CN116102524A - Asymmetric synthesis method of beta-amino alcohol compound - Google Patents

Asymmetric synthesis method of beta-amino alcohol compound Download PDF

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CN116102524A
CN116102524A CN202310172577.XA CN202310172577A CN116102524A CN 116102524 A CN116102524 A CN 116102524A CN 202310172577 A CN202310172577 A CN 202310172577A CN 116102524 A CN116102524 A CN 116102524A
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mmol
chiral
beta
amino alcohol
solvent
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叶金星
张磊
刘成玉
曹黎明
杨磊
程瑞华
马跃跃
孙茂林
梁超茗
王亚国
林慰霞
陈华亮
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East China University of Science and Technology
Guangdong University of Technology
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Guangdong University of Technology
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Abstract

The invention provides an asymmetric synthesis method of a beta-amino alcohol compound, which comprises the following steps: (1) Mixing and reacting a metal iridium complex and a chiral nitrogen-phosphorus tridentate ligand in a solvent A to prepare a chiral iridium catalyst; (2) And (3) carrying out asymmetric hydrogenation reaction on alpha-bromoketone, secondary amine compounds and alkali C in a solvent B under the catalysis of the chiral iridium catalyst prepared in the step (1), and separating after the reaction is finished to obtain chiral beta-amino alcohol. The chiral ligand L related by the invention has the advantages of simple and convenient synthesis, low cost, stable property and practical value; the invention has wide substrate applicability and high target product yield and enantioselectivity, avoids separation and purification of alpha-amino ketone in the prior art, thereby simplifying operation steps and improving reaction efficiency.

Description

Asymmetric synthesis method of beta-amino alcohol compound
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an asymmetric synthesis method of a beta-amino alcohol compound.
Background
Chiral beta-amino alcohols are a very important class of building blocks in pharmaceutical products, and are widely used in pharmaceutical synthesis, such as: (S) -chloropropanacolin, (R) -sartanolamine, (R) -dinopamine, (R) -naftopidil, and the like (Chem.Rev.1996, 96,835;J.Med.Chem.2002,45,2615;J.Med.Chem.2008,51,4978). Modern researches have proved that chiral beta-amino alcohols and their derivatives exhibit important pharmacological activities in other life processes. In addition, chiral β -amino alcohols are widely used in the field of asymmetric catalytic synthesis as chiral auxiliary or ligand side chains (Chem.Eur.J.2010, 16,8002;Chem.Eur.J.2017,23,970). Thus, this is a very interesting class of structures.
Figure BDA0004099707690000011
The asymmetric synthesis of chiral beta-amino alcohol has great significance, and the main method at present is still to synthesize raceme, and then resolution is carried out to obtain chiral amino alcohol. The method has the advantages of complicated steps, low efficiency and narrow substrate application range, different amino alcohol resolution methods can be different, and certain difficulties exist in establishing chiral beta-amino alcohol compound libraries. Asymmetric hydrogenation of α -amino ketones provides a powerful and efficient tool for synthesizing enantiomerically pure β -amino alcohols (Synthesis 2014,46,2910-2916; org. Chem. Front.2017,4, 1499-1502), but α -amino ketones need to be prepared in advance and are relatively unstable in air, making isolation and purification difficult. Therefore, development of an asymmetric catalytic synthesis method with high efficiency, high selectivity and wide substrate applicability is urgently needed for application in synthesis of drugs and fine chemical products.
Disclosure of Invention
Aiming at some defects of the prior art, the invention provides an asymmetric synthesis method of a beta-amino alcohol compound, which has the advantages of simple and convenient operation, wide substrate applicability, high yield and enantioselectivity of a target product and no need of separation and purification of an intermediate alpha-amino ketone.
The technical scheme of the invention is as follows: an asymmetric synthesis method of a beta-amino alcohol compound comprises the following steps:
(1) At room temperature, in an inert gas atmosphere, adding a metal iridium complex and a chiral ligand L into a solvent A for reaction, and preparing a chiral iridium catalyst to obtain a catalyst solution;
(2) Mixing alpha-bromoketone (I), amine compound (II), solvent B and alkali C, adding the catalyst solution prepared in the step (1), and carrying out asymmetric hydrogenation reaction under certain hydrogen pressure and temperature to generate chiral beta-amino alcohol compound (III); the specific reaction route is as follows:
Figure BDA0004099707690000021
wherein the chiral ligand L is a chiral tridentate nitrogen phosphine ligand, ar in the formula (I) is C 4 -C 20 Aryl or heteroaryl; the amine compound (II) is a secondary amine compound selected from C 1 -C 20 Aliphatic secondary amine compound, aromatic secondary amine compound or C 1 -C 20 One of the heterocyclic secondary amines. The inert gas atmosphere is preferably a nitrogen atmosphere.
In the present invention, it is further preferable that the amine compound (ii) is one selected from morpholine, piperidine, piperazine, tetrahydrothiophene pyridine, L-prolyl, tetrahydroisoquinoline and derivatives thereof.
It is further preferred that the metallic iridium complex is selected from [ Ir (COD) Cl ]] 2 Or [ Ir (COE) 2 Cl] 2 。
In a further preferred aspect of the present invention, the chiral ligand L has the following structural formula:
Figure BDA0004099707690000022
wherein R is 3 Selected from aryl or alkyl, further preferably C 1 -C 8 Alkyl or aryl groups of (a).
In the present invention, it is further preferable that the chiral ligand L is selected from any one of ligands L1 to L5, each ligand corresponds to two enantiomers, and the structures of the ligands L1 to L5 are as follows:
Figure BDA0004099707690000031
it is further preferred in the present invention that in step (1), the reaction time of the metal iridium complex and the chiral ligand L in the solvent a is 0.5 to 6 hours, wherein the molar ratio of the metal iridium complex to the chiral ligand L is 1:2 to 1:4.
It is further preferable that the solvent A is one or more selected from n-hexane, ethyl acetate, dichloromethane, 1, 2-dichloroethane, toluene, tetrahydrofuran, methanol, ethanol and isopropanol.
In the present invention, it is further preferable that the solvent B is one or more selected from n-hexane, dichloroethane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, and isopropanol.
In the present invention, it is further preferable that the base C is one selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium methoxide, and sodium ethoxide.
