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(z)-β-trifluoromethyl dehydrotryptophan compound and its synthesis method and application

The technology of a trifluoromethyl group and a synthesis method, which is applied in the field of organic synthesis, can solve the problems of poor atom economy, high operation requirements, long synthesis steps and the like, and achieves the effects of improving biological activity, high application value and easy operation.

Active Publication Date: 2022-03-29
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)-β-trifluoromethyl dehydrotryptophan compound and its synthesis method and application
  • (z)-β-trifluoromethyl dehydrotryptophan compound and its synthesis method and application
  • (z)-β-trifluoromethyl dehydrotryptophan compound and its synthesis method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Catalyst screening experiments: Different catalysts promote the reaction of 3-trifluoroacetyl indole with isocyanate, resulting in different yields.

[0032] 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.

[0033]

[0034]

[0035] The ratio in the table refers to the N - p-toluenesulfonyl-3-trifluoroacetylindole:methyl isocyanate:catalyst ratio.

Embodiment 2

[0037] The preparation method of compound A with the following structure:

[0038]

[0039] 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%.

[0040] 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

[0042] The preparation method of compound B with the following structure:

[0043]

[0044] Pick N -Phenylsulfonyl-3-trifluoroacetylindole (0.2 mmol), methyl isocyanate (0.4 mmol), AgOAc (0.02 mmol), add 2 mL of 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%.

[0045] 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 ( Z )- β ‑Trifluoromethyldehydrotryptophan compounds, especially (Z)‑β ‑Trifluoromethyl dehydrotryptophan compound and its synthesis method and application. Weigh 3-trifluoroacetylindole compounds, isocyanate compounds, catalysts and solvents in proportion, stir and react at 20-40°C for 15-60 hours, after the reaction is completed, obtain ( Z )- β ‑Trifluoromethyl dehydrotryptophans. The present invention uses 3-trifluoroacetyl indole as a trifluoromethyl source, and through the reaction with isocyanate, it is simple and efficient to construct ( Z )- β ‑Trifluoromethyl dehydrotryptophans. The introduction of trifluoromethyl groups can effectively improve the membrane permeability of cyclic active peptides containing dehydrotryptophan, increase the oil-water separation coefficient, enhance lipophilicity and metabolic stability, and improve the cyclic activity of dehydrotryptophan-containing peptides. Biological activity of active peptides.

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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Patent Type & Authority Patents(China)
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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