7.48(m, 1H),7.29-7.25(m,1H),7.13-7.12(m,2H),6.96-6.92(m,3H),5.99-5.97(m,1H),5.13-5.00(m,1H ),4.92(s,1H),4.89-4.86(m,1H),4.22(s,3H),3.63-3.60(m,1H),2.66(s,1H),2.47-2.41(m,1H). 13C NMR (100MHz, CDCl3): δ161.1,143.9,139.8,138.8,134.6,133.2,132.2,129.9,129.8,128.6,128.5,127.6,12 6.7,126.3,125.6,125.4,124.8,119.8,117.2,86.2,64.7,54.3,31.6.IR:3540,2948,1685,1459,1250,775cm -1 .HR-MS:Calcd for C 31 H 27 BrNO2[M+H] + 524.1220,found524.1221,MP163.1℃-163.9℃,[α] 25 D =-123.06 (c 0.75, CHCl3).

[0049] E: To a solution of (R,S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(naphthalen-1-yl)-1-phenylpent-4-en-2-ol (524 mg, 1.0 mmol, 1.0 equiv), 1,4-dioxane (3.0 mL), and H2O (1.0 mL) was added 2,6-lutidine (214 mg, 2.0 mmol, 2.0 equiv), K2OsO4·H2O (11 mg, 0.030 mmol, 3 mol%), and NaIO4 (856 mg, 4.0 mmol, 4.0 equiv) at room temperature. The reaction was stirred for 3 h. The reaction was quenched with water and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated to give (3S,4R)-4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutanal, which was used directly in the next step without further purification.

[0050] Under a nitrogen atmosphere, (3S,4R)-4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutanal and THF (15 mL) were added to a reaction tube. CHCOOH (1 mL), dimethylamine hydrochloride (0.76 mL, 1.3 mmol, 1.3 equiv, 2 M in THF), and Na(OAc)BH (424 mg, 1.8 mmol, 1.8 equiv) were added sequentially to the solution, and the resulting mixture was stirred at room temperature for 6 hours. When the reaction was complete as monitored by TLC analysis, saturated aqueous NaHCO (10 mL) was added, and the mixture was then extracted with EA (10 mL x 3). The organic extracts were combined, dried over NaSO, and concentrated. The crude residue was purified by flash silica gel column chromatography (PE:EA=6:1, Rf=0.21) to give (R,S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol (bedaquinol, 2-step yield: 61%, ee=96%) as a white solid.

[0051] Structural characterization data: 1 H NMR (400MHz, CDCl3): δ8.90(s,1H),8.61(d,J=8.7Hz,1H),7.97(d,J=2.0Hz,1H),7.9 0(dd,J1=12.7,J2=7.7Hz,2H),7.72(d,J=8.8Hz,1H),7.68-7.59(m,3H),7.49(t,J=7. 4Hz,1H),7.31(t,J=7.7Hz,1H),7.17-7.11(m,2H),6.92-6.86(m,3H),5.90(s,1H),4. 22(s,3H),2.55(d,J=12.7Hz,1H),2.18-2.02(m,2H),1.99(s,6H),1.97-1.89(m,1H). 13C NMR (100MHz, CDCl3): δ161.4,143.8,141.7,140.6,138.8,134.7,132.0,130.0,129.9,129.8,128.6,128.2,127.9,127.4,12 7.2,126.9,125.8,125.3,125.2,125.1,124.5,117.0,82.6,56.4,54.3,49.6,44.8,33.5.IR:2948,1598,1460,1396,1062cm -1 .HR-MS:Calcd for C 32 H 32 BrN2O2[M+H] + 555.1640,found 555.1634,[α] 25 D =-163.48 (c 0.25, CHCl3).

[0052] Example 2, preparation of WX-81.

[0053] This example is the same as Example 1, except that the starting material in this example is 3-benzyl-5-(4-chlorophenyl)-2-methoxypyridine. In this example, the obtained product is WX-81 with an overall yield of 18% and 94% ee.