In the step (2), the alpha-bromoketone (I), the amine compound (II), the solvent B and the alkali C are added into a reaction kettle under the nitrogen atmosphere, and finally the catalyst solution obtained in the step (1) is added, the reaction kettle is closed to replace hydrogen, and the asymmetric hydrogenation reaction is carried out under certain hydrogen pressure and temperature for 1-48h.
In the present invention, it is further preferable that the reaction temperature of the asymmetric hydrogenation reaction in the step (2) is 20 to 80℃and the pressure is 0.1 to 8.0MPa, and the reaction time is 1 to 48 hours. Preferably, the reaction temperature is 25+/-5 ℃ at room temperature, the pressure is 4.0-8.0MPa, and the reaction time is 6-24 hours.
It is further preferred in the present invention that in the step (2), the molar ratio of the chiral iridium catalyst to the α -bromoketone is 1:500-5000.
It is further preferred in the present invention that in the step (2), the molar ratio of the α -bromoketone, the amine compound and the base C is 1:1 to 2:1 to 2.
Compared with the prior art, the invention has the following beneficial effects:
(1) The technical scheme of the invention is that the chiral beta-amino alcohol is synthesized by taking the alpha-bromoaromatic ketone as a raw material, thereby avoiding the separation and purification of an intermediate alpha-amino ketone and simplifying the preparation steps.
(2) The ligand adopted in the technical scheme of the invention has simple synthetic route, high stability and easy regulation and control in steric hindrance and electrical property.
(3) The preparation method provided by the invention has the characteristics of high activity, high enantioselectivity, wide substrate applicability and the like.
(4) The technical scheme of the invention provides a useful and steady synthesis strategy for chiral beta-amino alcohol, effectively improves the synthesis efficiency and simplifies the operation.
Detailed Description
For a better understanding of the present invention, the following examples are set forth to illustrate the invention further, but are not to be construed as limiting the invention.
In the following examples, no particular technique or condition is noted, either in accordance with the techniques or conditions described in the literature in this field or in accordance with the product specifications; the reagents or apparatus used were conventional products available commercially without the manufacturer's attention.
The room temperature in the examples of the present invention was 25.+ -. 5 ℃.
EXAMPLE 1 Synthesis of ligand L1
In this example, the synthesis of ligand L1 includes the following steps:
(1) Synthesis of Compound 1:
Figure BDA0004099707690000041
according to the above reaction scheme, compound (R) -N, N-dimethyl-1-ferrocenylethylamine (30 mmol,7.71 g) was mixed with anhydrous diethyl ether (60 mL) under nitrogen atmosphere, stirred at-40℃and then N-butyllithium (15 mL, 2.5M) was slowly added dropwise to the reaction system, stirred for 1h, diphenyl phosphine chloride (13.23 g,60 mmol) was dissolved in 20mL diethyl ether at room temperature and slowly added dropwise to the reaction system, and after the addition was completed, the reaction system was refluxed overnight; the reaction was quenched with saturated aqueous sodium bicarbonate, separated and purified to give 7.4g of a yellow solid in 56% yield. Then, 2g of the separated and purified product was dissolved in 4mL of acetic anhydride, and reacted at 60℃overnight under nitrogen atmosphere. After completion of the reaction, compound 1 was obtained and used in the next step without treatment.
(2) Preparation of Compound 2
Figure BDA0004099707690000051
According to the above scheme, 2,4, 6-trimethylbenzenesulfonyl chloride (28.77 g,132 mmol) was mixed with pyridine (12 mL), and D-alaninol (4.51 g,60 mmol) and pyridine (4 mL) were added dropwise and stirred at room temperature. Acetic acid (6 mL), ice (60 g) and water (120 mL) are added for quenching reaction, ethyl acetate is added, then 2M hydrochloric acid aqueous solution is added into the system for neutralizing pyridine until no pyridine residue exists, and then the pale yellow solid 21.1g is obtained through extraction, washing, drying, rotary evaporation, separation and purification, and the yield is 80%. Then, the above-obtained compound (13.2 g,30 mmol) was dissolved in toluene (120 mL), and 50g of a 20% aqueous KOH solution was added dropwise thereto and stirred at room temperature for 2 hours. Adding water, separating the organic phase, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and rotary evaporating to remove solvent to obtain pale yellow solid. The prepared ternary nitrogen heterocyclic compound (2.39 g,10 mmol) was dissolved in methanol (20 mL), 25-28% ammonia (30 mL) was added, and the temperature was raised to 50℃for 2h. Rotary steaming, separating and purifying to obtain white solid 2.12g, and obtaining the required raw material compound 2 with the yield of 83 percent.
