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(Z)-beta-trifluoromethyl dehydrotryptophan compound and synthesis method and application thereof

A technology of trifluoromethyl group and synthesis method, applied in the field of organic synthesis, can solve the problems of poor atom economy, high operation requirements, low yield and the like

Active Publication Date: 2020-10-27
SHANGQIU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in many synthetic methods, there are certain problems, such as poor atom economy, long synthesis steps, high operation requirements, many by-products, low yield, etc.

Method used

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  • (Z)-beta-trifluoromethyl dehydrotryptophan compound and synthesis method and application thereof
  • (Z)-beta-trifluoromethyl dehydrotryptophan compound and synthesis method and application thereof
  • (Z)-beta-trifluoromethyl dehydrotryptophan compound and synthesis method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Catalyst screening experiments: Different catalysts promote the reaction of 3-trifluoroacetyl indole with isocyanate, resulting in different yields.

[0031] Pick N - p-toluenesulfonyl-3-trifluoroacetylindole (0.2 mmol), methyl isocyanate (0.4 mmol), catalyst (0.02 mmol), added to 2 mL of dichloromethane, 35 ° C for 48 hours, the reaction After completion, the solvent was removed under reduced pressure, and compound A was obtained by column chromatography.

[0032]

[0033]

[0034] The ratio in the table refers to the N - p-toluenesulfonyl-3-trifluoroacetylindole:methyl isocyanate:catalyst ratio.

Embodiment 2

[0036] The preparation method of compound A with the following structure:

[0037]

[0038] Pick N - p-toluenesulfonyl-3-trifluoroacetylindole (0.2 mmol), methyl isocyanate (0.4 mmol), AgOAc (0.02 mmol), added to 2 mL 1,4-dioxane, 35 °C The reaction was carried out for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure, and 92.3 mg of compound A was obtained as a white solid through column chromatography separation, with a yield of >99%.

[0039] NMR characterization is as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 8.14 (s, 1H),7.97 (d, J= 8.3 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.58 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.1 Hz, 3H), 3.19 (s,3H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 162.9, 158.0, 145.4, 134.9, 134.4, 134.3, 130.0, 130.0, 127.5, 126.9, 125.4, 123.9, 123.2 (q, J = 275.1Hz, 1C), 120.4, 113.5, 112.2, 108.9 (q, J = 32.6 Hz, 1C), 52.4, 21.6.

Embodiment 3

[0041] The preparation method of compound B with the following structure:

[0042]

[0043] Pick N -Phenylsulfonyl-3-trifluoroacetylindole (0.2 mmol), methyl isocyanate (0.4 mmol), AgOAc (0.02 mmol), add 2 mL 1,4-dioxane, and react at 35°C After 24 hours, after the reaction was completed, the solvent was removed under reduced pressure, and 87.7 mg of compound B was obtained by column chromatography separation as a colorless oil, with a yield of 97%.

[0044] NMR characterization is as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.96 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.85-7.78 (m, 2H), 7.50 (s, 1H), 7.48 (d, J = 7.4Hz, 1H), 7.39 (dd, J = 16.9, J = 8.4 Hz, 3H), 7.28 (d, J = 7.8 Hz, 1H), 7.24-7.19 (m, 1H), 3.07 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ162.8, 157.8, 137.9,134.5, 134.3, 134.2, 130.0, 129.5, 127.5, 126.9, 125.5, 124.0, 123.2 (q, J =275.1 Hz, 1C), 120.5, 113.5, 112.4, 108.7 (q, J = 33.5 Hz, 1C), 52.5.

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Abstract

The invention belongs to the field of organic synthesis, and relates to a (Z)-beta-trifluoromethyl dehydrotryptophan compound, in particular to a (Z)-beta-trifluoromethyl dehydrotryptophan compound and a synthesis method and application thereof. The synthesis method comprises the following steps of: weighing a 3-trifluoroacetyl indole compound, an isocyanate compound, a catalyst and a solvent according to a certain ratio, stirring and reacting for 15-60 h at a temperature of 20-40 DEG C, and after the reaction is finished, carrying out pressure reduction and separation to obtain the (Z)-beta-trifluoromethyl dehydrotryptophan compound. According to the synthesis method disclosed by the invention, the (Z)-beta-trifluoromethyl dehydrotryptophan compound is simply, conveniently and efficientlyconstructed by taking 3-trifluoroacetyl indole as a trifluoromethyl source and carrying out a reaction between the trifluoromethyl source and isocyanate. Due to the introduction of trifluoromethyl, the membrane permeation function of the dehydrotryptophan-containing cyclic active peptide is effectively improved, the oil-water separation coefficient is increased, the lipophilicity and metabolic stability are enhanced, and the biological activity of the dehydrotryptophan-containing cyclic active peptide is improved.

Description

technical field [0001] The invention belongs to the field of organic synthesis and relates to ( Z )- β - trifluoromethyl dehydrotryptophan compounds, especially (Z)-β -Trifluoromethyl dehydrotryptophan compound and its synthesis method and application. Background technique [0002] Dehydrotryptophan and its derivatives widely exist in cyclic bioactive peptide natural products and bioactive molecules (D. Sorensen et al. Phytochemistry 1999, 51, 1181; A. L. Johnson et al. Arkivoc 2002, 57; M .-T. Lorena et al. Chem. Commun. 2017, 53, 2740; E. W. Kelley et al. Org. Biomol. Chem. 2017, 15, 8634.). The main methods for synthesizing dehydrotryptophan compounds in the prior art include Erlenmeyer reaction synthesis method, Wittig reaction synthesis method, Horner-Wadsworth-Emmons reaction synthesis method, etc. (R. J. Block. Chem. Rev., 1946, 38, 501; R. Kimura et al. Bull. Chem. Soc. Jpn. 2002, 75, 2517; H. Kinoshita et al. Bull. , 12, 2162.). [0003] Patent CN201710709533....

Claims

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Application Information

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IPC IPC(8): C07D209/20C07D209/24C07D209/26
CPCC07D209/20C07D209/24C07D209/26
Inventor 张明亮吴冬青李高伟刘澜涛张安安赵聘袁浩张文宇郑琳琳
Owner SHANGQIU NORMAL UNIVERSITY
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