[0054] Structural characterization data: 1 H NMR (400MHz, CDCl3): δ8.52(d,J=2.4Hz,1H),8.48(d,J=8.8Hz,1H),8.07(d,J=7.2Hz,1H),7.87-7.80(m,4H),7.62(d,J=8.0Hz,1H),7.5 5(t,J=6.8Hz,1H),7.45-7.27(m,9H),5.62(s,1H),3.20(s,3H),2.49-2.43(m,1H),2.30-2.23(m,12H),2.21-2.03(m,2H),1.96(s,6H). 13C NMR (100MHz, CDCl3): δ160.8,141.5,141.3,138.2,137.2,134.7,132.8,131.4,130.1,129.5,128.9,128.2,128 .0,127.9,127.2,126.5,125.6,124.9,124.7,124.5,81.8,56.3,52.8,50.9,44.7,34.0.IR:2937,1642,1135cm -1 .HR-MS(m / z):Calcd for C 34 H 34 ClN2O2[M+H] + 537.2303, found 537.2314.[α] 25 D =-50.66 (c 0.25, CHCl3).

[0055] Example 3, Preparation of (R,S)-4-(dimethylamino)-1-(8-fluoro-2-methoxy-6-methylquinolin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol.

[0056] This example is identical to Example 1, except that the starting material used in this example is 3-benzyl-8-fluoro-2-methoxy-6-methylquinoline. In this example, the product (R,S)-4-(dimethylamino)-1-(8-fluoro-2-methoxy-6-methylquinolin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol was obtained in an overall yield of 32% and 94% ee.

[0057] Structural characterization data: 1H NMR (400MHz, CDCl3): δ8.88(s,1H),8.53(d,J=8.8Hz,1H),7.87(d,J=2.4Hz,1H),7.67(d d,J1=12.4,J2=7.2Hz,2H),7.60(d,J=8.4Hz,1H),7.68-7.59(m,3H),7.49(t,J=7.4Hz,1H ),7.31(t,J=7.7Hz,1H),7.17-7.11(m,2H),6.92-6.86(m,2H),5.90(s,1H),4.22(s,3H) ,2.55(d,J=12.7Hz,1H),2.36(s,3H),2.18-2.02(m,2H),1.99(s,6H),1.97-1.89(m,1H). 13 C NMR (100MHz, CDCl3): δ160.4,155.4,143.5,141.7,135.9,134.3,131.8,131.0,129.7,129.2,128.5,128.0,126.9,126.5,126. 2,125.9,124.7,124.3,124.2,124.1,121.9,114.5,83.3,56.6,54.4,49.6,47.0,36.8,21.7.IR:2951,1569,1519,1346,1162cm -1 .HR-MS:Calcd for C 33 H 34 FN2O2[M+H] + 508.2526,found508.2528,[α] 25 D =-131.51 (c 0.25, CHCl3).

[0058] Example 4, Preparation of (R,S)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenyl-1-(quinolin-3-yl)butan-2-ol.

[0059] This example is the same as Example 1, except that the starting material used in this example is 3-benzylquinoline. In this example, the product (R,S)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenyl-1-(quinolin-3-yl)butan-2-ol was obtained in an overall yield of 30% and 92% ee.

[0060] Structural characterization data: 1 H NMR(400MHz, CDCl3)δ8.57(s,1H),8.13(s,1H),8.04-8.02(m,1H),7.89(d,J=8.4H z,1H),7.77-7.75,(m,1H),7.63(t,J=8.8Hz,2H),7.52(t,J=7.2Hz,1H),7.40-7.3 6(m,3H),7.22-7.12(m,5H),7.07(d,J=6.4Hz,2H),6.20(d,J=5.6Hz,1H),5.32(br s,1H),2.65(d,J=12.7Hz,1H),2.18-2.02(m,2H),1.99(s,6H),1.87-1.79(m,1H).. 13 C NMR (100MHz, CDCl3) δ163.5,151.5,146.3,138.5,137.3,135.3,135.1,133.8,130.4,129.9,129.3,129.2,128.7,1 28.6,127.9,127.8,127.4,126.8,126.3,125.6,125.0,124.7,83.9,55.3,47.3,36.3.IR:2968,1464,1269,1073cm -1 .HR-MS(m / z):Calcdfor C 31 H 31 N2O[M+H] + 447.2355, found 447.2358.[α] 25 D =-128.81 (c 0.75, CHCl3).