(3) Synthetic ligand L1
Figure BDA0004099707690000052
According to the above scheme, compound 1 (228 mg,0.5 mmol) and compound 2 (256 mg,1.0 mmol) were refluxed overnight in anhydrous MeOH (2 mL) under nitrogen atmosphere and the solvent was evaporated in vacuo to give the crude product. Purification by isolation gave 198mg of yellow solid in 61% yield. The product L1 obtained was characterized and the results were as follows:
[α] D 25 ＝-81.3(c 0.5,CH 2 Cl 2 )； 1 H NMR(600MHz,CDCl 3 )δ7.52–7.49(m,2H),7.40–7.34(m,3H),7.21–7.07(m,5H),6.91(s,2H),5.26(d,J＝4.7Hz,1H),4.40(dt,J＝3.0,1.6Hz,1H),4.29(t,J＝2.5Hz,1H),4.01(s,5H),3.97(dd,J＝6.6,2.9Hz,1H),3.81–3.77(m,1H),2.59(s,6H),2.52(d,J＝6.9Hz,1H),2.29(s,3H),2.10(qd,J＝11.9,5.6Hz,2H),1.36(d,J＝6.5Hz,3H),0.56(d,J＝6.5Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ141.73,139.92(d,J＝9.8Hz),139.20,136.93(d,J＝9.0Hz),135.00,134.86,134.66,132.87,132.74,131.89,129.23,128.45(d,J＝3.0Hz),128.40,128.29,128.24,97.18(d,J＝23.8Hz),75.29(d,J＝7.0Hz),71.44(d,J＝4.9Hz),69.86,69.17(d,J＝4.6Hz),69.05,51.22,51.15(d,J＝9.1Hz),49.13,23.20,21.06,19.51,18.57； 31 P NMR(243MHz,CDCl 3 )δ-24.95(s)。
example 2: synthesis of ligand L2
Figure BDA0004099707690000061
Compound 1 (228 mg,0.5 mmol) and compound 3 (284 mg,1.0 mmol) were refluxed in anhydrous MeOH (2 mL) overnight under nitrogen atmosphere and the solvent was evaporated in vacuo to give the crude product. Purification by isolation gave 185mg of yellow solid in 54% yield. The product obtained was characterized and the results were as follows:
[α] D 25 ＝-87.6(c 0.5,CH 2 Cl 2 )； 1 H NMR(600MHz,CDCl 3 )δ7.55–7.48(m,2H),7.41–7.32(m,3H),7.22–7.04(m,5H),6.91(s,2H),5.25(s,1H),4.44(s,1H),4.30(s,1H),3.98(s,6H),3.86–3.77(m,1H),2.64(s,6H),2.38(d,J＝8.7Hz,2H),2.29(s,3H),2.20(s,1H),1.36(s,3H),1.16–1.06(m,1H),0.46(d,J＝6.8Hz,3H),0.40(d,J＝6.8Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ141.70,140.29(d,J＝9.6Hz),139.17,137.43(d,J＝9.0Hz),135.24,135.10,134.77,132.55,132.43,131.88,129.25,128.38,128.34,128.24,128.19,128.11,97.38,97.19,75.13(d,J＝7.0Hz),71.58(d,J＝5.1Hz),69.84,69.21(d,J＝4.9Hz),69.12,58.92,51.82(d,J＝9.6Hz),46.20,28.98,23.50,21.07,19.35,18.67,18.15； 31 P NMR(243MHz,CDCl 3 )δ-24.85(s)。
example 3: synthesis of ligand L3
Figure BDA0004099707690000071
Compound 1 (228 mg,0.5 mmol) and compound 4 (318 mg,1.0 mmol) were refluxed overnight in anhydrous MeOH (2 mL) under nitrogen atmosphere, and the solvent was evaporated in vacuo to give the crude product. Purification by isolation gave 149mg of yellow solid in 42% yield. The product obtained was characterized and the results were as follows:
[α] D 25 ＝-113.2(c 0.5,CH 2 Cl 2 )； 1 H NMR(600MHz,CDCl 3 )δ7.54–7.49(m,2H),7.39–7.35(m,3H),7.29–7.26(m,1H),7.22–7.14(m,4H),7.09–7.04(m,1H),7.01(t,J＝7.5Hz,2H),6.78(s,2H),6.74(d,J＝7.5Hz,2H),5.93(s,1H),4.55–4.37(m,1H),4.31(s,1H),4.01(s,5H),3.97(s,1H),3.88–3.76(m,1H),3.53(s,1H),2.43(s,7H),2.38–2.31(m,1H),2.24(s,3H),1.45(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ141.75,139.91(d,J＝10.5Hz),136.99(d,J＝9.1Hz),134.97,134.83,134.22,132.97,132.84,131.62,129.24,128.63,128.61,128.59,128.31,128.26,128.01,127.24,126.75,96.57,96.43,75.58(d,J＝7.1Hz),71.56(d,J＝5.0Hz),69.90,57.30,52.86,51.34(d,J＝3.5Hz),22.99,20.99,19.71； 31 P NMR(243MHz,CDCl 3 )δ-25.10(s)。
example 4: synthesis of ligand L4
Figure BDA0004099707690000072
(1) Synthesis of Compound 5: according to the above synthetic route, compound 5 was synthesized by substituting D-alaninol and adaptively adjusting the amounts of the respective reactants used in the synthesis process, as compared with example 1.
(2) Preparation of ligand L4:
Figure BDA0004099707690000081
according to the above equation, compound 1 (228 mg,0.5 mmol) and compound 5 (336 mg,1.0 mmol) were refluxed overnight in anhydrous MeOH (2 mL) under nitrogen atmosphere and the solvent was evaporated in vacuo to give the crude product. Purification by isolation gave 149mg of yellow solid in 41% yield. The product obtained was characterized and the results were as follows:
[α] D 25 ＝-129.2(c 0.5,CH 2 Cl 2 ). 1 H NMR(600MHz,CDCl 3 )δ7.55–7.48(m,2H),7.39–7.34(m,3H),7.30–7.25(m,1H),7.22–7.13(m,4H),7.09–7.03(m,1H),7.04–6.98(m,2H),6.78(d,J＝1.0Hz,2H),6.78–6.73(m,2H),5.84(s,1H),4.52–4.38(m,1H),4.29(t,J＝2.5Hz,1H),4.01(s,5H),3.93(dd,J＝6.5,2.9Hz,1H),3.82–3.75(m,1H),3.47(dd,J＝8.5,4.3Hz,1H),2.52(s,1H),2.43(s,6H),2.40–2.29(m,3H),2.24(s,3H),1.39(d,J＝6.4Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ141.73,139.99(d,J＝10.8Hz),139.37,139.35,137.02(d,J＝9.4Hz),134.97,134.83,134.24,133.00,132.87,131.62,129.21,128.62,128.58(d,J＝3.5Hz),128.30,128.24,127.98,127.19,126.77,96.99(d,J＝23.7Hz),75.59(d,J＝7.0Hz),71.52(d,J＝4.9Hz),69.87,69.84,69.19(d,J＝4.8Hz),69.08,57.44,53.04,51.21(d,J＝9.4Hz),22.99,20.99,19.65. 31 P NMR(243MHz,CDCl 3 )δ-24.84(s).HRMS(ESI):exact mass calculated for C 42 H 46 FeN 2 O 2 PS[M+H] + 729.2362,found 729.2354。
example 5: synthesis of ligand L5
Figure BDA0004099707690000091
(1) Synthesis of Compound 6: as shown above, in comparison with example 1, D-alaninol in the raw material was replaced with L-alaninol, and the amounts of the respective reactants used in the synthesis were adaptively adjusted to prepare Compound 6.
