A method for synthesizing chiral quinoxaline ketones

Abstract

This invention discloses a method for synthesizing chiral quinoxalones. Using a copper salt, a chiral ligand, and a base as a catalytic system, the target chiral quinoxalone compound is obtained by reaction in an organic solvent. This invention utilizes an economical and readily available copper catalyst, constructing C-N bonds through propargyl substitution and aminolysis of the ester group to synthesize chiral quinoxalones. This method has advantages such as good substrate universality, high yield, good enantioselectivity, and ease of industrial production. The synthesis method of this invention does not require the use of special and expensive catalysts, and the reaction conditions are simple, requiring no special reaction environment such as high-pressure hydrogen, with low requirements for reaction equipment, making it easy to scale up for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of chiral quinoxaline ketone, which is suitable for the synthesis of non-natural chiral quinoxaline ketone. BACKGROUND

[0002] Chiral quinoxaline ketone and its derivatives play a very important role in medicine, biology, materials and other aspects. In the field of pharmaceutical research, chiral quinoxaline ketone is not only an intermediate in the synthesis process of many drug molecules, but also an important skeleton structure of many drug molecules. For example, GW420867X containing a chiral quinoxaline ketone skeleton is a molecule with anti-HIV activity (HIV Clin. Trials 2001, 2, 307-316). At present, the strategies for synthesizing chiral quinoxaline ketone mainly include two types: (1) a synthesis strategy based on chiral auxiliary groups, which requires the use of equivalent chiral raw materials or auxiliary groups; (2) an asymmetric catalysis synthesis strategy, which requires the construction of a quinoxaline ketone skeleton in advance and the use of a noble metal catalyst. Therefore, the development of a simple and economical chiral quinoxaline ketone synthesis strategy has attracted widespread attention.

[0003] In 2015, the De Brabander team used 2-iodoaniline and its derivatives and α-chiral amino acids as raw materials to obtain a series of chiral quinoxaline ketones through copper-catalyzed cross-coupling and intramolecular cyclization (Tetrahedron Lett. 2015, 56, 3179-3182).

[0004]

[0005] This reaction requires the use of equivalent α-chiral amino acids as raw materials, and the reaction needs to be completed in two steps, which is complex and not conducive to operation.

[0006] In 2023, the Chen Fen'er team used quinoxaline ketone as a raw material to catalyze the asymmetric hydrogenation of the quinoxaline ketone skeleton under the catalysis of rhodium catalyst and chiral thiourea ligand to obtain chiral quinoxaline ketone products (Chem. Sci. 2023, 10.1039 / D3SC00803G).

[0007]

[0008] This type of reaction requires the construction of a quinoxaline ketone skeleton in advance and the use of high-pressure hydrogen, and the use of expensive rhodium catalysts during hydrogenation, which is a complex and costly synthesis strategy. SUMMARY

[0009] In order to overcome the above-mentioned defects of the prior art, the present application aims to provide a synthesis method of chiral quinoxaline ketone, so as to solve the technical problems of the prior art that the synthesis method is complex in operation, the reactants used are not easy to obtain, and the cost is high.

[0010] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0011] The present application discloses a synthesis method of chiral quinoxaline ketone, which uses propargyl ester compound and o-phenylenediamine as reaction raw materials, uses copper salt, chiral ligand and base as a catalytic system, and reacts in an organic solvent to prepare chiral quinoxaline ketone compound. The reaction general formula is as follows:

[0012]

[0013] Preferably, the structure formula of the o-phenylenediamine and propargyl ester compound is as follows:

[0014]

[0015] R 1 and R 2 are alkyl or aryl.

[0016] Preferably, the copper salt is CuI, Cu(OTf)2, Cu(ACN)4PF6, Cu(OAc )2 , CuCl, Cu(ACN)4BF4, CuBr2, CuSO4·5H2O or CuBr.

[0017] Preferably, the chiral ligand is:

[0018]

[0019] In the formula, X is H or alkyl.

[0020] Preferably, the base is quinuclidine, N,N-diisopropylethylamine, triphenylguanidine or N-methyl dicyclohexylamine.

[0021] Preferably, the molar amount of the o-phenylenediamine is 1.2 times the molar amount of the propargyl ester compound; and the molar amount of the base is 1.2 times the molar amount of the propargyl ester compound.

[0022] Preferably, the organic solvent is a mixed solvent of trifluoroethanol and chloroacetonitrile, and the volume ratio of trifluoroethanol to chloroacetonitrile in the mixed solvent is (1-6):1.

