Method for synthesizing chiral alpha-tertiary amine through catalytic kinetic resolution
A synthetic method and chiral technology, which is applied in the field of catalytic kinetic resolution and synthesis of chiral α-tertiary amines, which can solve the problems of unexplored, limited substrate applicability, and few reaction types of α-tertiary amines.
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[0018] The invention provides a method for the resolution and synthesis of chiral α-tertiary amines, comprising:
[0019] The racemic formula A compound is subjected to an asymmetric electrophilic aromatic substitution reaction with azodicarboxylate in the presence of a catalyst to provide (R) or (S) configuration of the formula A compound and opposite to the formula A compound The formula C compound of configuration:
[0020]
[0021] Among them, R 1 , R 2 Each independently selected from H, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy substituted or unsubstituted aryl Base, arylalkyl, heteroaryl, -OC(O)R', R' is selected from C1-C6 alkyl;
[0022] X is selected from NR", O, S, C(O)OR"', C(O)R"', or absent, R" is selected from H, C1-C6 alkyl, R"' is selected from C1-C6 alkyl;
[0023] Y is selected from C, or absent;
[0024] R 3 , R 6 each independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, or subst...
Embodiment 1
[0077] Synthesis method of substrate:
[0078] The first synthetic method of tetrahydroquinoline substrate:
[0079]
[0080] Under nitrogen atmosphere, 2-bromoquinoline (15.0 mmol), aryl boronic acid (22.5 mmol, 1.5 equivalents) and Pd(Ph 3 P) 4 (866 mg, 0.75 mmol, 5 mol%) in toluene (105 mL) and methanol (18 mL) was added aqueous potassium carbonate (2.5M, 18 mL, 3.0 equiv). After reacting at 80°C for 2 hours, it was cooled to room temperature and extracted three times with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and 2-arylquinoline S1 was obtained by petroleum ether / dichloromethane column chromatography.
[0081] To a solution of 2-arylquinoline S1 (7.5 mmol) in glacial acetic acid (50 mL) was added NaBH in one portion at room temperature 3 CN (15.0 mmol, 2.0 equiv). After reacting overnight, remove most of the glacial acetic acid by rotary evaporation, add dichloromethane (50 ml) and t...
Embodiment 2
[0100] Kinetic Resolution of Racemic Tetrahydroquinoline
[0101] The chiral phosphoric acid catalyst structure used in the present embodiment is as follows:
[0102]
[0103] General method for the kinetic resolution of tetrahydroquinoline substrates:
[0104] Under nitrogen atmosphere, racemic substrate (0.2 mmol), phosphoric acid catalyst (0.02 mmol, 10mol%) and Molecular sieves (100 mg) were added to an 8 ml glass bottle, and 2 ml of dry chloroform was added. Put the glass bottle with a balloon into a cold bath at a certain temperature and stir for 3 minutes. 2 mL of dry chloroform in which dibenzyl azodicarboxylate (36 mg, 0.12 mmol, 0.6 equiv) was dissolved was added dropwise thereto. When detection by chiral high-performance liquid chromatography reveals that the raw material has been converted by about 50%, 20 microliters of triethylamine is added to the reaction system to quench the reaction. Then after filtering through diatomaceous earth, dichloromethane was...
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