(2) Synthetic ligand L5:
Figure BDA0004099707690000092
compound 1 (228 mg,0.5 mmol) and compound 6 (256 mg,1.0 mmol) were refluxed overnight in anhydrous MeOH (2 mL) under nitrogen atmosphere and the solvent was evaporated in vacuo to give the crude product. Purification by isolation gave 176mg of yellow solid in 54% yield. The product obtained was characterized and the results were as follows:
[α] D 25 ＝-106.2(c 0.5,CH 2 Cl 2 )； 1 H NMR(600MHz,CDCl 3 )δ7.53–7.47(m,2H),7.41–7.31(m,3H),7.23–7.12(m,5H),6.92(s,2H),5.16(s,1H),4.43(s,1H),4.32(t,J＝2.5Hz,1H),4.04(d,J＝7.6Hz,1H),3.99(s,5H),3.82(s,1H),2.57(s,7H),2.32(s,3H),2.05(t,J＝4.8Hz,2H),1.38(s,3H),0.51(d,J＝6.5Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ141.76,139.72(d,J＝9.8Hz),139.04,136.81(d,J＝8.9Hz),134.96,134.82,134.55,132.78,132.65,131.96,129.28,128.61,128.56,128.51,128.31,128.25,97.02(d,J＝27.1Hz),75.21(d,J＝7.5Hz),71.44(d,J＝4.9Hz),69.84,69.49(d,J＝4.6Hz),69.27,50.77(d,J＝10.0Hz),50.08,48.69,23.15,21.09,19.52,18.72； 31 P NMR(243MHz,CDCl 3 )δ-25.93(s)。
example 6: synthesis of beta-amino alcohol 9a
Figure BDA0004099707690000101
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.4 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the purified product 9a was obtained, and the yield and ee value were measured. White solid, yield 95%,>99% ee. The product obtained was characterized and the results were as follows:
[α] D 25 ＝-38.2(c 1.0,CH 2 Cl 2 )； 1 H NMR(400MHz,CDCl 3 )δ7.34–7.24(m,4H),7.23–7.17(m,1H),4.68(dd,J＝10.3,3.7Hz,1H),3.78–3.60(m,4H),2.74–2.61(m,2H),2.52–2.32(m,4H)； 13 C NMR(101MHz,CDCl 3 )δ141.94,128.50,127.70,125.94,68.68,67.14,66.79,53.56；HRMS(EI):exact mass calculated for C 12 H 17 NO 2 [M] + 207.1259,found207.1054。
example 7: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing α -bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), tBuONa (25.0 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the mixture was separated and purified to obtain pure 9a. White solid, yield 66%,99% ee.
Example 8: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing α -bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), tBuOLi (20.8 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 59%,96% ee.
Example 9: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing α -bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), liOH (6.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. Separating and purifying to obtain the pure product 9a. White solid, yield 46%,97% ee.
Example 10: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous toluene (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 85%,98% ee.
Example 11: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing α -bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous THF (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 71%,97% ee.
Example 12: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100 μl,0.0004 mmol) was transferred to a 10mL vial containing α -bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCM (2.0 mL) and placed in an autoclave, which was flushed with 40atm of hydrogen and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 91%,>99％ee。
example 13: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L2 (2.9 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 93%,98% ee.
Example 14: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L4 (3.1 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 94%,99% ee.
Example 15: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L5 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. Separating and purifying to obtain the pure product 9a. White solid, yield 89%,80% ee.
Example 16: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (4.4 mg,0.0063 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 92%,99% ee.
Example 17: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (5.8 mg,0.0084 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 86%,99% ee.
Example 18: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and anhydrous toluene (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.4 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 93%,>99％ee。
example 19: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and methanol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.4 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 68%,99% ee.
Example 20: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and methylene chloride (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.4 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 43%,99% ee.
Example 21: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, the [ Ir (COE) 2 Cl] 2 (1.8 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 57%,95% ee.
Example 22: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 19a (39.8 mg,0.2 mmol), morpholine 20a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at 45℃for 6h. After the reaction is finished, the solvent is removed by rotary evaporation, and the pure product is obtained by separation and purification21a. White solid, yield 92%,99% ee.
Example 23: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at 80℃for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 95%,99% ee.
Example 24: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing α -bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (34.8 mg,0.4 mmol), naOH (16 mg,0.4 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, into which 10atm hydrogen was flushed and stirred at room temperature for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 64%,98% ee.
Example 25: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 80atm hydrogen was flushed into the autoclave and stirred at room temperature for 6h. After the reaction is finished, rotary evaporation is carried out to removeRemoving solvent, separating and purifying to obtain pure product 9a. White solid, yield 94%,>99％ee。
example 26: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (20.9 mg,0.24 mmol), naOH (10.2 mg,0.26 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave and stirred at room temperature for 48h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 95%,>99％ee。
example 27: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 30mL vial containing α -bromoacetophenone 7a (390 mg,2 mmol), morpholine 8a (209 mg,2.4 mmol), naOH (10.4 mg,2.6 mmol) and anhydrous DCE (20 mL) and placed in an autoclave, 50atm hydrogen was flushed into the autoclave and stirred at room temperature for 24h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 84%,98% ee.
Example 28: synthesis of beta-amino alcohol 9a
Under nitrogen atmosphere, [ Ir (COD) Cl] 2 (1.4 mg, 0.002mmol), ligand L1 (2.8 mg,0.0042 mmol) and isopropyl alcohol (1 mL) were added to a dried 10mL schlenk reaction tube and stirred at room temperature for 2.5h to give a catalyst solution. The catalyst solution (100. Mu.L, 0.0004 mmol) was transferred to a 10mL vial containing alpha-bromoacetophenone 7a (39.8 mg,0.2 mmol), morpholine 8a (34.8 mg,0.4 mmol), naOH (16 mg,0.4 mmol) and anhydrous DCE (2.0 mL) and placed in an autoclave, 40atm hydrogen was flushed into the autoclave, chamberStirring for 6h. After the reaction, the solvent was removed by rotary evaporation, and the mixture was separated and purified to obtain a pure product 9a. White solid, yield 90%,99% ee.