[0023] Preferably, the specific reaction steps are as follows:

[0024] The copper salt and the chiral ligand are first added into an organic solvent, stirred at room temperature for 1 hour, then the propargyl ester compound, o-phenylenediamine and a base are added, the reaction is continued, then after removing the solvent, the chiral quinoxaline ketone is prepared by silica gel column chromatography.

[0025] Further preferably, the reaction time is 24-72 hours.

[0026] Further preferably, the reaction temperature is -30 DEG C.

[0027] Compared with the prior art, the present application has the following beneficial effects:

[0028] The present application uses the propargyl ester compound and o-phenylenediamine as the reaction raw materials, uses the copper salt, the chiral ligand and the base as the catalytic system, and reacts in an organic solvent to obtain the target chiral quinoxaline ketone compound. DETAILED DESCRIPTION

[0029] In order for those skilled in the art to better understand the present application, the technical solutions of the present application will be clearly and completely described below in combination with specific embodiments of the present application.

[0030] It should be noted that the terms "first", "second" and the like in the specification and claims of the present application are used to distinguish similar objects, and do not necessarily indicate a specific order or a chronological sequence. It should be understood that the data thus used can be interchanged under appropriate circumstances, so that the embodiments of the present application described herein can be implemented in an order other than that described herein. In addition, the terms "include" and "have" and any variations thereof are intended to cover non-exclusive inclusion, for example, a process, method, system, product or device that includes a series of steps or units does not have to be limited to only those steps or units clearly listed, but can include other steps or units that are not clearly listed or inherent to the process, method, product or device.

[0031] The present application will be further described in detail below in combination with specific embodiments:

[0032] Embodiment 1

[0033]

[0034] In a 2 mL reaction vial, 0.9 mg of copper acetate, 3.3 mg of (4R, 5S)-L1 ligand and 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1) were added in turn, and stirred at room temperature for 1 hour, then cooled to -30 °C. 23.2 mg of propargyl ester I-1, 13.0 mg of o-phenylenediamine II-1 and 34.4 mg of triphenyl guanidine were dissolved in 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1), and slowly added into the reaction vial by microsyringe. The reaction system was stirred at -30 °C for 36 hours. The reaction solution was concentrated and dried by rotary evaporation, and the purified product (R)-III-1 was obtained by silica gel column separation. The yield was 88%, and the ee value was 94%. The structure characterization data of the pure product are as follows:

[0035] 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.85-7.76 (m, 2H), 7.47-7.37 (m, 3H), 6.99 (td, J = 7.6, 1.3 Hz, 1H), 6.88 (td, J = 7.6, 1.2 Hz, 1H), 6.79 (dd, J = 7.1, 4.9 Hz, 2H), 4.42 (s, 1H), 2.69 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 165.3, 138.3, 132.2, 129.1, 128.6, 127.8, 125.5, 124.2, 120.8, 115.7, 115.0, 81.2, 76.8, 61.4. IR (neat, cm -1 ) 3288, 3050, 1675, 1605, 1499, 1350, 1312, 912, 731, 689. HRMS (ESI): m / z: calcd for C 16 H 12 N2ONa[M+Na] + : 271.0847, found: 271.0852.

[0036] Example 2

[0037]

[0038] In a 2 mL reaction vial, 0.9 mg of anhydrous copper acetate, 3.3 mg of (4R, 5S)-L1 ligand and 0.5 mL of mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio of 3:1) were added in sequence. After stirring at room temperature for 1 hour, it was cooled to -30 °C. 24.6 mg of propargyl ester I-2, 13.0 mg of o-phenylenediamine II-1 and 34.4 mg of triphenyl guanidine were dissolved in 0.5 mL of mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio of 3:1), and slowly added into the reaction vial by microsyringe. The reaction system was stirred at -30 °C for 36 hours. The reaction solution was concentrated and dried by rotary evaporation, and the purified product (R)-III-2 was obtained by silica gel column separation. The yield was 81% and the ee value was 92%. The structure characterization data of the pure product were as follows:

[0039] 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.97 (td, J = 7.6, 1.3 Hz, 1H), 6.86 (td, J = 7.6, 1.2 Hz, 1H), 6.78 (d, J = 7.8 Hz, 2H), 4.40 (s, 1H), 2.66 (s, 1H), 2.37 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.3, 139.0, 135.4, 132.3, 129.3, 127.6, 125.5, 124.1, 120.7, 115.5, 115.0, 81.3, 76.6, 61.2, 21.3. IR (neat, cm -1 ) 3279, 3057, 1684, 1607, 1505, 1447, 1353, 1311, 1271, 812, 744. HRMS (ESI): m / z: calcd for C 17 H 14 N2ONa[M+Na] + : 285.1004, found: 285.1010.

