Chiral 2, 3-disubstituted indoleamine compound and preparation method thereof

A two-substituted, compound technology, applied in the field of organic chemical pharmaceutical intermediates, can solve problems such as unfavorable industrialization promotion, and achieve the effects of mild conditions, environmental friendliness and simple process.

Active Publication Date: 2021-10-01
SHANGHAI UNIV OF ENG SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method in this technical scheme needs two steps, is unfavorable for realizing the popularization of industrialization

Method used

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  • Chiral 2, 3-disubstituted indoleamine compound and preparation method thereof
  • Chiral 2, 3-disubstituted indoleamine compound and preparation method thereof
  • Chiral 2, 3-disubstituted indoleamine compound and preparation method thereof

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preparation example Construction

[0041] The synthesis method includes the following steps: mixing an organic small molecule catalyst chiral bissulfonimide and an organic solvent, stirring uniformly, then adding aldimine and 3-substituted indole in sequence, and performing the reaction while stirring until the reaction ends, and the steps are carried out in sequence. Quenching and extraction to obtain a crude product, which is purified by silica gel column chromatography to obtain the chiral disubstituted indoleamines, wherein,

[0042] The structure of aldimine is

[0043] The structure of 3-substituted indole is

[0044] R 1 is selected from aryl or C1-C8 alkyl, R 2 One of the alkyl or aryl groups selected from C1-C5, R 3 One selected from alkyl or aryl, R 4 Selected from C1-C2 alkyl or halogen.

[0045] The general reaction equation of the present invention is as follows:

[0046]

[0047] The structural formula of chiral bissulfonimide is as follows:

[0048]

[0049] where the R 5 One se...

Embodiment 1

[0052]

[0053] Under nitrogen protection, imine II-a (30.1 mg, 0.1 mmol) and catalyst IV-a (82 mg, 0.01 mmol) were placed in a 10 mL dry reaction tube, 1.0 mL of anhydrous toluene was injected through a syringe, and 3- Substituted indole I-a (26.2 mg, 0.2 mmol) was heated to 35 °C for 2 h. After the reaction was completed, 1.0 mL of water was added to quench, extracted with ethyl acetate three times, washed with saturated brine, and the organic phase was washed with anhydrous Na 2 SO 4 After drying, concentration, the crude product was purified by column chromatography to obtain product 1, namely III-a (32.5 mg, 75%), 1 H NMR (400MHz, CDCl 3)δ8.00(br,s,1H),7.63-7.53(m,2H),7.42(d,J=7.7Hz,1H),7.18-7.24(m,6H),7.15-7.03(m,3H) , 5.87(q, J=7.0Hz, 2H), 2.02(s, 3H), 1.22(s, 9H). 13 CNMR (101MHz, CDCl 3 )δ156.4, 138.8, 136.4, 135.7, 131.3, 128.7, 128.6, 127.9, 127.0, 126.8, 125.6, 122.2, 119.3, 118.7, 110.9, 109.5, 53.9, 35.0, 31.0, 8.2. HPLC analysis conditions: Daicel CHIR c...

Embodiment 2

[0068]

[0069] The difference from Example 1 is: the imine II-a of the tert-butyl substituted substrate used is 4-bromo-substituted imine II-b (0.1mmol, 32.4mg), other reaction conditions and operation steps and implementation Same as Example 1, white solid product III-b (30.0 mg, 68%) was obtained, 1 H NMR (400MHz, CDCl 3 )δ7.83(s,1H),7.46(d,J=7.6Hz,1H),7.41(d,J=8.6Hz,2H),7.29-7.21(m,7H),7.19-7.06(m,3H) ), 5.91(s, 1H), 5.72(br, s, 1H), 2.10(s, 3H). 13 C NMR (101MHz, CDCl 3 )δ138.6, 138.213, 135.6, 131.7, 130.6, 128.9, 128.5, 128.2, 128.2, 127.6, 127.0, 122.7, 119.6, 118.8, 110.8, 110.1, 54.1, 8.4. HPLC analysis conditions: DaicelCHIRALPAK AD-H column, 25nm, 4nm -hexane / i-PrOH=90 / 10, 1.0 mL / min, 12.54 min (minor), 17.66 min (major), 90% ee.

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Abstract

The invention relates to a chiral 2, 3-disubstituted indoleamine compound and a preparation method thereof. The preparation method comprises the steps: taking chiral bisulfimide as an organic small molecule catalyst, mixing the organic small molecule catalyst with an organic solvent, and stirring the mixture to be uniform to obtain mixed dispersion liquid A; sequentially adding aldimine and 3-substituted indole, performing reacting under a stirring condition, and sequentially performing quenching and extracting to obtain a crude product; carrying out silica gel column chromatography purification on the crude product to obtain the chiral 2, 3-disubstituted indoleamine compound. Compared with the prior art, the method provided by the invention has the advantages that the simple and easily available chiral bisulfonimide is used as a catalyst, in the presence of an organic solvent, 3-substituted indole and the sulfonimide compound are subjected to Friedel-Crafts reaction to directly form the corresponding 2, 3-disubstituted indoleamine compound, the reaction condition is mild, the method is environment-friendly, the reaction reagent is cheap and easily available, the reaction substrate range is wide, and the enantioselectivity is high.

Description

technical field [0001] The invention relates to the technical field of organic chemical pharmaceutical intermediates, in particular to a chiral 2,3-disubstituted indoleamine compound and a preparation method thereof. Background technique [0002] Asymmetric catalysis is one of the hottest fields in organic synthesis today. It meets the development requirements of green chemistry and is the most effective method for synthesizing chiral compounds. Organic small molecule catalysis has great advantages due to its green environmental protection and mild reaction (Catalysts 2018, 8, 605). Since the 21st century, organic small-molecule catalysts represented by proline derivatives, chiral phosphoric acid, and cinchonadine have developed rapidly. [0003] 2,3-Disubstituted indoleamines are widely found in many natural products and drug molecules, and have good biological activity, and are of great significance in many chemical fields such as organic synthesis and drug synthesis. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14
CPCC07D209/14C07B2200/07
Inventor 陈玲艳孙朋
Owner SHANGHAI UNIV OF ENG SCI
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