Example 29: synthesis of beta-amino alcohol 9b
Figure BDA0004099707690000171
In this example, 2-bromo-4' -fluoroacetophenone (43.4 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, and the other steps were the same as in example 7, except that the product 9b was a white solid in 95% yield of 98% ee. The product 9b obtained was characterized and the results were as follows:
[α] D 25 ＝-52.7(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.38–7.28(m,2H),7.07–6.97(m,2H),4.72(dd,J＝10.5,3.5Hz,1H),3.82–3.67(m,4H),2.81–2.67(m,2H),2.54–2.36(m,4H). 13 C NMR(101MHz,CDCl 3 )δ162.33(d,J＝245.2Hz),137.60(d,J＝3.2Hz),127.58(d,J＝8.1Hz),115.34(d,J＝21.3Hz),68.08,67.11,66.77,53.52.HRMS(EI):exact mass calculated for C 12 H 16 FNO 2 [M] + 225.1165,found 225.1162。
example 30: synthesis of beta-amino alcohol 9c
Figure BDA0004099707690000172
In this example, 2-bromo-4' -bromoacetophenone (55.2 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, the other steps being the same as in example 7, product 9c being a white solid in 91% yield, >99% ee. The product 9c obtained was characterized and the results were as follows:
[α] D 25 ＝-42.2(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.44–7.36(m,2H),7.22–7.12(m,2H),4.64(dd,J＝10.6,3.4Hz,1H),3.77–3.61(m,4H),2.73–2.61(m,2H),2.50–2.28(m,4H). 13 C NMR(101MHz,CDCl 3 )δ141.00,131.59,127.65,121.41,68.07,67.09,66.55,53.51.HRMS(EI):exact mass calculated for C 12 H 16 BrNO 2 [M] + 285.0364,found 285.0366。
example 31: synthesis of beta-amino alcohol 9d
Figure BDA0004099707690000181
In this example, 2-bromo-4' -cyanoacetophenone (44.8 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, the other steps being the same as in example 7, product 9d being a white solid in 92% yield, >99% ee. The product 9d obtained was characterized and the results were as follows:
[α] D 25 ＝-52.0(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝8.1Hz,2H),7.48(d,J＝8.1Hz,2H),4.78(dd,J＝10.6,3.5Hz,1H),3.82–3.67(m,4H),2.80–2.68(m,2H),2.56(dd,J＝12.5,3.5Hz,1H),2.50–2.34(m,3H). 13 C NMR(101MHz,CDCl 3 )δ147.54,132.34,126.53,118.95,111.35,68.04,67.04,66.22,53.44.HRMS(EI):exact mass calculated for C 13 H 16 N 2 O 2 [M] + 232.1212,found 232.1215。
example 32: synthesis of beta-amino alcohol 9e
Figure BDA0004099707690000182
In this example, 2-bromo-3' -bromoacetophenone (55.6 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, the other steps being the same as in example 7, product 9e being a white solid in 90% yield, >99% ee. The product 9e obtained was characterized and the results were as follows:
[α] D 25 ＝-36.6(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.55(s,1H),7.40(d,J＝7.9Hz,1H),7.28(d,J＝7.9Hz,1H),7.21(t,J＝7.7Hz,1H),4.71(dd,J＝10.6,3.4Hz,1H),3.82–3.65(m,4H),2.81–2.68(m,2H),2.57–2.37(m,4H). 13 C NMR(101MHz,CDCl 3 )δ144.40,130.72,130.06,129.01,124.53,122.67,68.02,67.09,66.55,53.50.HRMS(EI):exact mass calculated for C 12 H 16 BrNO 2 [M] + 285.0364,found 285.0367。
example 33: synthesis of beta-amino alcohol 9f
Figure BDA0004099707690000191
In this example, 2-bromo-3' -methoxyacetophenone (45.8 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, the other steps being the same as in example 7, product 9f being a yellow solid in 91% yield, >99% ee. The product 9f obtained was characterized and the results were as follows:
[α] D 25 ＝-41.1(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.30–7.22(m,1H),6.99–6.89(m,2H),6.82(dd,J＝8.4,2.5Hz,1H),4.73(dd,J＝10.4,3.6Hz,1H),3.81(s,3H),3.79–3.70(m,4H),2.80–2.69(m,2H),2.59–2.40(m,4H). 13 C NMR(101MHz,CDCl 3 )δ159.86,143.71,129.51,118.22,113.23,111.31,68.58,67.14,66.71,55.34,53.55.HRMS(EI):exact mass calculated for C 13 H 19 NO 3 [M] + 237.1365,found 237.1362。
example 34: synthesis of beta-amino alcohol Compound 9g
Figure BDA0004099707690000192
In this example, 2-bromo-2' -chloroacetophenone (46.7 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, and the other steps were the same as in example 7, except that 9g of the product was a yellow oil, yield 91%,97% ee. The product 9g obtained was characterized and the results were as follows:
[α] D 25 ＝-50.8(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝7.8Hz,1H),7.29–7.19(m,2H),7.17–7.09(m,1H),5.11(dd,J＝10.3,2.9Hz,1H),3.76–3.61(m,4H),2.78–2.62(m,3H),2.47–2.35(m,2H),2.29–2.19(m,1H). 13 C NMR(101MHz,CDCl 3 )δ139.36,131.74,129.35,128.62,127.31,127.28,67.16,65.81,64.61,53.56.HRMS(EI):exact mass calculated for C 12 H 16 ClNO 2 [M] + 241.0870,found 241.0872。
example 35: synthesis of beta-amino alcohol compound 9h
Figure BDA0004099707690000201
In this example, 2-bromo-3 ',4' -dichloroacetophenone (53.6 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, the other steps being the same as in example 7, the product 9h being a yellow solid with a yield of 93%, >99% ee. The product 9h obtained was characterized and the results were as follows:
[α] D 25 ＝-37.0(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝1.9Hz,1H),7.40(d,J＝8.3Hz,1H),7.18(dd,J＝8.3,2.0Hz,1H),4.69(dd,J＝10.6,3.4Hz,1H),3.80–3.67(m,4H),2.79–2.66(m,2H),2.56–2.32(m,4H). 13 C NMR(101MHz,CDCl 3 )δ142.36,132.63,131.42,130.45,127.94,125.24,67.56,67.07,66.38,53.47.HRMS(EI):exact mass calculated for C 12 H 15 Cl 2 NO 2 [M] + 275.0480,found 275.0482。