[0040] Example 3

[0041]

[0042] In a 2 mL reaction vial, 0.9 mg of anhydrous copper acetate, 3.3 mg of (4R, 5S)-L1 ligand and 0.5 mL of mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio of 3:1) were added in sequence. After stirring at room temperature for 1 hour, it was cooled to -30 °C. 28.8 mg of propargyl ester I-3, 13.0 mg of o-phenylenediamine II-1 and 34.4 mg of triphenyl guanidine were dissolved in 0.5 mL of mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio of 3:1), and slowly added into the reaction vial by microsyringe. The reaction system was stirred at -30 °C for 36 hours. The reaction solution was concentrated and dried by rotary evaporation, and the purified product (R)-III-3 was obtained by silica gel column separation. The yield was 72% and the ee value was 93%. The structure characterization data of the pure product were as follows:

[0043] 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.96 (td, J = 7.6, 1.2 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.81-6.72 (m, 2H), 4.42 (s, 1H), 2.66 (s, 1H), 1.33 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 165.5, 152.0, 135.4, 132.3, 127.4, 125.6, 125.5, 124.1, 120.6, 115.7, 114.9, 81.4, 76.5, 61.1, 34.7, 31.4. IR (neat, cm -1 ) 3283, 2962, 1686, 1608, 1506, 1459, 1360, 1311, 1270, 735, 650. HRMS (ESI): m / z: calcd for C 20 H 20 N2ONa[M+Na] + : 327.1473, found: 327.1473.

[0044] Example 4

[0045]

[0046] In a 2 mL reaction vial, 0.9 mg of copper acetate, 3.3 mg of (4R, 5S)-L1 ligand and 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1) were added in turn, and stirred at room temperature for 1 hour, then cooled to -30 °C. 30.8 mg of propargyl ester I-4, 13.0 mg of o-phenylenediamine II-1 and 34.4 mg of triphenyl guanidine were dissolved in 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1), and slowly added into the reaction vial by microsyringe. The reaction system was stirred at -30 °C for 36 hours. The reaction solution was concentrated and dried by rotary evaporation, and the purified product (R)-III-4 was obtained by silica gel column separation. The yield was 75%, and the ee value was 93%. The structure characterization data of the pure product are as follows:

[0047] 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.96-7.83 (m, 2H), 7.74-7.54 (m, 4H), 7.52-7.41 (m, 2H), 7.41-7.34 (m, 1H), 6.98 (td, J = 7.6, 1.5 Hz, 1H), 6.86 (td, J = 7.7, 1.2 Hz, 1H), 6.83-6.75 (m, 2H), 4.47 (s, 1H), 2.71 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 165.3, 142.0, 140.7, 137.3, 132.2, 128.9, 128.2, 127.7, 127.4, 127.3, 125.5, 124.2, 120.8, 115.7, 115.0, 81.2, 76.9, 61.2. IR (neat, cm -1 ) 3283, 3058, 2925, 1685, 1607, 1505, 1355, 1311, 909, 733. HRMS (ESI): m / z: calcd for C 22 H 16 N2ONa[M+Na] + : 347.1160, found: 347.1161.

[0048] Example 5

[0049]

[0050] In a 2 mL reaction vial, 0.9 mg of copper acetate, 3.3 mg of (4R, 5S)-L1 ligand and 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1) were added in turn, and stirred at room temperature for 1 hour, then cooled to -30 °C. 31.0 mg of propargyl ester I-5, 13.0 mg of o-phenylenediamine II-1 and 34.4 mg of triphenyl guanidine were dissolved in 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1), and slowly added into the reaction vial by microsyringe. The reaction system was stirred at -30 °C for 36 hours. The reaction solution was concentrated and dried by rotary evaporation, and the purified product (R)-III-5 was obtained by silica gel column separation. The yield was 78%, and the ee value was 90%. The structure characterization data of the pure product are as follows:

