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Phenylalanine derivative containing 4-(benzenesulfonyl)piperazine-2-ketone and preparing method and application of phenylalanine derivative

A technology of phenylalanine and benzenesulfonyl, which is applied in the field of organic compound synthesis and medical application, can solve the problems of low curative effect, easily induced drug resistance, poor drug-like properties, etc., and achieves the effect of high application value

Active Publication Date: 2019-05-31
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although PF-74 has a novel structure, unique mechanism, and clear targets, compared with currently marketed anti-HIV-1 drugs, PF-74 has lower efficacy, poor drug-like properties, and is very easy to induce drug resistance

Method used

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  • Phenylalanine derivative containing 4-(benzenesulfonyl)piperazine-2-ketone and preparing method and application of phenylalanine derivative
  • Phenylalanine derivative containing 4-(benzenesulfonyl)piperazine-2-ketone and preparing method and application of phenylalanine derivative
  • Phenylalanine derivative containing 4-(benzenesulfonyl)piperazine-2-ketone and preparing method and application of phenylalanine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: (S)-(1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate tert-butyl ester (2 ) preparation

[0047] Starting materials Boc-L-phenylalanine (1) (2.90g, 10.93mmol, 1.5eq.), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (5.69g, 10.93mmol, 1.5eq) was added to 20mL of dichloromethane, stirred in ice bath for 30min; then N,N-diisopropylethylamine (3.61mL, 21.87mmol, 3eq.) and N-methyl- 4-Aminoanisole (1.0g 7.29mmol, 1eq.), removed from the ice bath and stirred at room temperature, monitored by TLC; after 6h, the reaction was completed, the solvent was evaporated under reduced pressure, and then saturated sodium bicarbonate was added to the residue in the bottle solution 40mL, extracted with 40mL of dichloromethane, separated the organic phase, added 40mL of 1N HCl solution to wash, separated the organic phase, added 40mL of saturated sodium chloride solution to wash, dried the organic phase with anhydrous sodium sulfate, filtered...

Embodiment 2

[0052] Example 2: Preparation of (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (3)

[0053] Intermediate 2 (4.0g, 10.40mmol, 1.0eq.) was added to 30mL of dichloromethane, then trifluoroacetic acid (3.86mL, 52.02mmol, 5.0eq.) was slowly added to this solution, stirred at room temperature, monitored by TLC After 1h, the reaction was completed, then the pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate solution, 40 mL of dichloromethane was added for extraction, the organic phase was separated, washed with saturated sodium chloride solution (20 mL × 3 times), and dried over anhydrous sodium sulfate , filtered, and concentrated under reduced pressure to obtain 2.36 g of crude product of intermediate (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (3), yellow oil material with a yield of 80%.

[0054] Spectral data:

[0055] 1 H NMR (400MHz, DMSO-d 6 )δ7.29–7.13(m,3H,Ph-H),7.03–6.75(m,6H,Ph-H),3.77(s,3H,OCH 3 ),3.44–3.3...

Embodiment 3

[0058] Example 3: Preparation of intermediate (S)-2-(2-bromoacetyl)-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (4)

[0059] Bromoacetic acid (117mg, 0.84mmol, 1.2eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ( 401mg, 1.06mmol, 1.5eq.) was added to 15mL of dichloromethane, stirred in ice bath for 1h; then intermediate 3 (200mg, 0.70mmol, 1eq.) and N,N-diisopropyl Ethylamine (232μL, 1.41mmol, 2eq.), after removing the ice bath, stirred at room temperature, and monitored by TLC; after 6h, the reaction was completed, the solvent was evaporated under reduced pressure, and silica gel column chromatography (eluent EA:PE=1:4 + 2.5% triethylamine) to the intermediate (S)-2-(2-bromoacetyl)-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (4) 190 mg, white oil, yield 68%.

[0060] Spectral data:

[0061] ESI-MS: m / z 405.4(M+1).C 19 h 21 BrN 2 o 3 [404.1].

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Abstract

The invention provides a phenylalanine derivative containing 4-(benzenesulfonyl)piperazine-2-ketone and a preparing method and application of the phenylalanine derivative. The derivative has a structure shown in a formula I. The invention further relates to the preparing method of the derivative and the application of the derivative in preparing anti-AIDS drugs as an HIV-1 inhibitor. The formula Iis shown in the description.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a phenylalanine derivative containing 4-(benzenesulfonyl)piperazin-2-one, a preparation method and application thereof. Background technique [0002] AIDS (Acquired Immune Deficiency Syndrome, AIDS) is a major infectious disease mainly caused by Human Immunodeficiency Virus Type 1 (Human Immunodeficiency Virus Type 1, HIV-1), which endangers human life and health. At present, clinically used drugs for the treatment of AIDS are mainly divided into four categories: reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and invasion inhibitors according to different targets. "Highly Active Antiretroviral Therapy" (Highly Active Antiretroviral Therapy, HAART) prolongs the survival time of patients to a large extent and improves the quality of life of patients, but drug resistance, drug side effects, latent in...

Claims

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Application Information

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IPC IPC(8): C07K5/078C07K1/16C07K1/06A61K38/05A61P31/18
Inventor 刘新泳孙林展鹏黄天广李国雄卞钰莹高萍程锡强
Owner SHANDONG UNIV
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