example 36: synthesis of beta-amino alcohol 9i
Figure BDA0004099707690000202
In this example, 2-bromo-3 '-trifluoromethyl-4' -fluoroacetophenone (57.0 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, and the other steps were the same as in example 7, except that the product 9i was a pale yellow oil, yield 85%,98% ee. The product 9i obtained was characterized and the results were as follows:
[α] D 25 ＝-38.1(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.62(dd,J＝6.9,2.2Hz,1H),7.57–7.49(m,1H),7.16(dd,J＝10.0,8.6Hz,1H),4.76(dd,J＝10.7,3.4Hz,1H),3.83–3.66(m,4H),2.82–2.67(m,2H),2.54(dd,J＝12.5,3.4Hz,1H),2.51–2.43(m,2H),2.39(dd,J＝12.5,10.7Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ160.43(q,J＝2.2Hz),157.89(q,J＝2.1Hz),138.27(d,J＝3.7Hz),131.36(d,J＝8.5Hz),124.68(q,J＝4.7Hz),122.70(q,J＝272.2Hz),118.45(q,J＝32.8Hz),118.32(q,J＝32.9Hz),116.95(d,J＝20.9Hz),67.62,67.05,66.53,53.47.HRMS(EI):exact mass calculated for C 13 H 15 F 4 NO 2 [M] + 293.1039,found 293.1042。
example 37: synthesis of beta-amino alcohol 9j
Figure BDA0004099707690000211
In this example, 2-bromo-2' -naphthacenedione (49.8 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, and the other steps were the same as in example 7, except that the product 9j was a white solid in 92% yield, 99% ee. The product 9j obtained was characterized and the results were as follows:
[α] D 25 ＝-43.7(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ8.05–7.77(m,4H),7.55–7.42(m,3H),4.93(dd,J＝10.2,3.7Hz,1H),3.88–3.68(m,4H),2.85–2.72(m,2H),2.67–2.54(m,2H),2.53–2.43(m,2H). 13 C NMR(101MHz,CDCl 3 )δ139.41,133.42,133.12,128.23,127.98,127.78,126.20,125.87,124.74,123.99,68.80,67.14,66.66,53.59.HRMS(EI):exact mass calculated for C 16 H 19 NO 2 [M] + 257.1416,found 257.1419。
example 38: synthesis of beta-amino alcohol 9k
Figure BDA0004099707690000212
In this example, 2-bromo-1- (2-thiophene) ethanone (41.0 mg,0.2 mmol) was used instead of α -bromoacetophenone 7a (39.8 mg,0.2 mmol) in example 7, and the other steps were the same as in example 7, with product 9k as a yellow solid in 88% yield, 97% ee. The product 9k obtained was characterized and the results were as follows:
[α] D 25 ＝-19.7(c 1.0,CH 2 Cl 2 ). 1 H NMR(600MHz,CDCl 3 )δ7.25(dd,J＝4.9,1.4Hz,1H),7.01–6.94(m,2H),5.02(m,1H),3.80–3.69(m,4H),2.78–2.68(m,2H),2.64(d,J＝6.9Hz,2H),2.53–2.43(m,2H). 13 C NMR(151MHz,CDCl 3 )δ145.57,126.73,124.66,123.90,67.08,66.47,65.31,53.57.HRMS(EI):exact mass calculated for C 10 H 15 NO 2 S[M] + 213.0823,found 213.0825。
example 39: synthesis of beta-amino alcohol 9l
Figure BDA0004099707690000213
In this example, piperidine (20.4 mg,0.24 mmol) was used in place of morpholine 8a (20.9 mg,0.24 mmol) in example 7, and the other steps were the same as in example 7 except that 9l of the product was a white solid in 92% yield >99% ee.
The product 9l obtained was characterized and the results were as follows:
[α] D 25 ＝-39.7(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.40–7.23(m,4H),7.23–7.14(m,1H),4.65(dd,J＝10.6,3.6Hz,1H),2.62(s,2H),2.47–2.19(m,4H),1.65–1.47(m,4H),1.47–1.34(m,2H). 13 C NMR(101MHz,CDCl 3 )δ142.58,128.44,127.51,125.99,68.79,67.07,54.59,26.29,24.42.HRMS(EI):exact mass calculated for C 13 H 19 NO[M] + 205.1467,found 205.1469。
example 40: synthesis of beta-amino alcohol 9m
Figure BDA0004099707690000221
In this example, morpholine 8a (20.9 mg,0.24 mmol) in example 7 was replaced with tetrahydroisoquinoline (32.0 mg,0.24 mmol), and the product 9m was a white solid in 86% yield, 98% ee in the same manner as in example 7. The product 9m obtained was characterized and the results were as follows:
[α] D 25 ＝-24.9(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.38–7.24(m,4H),7.23–7.17(m,1H),7.12–7.01(m,3H),7.00–6.92(m,1H),4.78(dd,J＝10.1,3.8Hz,1H),3.85(d,J＝14.9Hz,1H),3.59(d,J＝14.9Hz,1H),3.00–2.91(m,1H),2.90–2.77(m,2H),2.74–2.66(m,1H),2.65–2.51(m,2H). 13 C NMR(101MHz,CDCl 3 )δ142.17,134.39,134.22,128.85,128.49,127.64,126.65,126.48,125.99,125.91,69.17,66.12,55.86,51.02,29.20.HRMS(EI):exact mass calculated for C 17 H 19 NO[M] + 253.1467,found 253.1466。
example 41: synthesis of beta-amino alcohol 9n
Figure BDA0004099707690000222
In this example, 4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine (33.4 mg,0.24 mmol) was used in place of morpholine 8a (20.9 mg,0.24 mmol) in example 7, and the other steps were the same as in example 7 except that the product 9n was a pale yellow solid in 88% yield >99% ee. The product 9n obtained was characterized and the results were as follows:
[α] D 25 ＝-24.3(c 1.0,CH 2 Cl 2 ). 1 H NMR(600MHz,CDCl 3 )δ7.45–7.40(m,2H),7.40–7.35(m,2H),7.33–7.28(m,1H),7.13(d,J＝5.1Hz,1H),6.77(d,J＝5.1Hz,1H),4.85(dd,J＝10.6,3.3Hz,1H),3.86(d,J＝14.4Hz,1H),3.64(d,J＝14.3Hz,1H),3.15–3.07(m,1H),3.01–2.89(m,2H),2.88–2.81(m,1H),2.78(dd,J＝12.6,3.3Hz,1H),2.67(dd,J＝12.6,10.6Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ142.13,133.46,133.44,128.47,127.64,125.96,125.27,122.98,69.33,65.52,52.99,50.97,25.44.HRMS(EI):exact mass calculated for C 15 H 17 NOS[M] + 259.1031,found 259.1034。
example 42: synthesis of beta-amino alcohol 9o
Figure BDA0004099707690000231