[0051] 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 6.99 (td, J = 7.6, 1.3 Hz, 1H), 6.89 (td, J = 7.6, 1.2 Hz, 1H), 6.80 (t, J = 6.5 Hz, 2H), 4.39 (s, 1H), 2.69 (s, 1H). 13 C NMR (100 MHz, CDCl3) one carbon signal was overlapped δ 164.6, 137.3, 132.0, 131.7, 129.6, 125.4, 124.3, 123.5, 121.1, 115.6, 115.2, 80.7, 61.1. IR (neat, cm -1 ) 3287, 1686, 1608, 1505, 1486, 1355, 1312, 1074, 1011, 748, 659. HRMS (ESI): m / z: calcd for C 16 H 11 N2OBrNa[M+Na] + : 348.9952, found: 348.9958.

[0052] Example 6

[0053]

[0054] In a 2 mL reaction vial, 0.9 mg of copper acetate, 3.3 mg of (4R, 5S)-L1 ligand and 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1) were added in turn, and stirred at room temperature for 1 hour, then cooled to -30 °C. 17.0 mg of propargyl ester I-6, 13.0 mg of o-phenylenediamine II-1 and 34.4 mg of triphenyl guanidine were dissolved in 0.5 mL of trifluoroethanol and chloroacetonitrile mixed solvent (volume ratio of 3:1), and slowly added into the reaction vial by microsyringe. The reaction system was stirred at -30 °C for 36 hours. The reaction solution was concentrated and dried by rotary evaporation, and the purified product (R)-III-6 was obtained by silica gel column separation. The yield was 60%, and the ee value was 60%. The structure characterization data of the pure product are as follows:

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 6.96 (td, J = 7.6, 1.4 Hz, 1H), 6.87 (td, J = 7.6, 1.3 Hz, 1H), 6.79 (dd, J = 8.9, 4.4 Hz, 2H), 4.16 (s, 1H), 2.36 (s, 1H), 1.80 (s, 3H). 13 CNMR (100 MHz, CDCl3) one carbon signal was overlapped δ 165.5, 132.5, 125.9, 124.1, 120.9, 115.4, 115.2, 73.3, 53.2, 25.1. IR (neat, cm -1 ) 3325, 3270, 1664, 1604, 1507, 1388, 1314, 1146, 746, 663. HRMS (ESI): m / z: calcd for C 11 H 11 N2O [M+H] + : 187.0871, found: 187.0874.

[0056] The above is only to illustrate the technical idea of the present application, and cannot limit the protection scope of the present application. Any modification made according to the technical idea of the present application on the basis of the technical scheme falls within the protection scope of the claims of the present application.

Claims

1. A method for the synthesis of chiral quinoxaline ketones, characterized in that, A chiral quinoxaline ketone compound is prepared by using propargyl ester compound and o-phenylenediamine as raw materials, copper salt, chiral ligand and base as catalytic system, and reacting in an organic solvent. The propargyl ester compound has the following structural formula: , R 2 is alkyl or aryl; The o-phenylenediamine has the following structural formula: , R 1 is alkyl or aryl; The chiral ligand is ； The copper salt is Cu(OAc)2.

2. The method of synthesis of chiral quinoxaline ketones according to claim 1, characterized by, The base is quinuclidine, N,N-diisopropylethylamine, triphenylguanidine or N-methyl dicyclohexylamine.

3. The method of synthesis of chiral quinoxaline ketones according to claim 1, characterized by, The molar amount of the o-phenylenediamine is 1.2 times of the molar amount of the propargyl ester compound, and the molar amount of the base is 1.2 times of the molar amount of the propargyl ester compound.

4. The method of synthesis of chiral quinoxaline ketones according to claim 1, characterized by, The organic solvent is a mixed solvent of trifluoroethanol and chloroacetonitrile, and the volume ratio of trifluoroethanol to chloroacetonitrile in the mixed solvent is (1-6):

1.

5. The method of synthesis of chiral quinoxaline ketones according to claim 1, wherein, The specific reaction steps are as follows: First, the copper salt and the chiral ligand are added to the organic solvent, stirred at room temperature for 1 hour, then the propargyl ester compound, the o-phenylenediamine and the base are added, and the reaction is continued, then the solvent is removed, and the chiral quinoxaline ketone is prepared by silica gel column chromatography.

6. The method of synthesis of chiral quinoxaline ketones according to claim 5, wherein, The reaction time is 24-72 hours.

7. The method of synthesis of chiral quinoxaline ketones according to claim 5, wherein, The reaction temperature is -30℃.

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