[0061] It should be noted that although the above embodiments have been described herein, this does not limit the scope of patent protection of the present invention. Based on the innovative concept of the present invention, changes and modifications to the embodiments described herein, or equivalent structural or equivalent process transformations made using the contents of the present invention specification, directly or indirectly applying the above technical solutions to other related technical fields, are all included in the scope of patent protection of the present invention.

Claims

1. A method for preparing (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol, characterized in that: Using 1-aryl-N-heteroarylmethane and N-arylformylpyrrole as starting materials, asymmetric transfer hydrogenation and diastereoselective allylation are used as key reactions to construct two adjacent chiral centers and synthesize the target product. The specific synthetic route is as follows: In the formula, the substituents R1, R2, and R3 are halogen, aromatic ring, methoxy, acetoxy, trifluoromethyl, etc.; the substituent R' is halogen, aromatic ring, methoxy, or trifluoromethyl; the substituents Ar and Ar1 are benzene ring, naphthalene ring, or substituted aromatic ring; The specific steps are as follows: (1) Under alkaline conditions, 1-aryl-N-heteroarylmethane (5) and N-arylformylpyrrole (6) undergo an aromatic acylation reaction in an organic solvent to obtain 1,2-diaryl-2-N-heteroarylethyl ketone (7); (2) In an inert gas atmosphere, 1,2-diaryl-2-N-heteroaryl ethyl ketone (7) is used as a substrate, rhodium metal is used as a chiral catalyst, and formate is used as a hydrogen source. Asymmetric transfer hydrogenation is carried out in an organic solvent to obtain (R,S)-1,2-diaryl-2-N-heteroaryl ethanol (8); (3) (R,S)-1,2-diaryl-2-N-heteroarylethanol (8) and Dess-Martin reagent react in dichloromethane solvent at room temperature for 3-6 hours to obtain 1,2-diaryl-2-N-heteroarylethyl ketone (9) with R configuration at the α position; (4) Under low temperature conditions, (R)-1,2-diaryl-2-N-heteroaryl ethyl ketone (9) is used as a substrate, allyl magnesium chloride is used as a nucleophilic reagent, and TADDOL is used as a chiral reagent to carry out an asymmetric allylation reaction in an organic solvent to obtain (R,S)-1-allyl-1,2-diaryl-2-N-heteroaryl ethanol (10); (5) At room temperature, (R,S)-1-allyl-1,2-diaryl-2-N-heteroarylethanol (10), dioxane, water, 2,6-lutidine, K2OsO4·H2O, and NaIO4 were added to the reaction flask in sequence and stirred for 3-6 hours. The crude product (11) was treated with CH3COOH, dimethylamine, and NaBH(OAc)3 and stirred in THF solvent under an inert gas atmosphere at room temperature for 6-12 hours to obtain the target product (R,S)-3-(dimethylamino)-1,2-diaryl-2-N-heteroarylethanol (12).

2. The synthesis method according to claim 1, wherein In step (1): The ratio of the 1-aryl-N-heteroarylmethane, N-arylformylpyrrole and base is 1:(1-1.5):(2-4); The base is selected from the group consisting of non-nucleophilic bases such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium diisopropylamide; The reaction temperature is 30°C-70°C; the reaction time is 6 to 18 hours; The organic solvent is selected from tetrahydrofuran, dimethyltetrahydrofuran and dioxane.

3. The synthesis method according to claim 1, wherein In step (2): The ratio of rhodium metal, 1,2-diaryl-2-N-heteroaryl ethyl ketone and formate is (0.02-0.1):1:(5-15); The formate is selected from sodium formate, potassium formate, ammonium formate, HCOOH / Et3N; The reaction temperature is 40°C-70°C; the reaction time is 18 to 36 hours; The organic solvent is selected from tetrahydrofuran, ethyl acetate, dioxane and toluene.

4. The synthesis method according to claim 1, characterized in that In step (4): The ratio of the (R)-1,2-diaryl-2-N-heteroaryl ethanone, chiral reagent and allyl magnesium chloride is 1:(1-5):(3-15); The reaction temperature is -80°C to 0°C; the reaction time is 4 to 16 hours; The organic solvent is selected from dichloromethane, ether and chloroform.

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