In this example, morpholine 8a (20.9 mg,0.24 mmol) in example 7 was replaced with 4-hydroxypiperidine (24.3 mg,0.24 mmol), and the other steps were the same as in example 7, product 9o being a white solid in 95% yield, 99% ee. The product 9o obtained was characterized and the results were as follows:
[α] D 25 ＝-31.2(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.33–7.24(m,4H),7.23–7.16(m,1H),4.64(dd,J＝9.9,4.1Hz,1H),3.71–3.60(m,1H),3.01–2.92(m,1H),2.69–2.60(m,1H),2.48–2.33(m,3H),2.16–2.06(m,1H),1.90–1.78(m,2H),1.62–1.46(m,2H). 13 C NMR(101MHz,CDCl 3 )δ142.18,128.45,127.61,125.95,69.07,67.70,66.14,51.94,50.16,34.68,34.50.HRMS(EI):exact mass calculated for C 13 H 19 NO 2 [M] + 221.1416,found 221.1418。
example 43: synthesis of beta-amino alcohol 9p
Figure BDA0004099707690000232
In this example, morpholine 8a (20.9 mg,0.24 mmol) in example 7 was replaced with 4-dimethylaminopiperidine (48.2 mg,0.24 mmol) and the product 9p was a white solid in 85% yield, 98% ee in the same manner as in example 7. The product 9b obtained was characterized and the results were as follows:
[α] D 25 ＝-17.8(c 1.0,CH 2 Cl 2 ). 1 H NMR(600MHz,CDCl 3 )δ7.39–7.32(m,4H),7.29–7.24(m,1H),4.71(dd,J＝10.1,4.0Hz,1H),3.24–3.18(m,1H),2.90–2.84(m,1H),2.52–2.42(m,2H),2.35–2.31(m,1H),2.30(s,6H),2.21–2.14(m,1H),2.07–2.01(m,1H),1.89–1.81(m,2H),1.63–1.49(m,2H). 13 C NMR(151MHz,CDCl 3 )δ142.37,128.46,127.58,125.97,69.06,66.24,62.21,54.80,51.35,41.85,28.85,28.52.HRMS(EI):exact mass calculated for C 15 H 24 N 2 O[M] + 248.1889,found 248.1891。
example 44: synthesis of beta-amino alcohol 9q
Figure BDA0004099707690000241
In this example, L-prolyl (24.3 mg,0.24 mmol) was used in place of morpholine 8a (20.9 mg,0.24 mmol) in example 7, the other steps being the same as in example 7, product 9q being a pale yellow oil in 85% yield >99:1dr. The product 9q obtained was characterized and the results were as follows:
[α] D 25 ＝-38.7(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.39–7.23(m,4H),7.23–7.15(m,1H),4.66(dd,J＝10.7,3.0Hz,1H),3.57(dd,J＝11.1,4.0Hz,1H),3.42(dd,J＝11.1,4.2Hz,1H),3.32–3.23(m,1H),2.82(dd,J＝12.7,10.7Hz,1H),2.70–2.61(m,1H),2.49(dd,J＝12.6,3.0Hz,1H),2.36–2.27(m,1H),1.88–1.62(m,4H). 13 C NMR(101MHz,CDCl 3 )δ142.23,128.48,127.71,126.03,71.68,65.38,63.89,63.72,54.51,27.32,23.88.HRMS(EI):exact mass calculated for C 13 H 19 NO 2 [M] + 221.1416,found221.1413。
example 45: synthesis of beta-amino alcohol 9r
Figure BDA0004099707690000242
In this example, morpholine 8a (20.9 mg,0.24 mmol) in example 7 was replaced with N-phenylpiperazine (38.9 mg,0.2 mmol) and the other steps were the same as in example 7, product 9r being a white solid in 90% yield, 99% ee. The product 9r obtained was characterized and the results were as follows:
[α] D 25 ＝-29.1(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.47–7.35(m,4H),7.34–7.25(m,3H),6.97(d,J＝8.1Hz,2H),6.90(t,J＝7.3Hz,1H),4.81(dd,J＝9.4,4.6Hz,1H),3.34–3.20(m,4H),3.00–2.89(m,2H),2.70–2.52(m,4H). 13 C NMR(101MHz,CDCl 3 )δ151.26,142.05,129.25,128.50,127.68,125.96,120.03,116.28,68.91,66.30,53.14,49.44.HRMS(EI):exact mass calculated for C 18 H 22 N 2 O[M] + 282.1732,found282.1735。
example 46: synthesis of beta-amino alcohol 9s
Figure BDA0004099707690000251
In this example, 4- (1, 2-benzisothiazol-3-yl) -1-piperazine (52.6 mg,0.24 mmol) was used instead of morpholine 8a (20.9 mg,0.24 mmol) in example 7, and the other steps were the same as in example 7, with product 9s as a pale yellow solid in 93% yield >99% ee. The product 9s obtained was characterized and the results were as follows:
[α] D 25 ＝-10.9(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.82(d,J＝8.2Hz,1H),7.73(d,J＝8.1Hz,1H),7.44–7.35(m,1H),7.35–7.25(m,5H),7.24–7.15(m,1H),4.74(dd,J＝10.2,3.8Hz,1H),3.62–3.45(m,4H),2.99–2.85(m,2H),2.71–2.44(m,4H). 13 C NMR(101MHz,CDCl 3 )δ163.89,152.87,142.01,128.52,128.06,127.71,125.98,124.07,123.92,120.72,68.89,66.43,52.96,50.26.HRMS(EI):exact mass calculated for C 19 H 21 N 3 OS[M] + 339.1405,found 339.1402。
example 47: synthesis of beta-amino alcohol 9t
Figure BDA0004099707690000252
In this example, 1- (2-furoyl) piperazine (43.2 mg,0.24 mmol) was used instead of morpholine 8a (20.9 mg,0.24 mmol) in example 7, and the other steps were the same as in example 7, and the product 9t was a pale yellow oil in 94% yield, 99% ee. The product 9t obtained was characterized and the results were as follows:
[α] D 25 ＝-17.5(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.45–9.38(m,1H),7.35–7.24(m,4H),7.23–7.16(m,1H),6.93(d,J＝3.4Hz,1H),6.40(dd,J＝3.5,1.8Hz,1H),4.84–4.56(m,1H),3.79(s,4H),2.80–2.66(m,2H),2.55–2.39(m,4H). 13 C NMR(101MHz,CDCl 3 )δ159.12,147.87,143.81,141.79,128.49,127.74,125.90,116.67,111.40,68.98,66.20,53.24,46.43,43.38.HRMS(EI):exact mass calculated for C 17 H 20 N 2 O 3 [M] + 300.1474,found 300.1471。
example 48: synthesis of beta-amino alcohol 9u
Figure BDA0004099707690000261
In this example, morpholine 8a (20.9 mg,0.24 mmol) in example 7 was replaced with N-methylbenzylamine (29.1 mg,0.24 mmol), and the other steps were the same as in example 7, with product 9u being a yellow oil in 90% yield >99% ee. The product 9u obtained was characterized and the results were as follows:
