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Substituted glycin-3, 5-difluorophenylalanine peptide derivative as well as preparation method and application thereof

A technology of difluorophenylalanine and peptide derivatives, applied in dipeptide components, peptides, pharmaceutical formulations, etc., can solve problems such as high cost, poor single drug treatment effect, and high mutation rate

Active Publication Date: 2022-05-10
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the high mutation rate of HIV-1, it is easy to develop drug resistance, and the effect of single drug therapy is poor.
"Highly Active Antiretroviral Therapy" (Highly Active Antiretroviral Therapy, HAART) can effectively reduce the HIV load in patients and improve the life expectancy and quality of life of patients, but serious adverse reactions, drug resistance, latent infection and Problems such as high cost make it urgent to discover new structural types of HIV inhibitors

Method used

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  • Substituted glycin-3, 5-difluorophenylalanine peptide derivative as well as preparation method and application thereof
  • Substituted glycin-3, 5-difluorophenylalanine peptide derivative as well as preparation method and application thereof
  • Substituted glycin-3, 5-difluorophenylalanine peptide derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: (S)-(3-(3,5-difluorophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-yl ) Preparation of tert-butyl carbamate (I-2)

[0041] Starting materials Boc-L-phenylalanine (I-1) (2.00g, 6.64mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (3.46g, 6.64mmol ) was added to 20mL of dichloromethane, and stirred for 30min under ice-bath conditions; then N,N-diisopropylethylamine (2.23mL, 13.29mmol) and N-methyl-4-aminoanisole (610mg , 4.43mmol), remove the ice bath and stir at room temperature, TLC monitoring; 6h after the reaction is complete, evaporate the solvent under reduced pressure, then add 40mL of saturated sodium bicarbonate solution to the residue in the bottle, extract with 40mL of dichloromethane, and separate The organic phase was washed by adding 40 mL of 1N HCl solution, the organic phase was separated and washed by adding 40 mL of saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, filter...

Embodiment 2

[0045] Example 2: Preparation of (S)-2-amino-3-(3,5-difluorophenyl)-N-(4-methoxyphenyl)-N-methylpropionamide (I-3)

[0046] Intermediate I-2 (500mg, 1.19mmol) was added to 30mL of dichloromethane, then trifluoroacetic acid (410mg, 3.57mmol) was slowly added to the solution, stirred at room temperature, monitored by TLC; the reaction was completed after 1h, and then used Adjust the pH of the reaction solution to 7 with saturated sodium bicarbonate solution, add 40 mL of dichloromethane for extraction, separate the organic phase, wash with saturated sodium chloride solution (3×20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain intermediate The crude product of (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (3) was 2.36 g, a yellow oil, and the yield was 80%.

[0047] Spectral data:

[0048] 1 H NMR (400MHz, DMSO-d 6 )δ7.07(d, J=8.3Hz, 2H), 7.05–6.93(m, 3H), 6.57(h, J=4.0Hz, 2H), 3.78(s, 3H), 3.35(dd, J=7.6 ,5.9Hz...

Embodiment 3

[0049] Example 3: Intermediate (S)-3-(3,5-difluorophenyl)-2-formamido-N-(4-methoxyphenyl)-N-methylpropionamide (I- 4) Preparation

[0050] Intermediate I-3 (340mg, 1.06mmol) was added to 10mL of acetonitrile, then ammonium formate (130mg, 2.12mmol) was added to the solution, heated to reflux at 90°C for 24h, monitored by TLC; after 24h, the reaction was complete, filtered, and water , extracted with ethyl acetate (3 × 10mL), combined the organic phases; adding 20mL of saturated sodium chloride solution to wash, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (washing Removal agent EA:PE=1:8) to obtain the intermediate (S)-(3-(3,5-difluorophenyl)-1-((4-methoxyphenyl))methyl)amino)- 1.68 g of crude product of tert-butyl 1-oxopropan-2-yl)carbamate (I-4), yellow oil, yield 60%.

[0051] Spectral data:

[0052] 1 H NMR (400...

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Abstract

The invention provides a peptide derivative containing substituted glycin-3, 5-difluorophenylalanine as well as a preparation method and application of the peptide derivative. The derivative has a structure as shown in a general formula I. The invention also relates to a preparation method of the derivative and application of the derivative as an HIV inhibitor in preparation of anti-AIDS drugs.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a substituted glycine-3,5-difluorophenylalanine peptide derivative and its preparation method and application. Background technique [0002] Acquired Immune Deficiency Syndrome (AIDS), also known as AIDS, is a chronic infectious disease caused by human immunodeficiency virus (HIV) that endangers human life and health. HIV belongs to RNA retrovirus, which is divided into two subtypes, HIV-1 / 2. Among them, HIV-1 has strong infectivity and high lethality, and is the main pathogen of AIDS. HIV-2 is mainly limited to West Africa, but with the continuous development of globalization and increasingly close personnel exchanges, HIV-2 infection cases have also been found in the United States, Europe, South Africa, India and China, which should be paid attention to. There are more than 30 drugs currently on the market for the treatment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05A61P31/18
CPCC07K5/06026A61P31/18A61K38/00Y02P20/55
Inventor 展鹏姜向毅刘新泳李敬
Owner SHANDONG UNIV
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