[α] D 25 ＝-75.6(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.34–7.13(m,10H),4.67(dd,J＝10.4,3.6Hz,1H),3.67(d,J＝13.1Hz,1H),3.45(d,J＝13.1Hz,1H),2.58–2.41(m,2H),2.24(s,3H). 13 C NMR(101MHz,CDCl 3 )δ142.24,138.23,129.18,128.52,128.44,127.59,127.45,126.00,69.49,65.58,62.46,41.84.HRMS(EI):exact mass calculated for C 16 H 19 NO[M] + 241.1467,found 241.1470。
example 49: synthesis of beta-amino alcohol 9v
Figure BDA0004099707690000262
In this example, morpholine 8a (20.9 mg,0.24 mmol) in example 7 was replaced with di-n-butylamine (31.0 mg,0.24 mmol), and the other steps were the same as in example 7, product 9v being a yellow oil in 89% yield >99% ee. The product 9v obtained was characterized and the results were as follows:
[α] D 25 ＝-65.9(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.45–7.31(m,4H),7.30–7.20(m,1H),4.64(dd,J＝10.5,3.6Hz,1H),2.72–2.55(m,3H),2.54–2.40(m,3H),1.55–1.30(m,8H),0.93(t,J＝7.3Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ142.65,128.41,127.46,125.94,69.38,63.21,53.88,29.37,20.70,14.19.HRMS(EI):exact mass calculated for C 16 H 27 NO[M] + 249.2093,found 249.2096。
according to the experimental results of the embodiment, the chiral iridium catalyst prepared by the reaction of the prepared chiral ligand L and the metal iridium complex is used for catalyzing the mixed reaction of the alpha-bromoketone and the amine compound to directly prepare the beta-amino alcohol compound, the reaction shows high activity and high corresponding selectivity, and the technical scheme for synthesizing the beta-amino alcohol compound shows wide substrate applicability and provides a wider path for synthesizing the beta-amino alcohol compound.
It should be noted that the above-mentioned embodiments are to be understood as illustrative, and not limiting, the scope of the invention, which is defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made to the present invention without departing from its spirit or scope.

Claims (10)

1. The asymmetric synthesis method of the beta-amino alcohol compound is characterized by comprising the following steps of:
(1) At room temperature, in an inert gas atmosphere, adding a metal iridium complex and a chiral ligand L into a solvent A to prepare a chiral iridium catalyst, so as to obtain a catalyst solution;
(2) Mixing alpha-bromoketone (I), amine compound (II), solvent B and alkali C, adding the catalyst solution prepared in the step (1), and carrying out asymmetric hydrogenation reaction under certain hydrogen pressure and temperature to generate chiral beta-amino alcohol compound (III), wherein the specific reaction route is as follows:
Figure FDA0004099707680000011
wherein the chiral ligand L is a chiral tridentate nitrogen phosphine ligand, ar in the formula (I) is C 4 -C 20 Aryl or heteroaryl, said amine compound (II) being selected from C 1 -C 20 Aliphatic secondary amine compound, aromatic secondary amine compound or C 1 -C 20 One of the heterocyclic secondary amines.
2. The asymmetric synthesis method of β -aminoalcohol compound according to claim 1 wherein said amine compound (ii) is selected from the group consisting of morpholine, piperidine, piperazine, tetrahydrothiophene pyridine, L-prolyl, tetrahydroisoquinoline and derivatives thereof.
3. The asymmetric synthesis method of β -aminoalcohol compound according to claim 1 wherein the metal iridium complex is selected from the group consisting of [ Ir (COD) Cl] 2 Or [ Ir (COE) 2 Cl] 2 。
4. The asymmetric synthesis method of a β -aminoalcohol compound according to claim 1, wherein the chiral ligand L is any one of ligands L1 to L5, and the structures of the ligands L1 to L5 are as follows:
Figure FDA0004099707680000021
5. the asymmetric synthesis method of a β -aminoalcohol compound according to claim 1, wherein in step (1), the reaction time of the metal iridium complex and chiral ligand L in solvent a is 0.5 to 6 hours, and wherein the molar ratio of the metal iridium complex to chiral ligand L is 1:2 to 1:4.
6. The method for asymmetric synthesis of β -aminoalcohol compound according to claim 1, wherein solvent a is one or more selected from n-hexane, ethyl acetate, dichloromethane, 1, 2-dichloroethane, toluene, tetrahydrofuran, methanol, ethanol, isopropanol.
7. The asymmetric synthesis method of a β -aminoalcohol compound according to claim 1, wherein the solvent B is one or more selected from the group consisting of n-hexane, dichloroethane, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, and isopropanol.
8. The asymmetric synthesis method of β -aminoalcohol compound according to claim 1, wherein the base C is selected from one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, sodium methoxide, and sodium ethoxide.
9. The asymmetric synthesis method of β -aminoalcohol compound according to claim 1, wherein in step (2), the reaction temperature of the asymmetric hydrogenation reaction is 20 to 80 ℃, the pressure is 0.1 to 8.0MPa, and the reaction time is 1 to 48 hours.
10. The asymmetric synthesis method of a β -aminoalcohol compound according to claim 1, wherein in step (2), the molar ratio of chiral iridium catalyst to α -bromoketone is 1:500 to 5000, and the molar ratio of α -bromoketone, amine compound and base C is 1:1 to 2:1 to 2.
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