Phenylalanine derivative containing benzothiadiazin-3-one 1,1-dioxide and its preparation method and application

A technology of benzothiadiazine and dioxide, which is applied in the field of organic compound synthesis and pharmaceutical application, and can solve problems such as easy induction of drug resistance, low curative effect, and poor drug-like properties

Active Publication Date: 2022-07-12
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 benzothiadiazin-3-one 1,1-dioxide and its preparation method and application
  • Phenylalanine derivative containing benzothiadiazin-3-one 1,1-dioxide and its preparation method and application
  • Phenylalanine derivative containing benzothiadiazin-3-one 1,1-dioxide and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: tert-butyl (S)-(1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (2 ) preparation

[0044] The 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 for 30min under ice bath conditions; then N,N-diisopropylethylamine (3.61mL, 21.87mmol, 3eq.) and N-methyl were added -4-Aminoanisole (1.0g 7.29mmol, 1eq.), remove the ice bath and stir at room temperature, TLC monitoring; After 6h, the reaction is completed, the solvent is evaporated under reduced pressure, and then saturated hydrogen carbonate is added to the residue in the bottle Sodium solution 40mL, extracted with dichloromethane 40mL, the organic phase was separated, 40mL of 1N HCl solution was added to wash, the organic phase was separated, 40mL of saturated sodium chloride solution was added to wash, the organic phase was dried with anh...

Embodiment 2

[0049] Example 2: Preparation of (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (3)

[0050] 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, and monitored by TLC After 1 h, 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 intermediate (S)-2-amino-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (3) as yellow oil product, the yield was 80%.

[0051] Spectral data:

[0052] 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 ),3.44–3.35(m,1...

Embodiment 3

[0055] Example 3: Preparation of intermediate (S)-2-(2-bromoacetyl)-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (4)

[0056] Bromoacetic acid (117mg, 0.84mmol, 1.2eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ( 401mg, 1.06mmol, 1.5eq.) was added to 15mL of dichloromethane, stirred in an ice bath for 1h; then to this solution was added Intermediate 3 (200mg, 0.70mmol, 1eq.) and N,N-diisopropyl Ethylamine (232 μL, 1.41 mmol, 2 eq.), after removing the ice bath, stirred at room temperature, and monitored by TLC; after 6 h, the reaction was completed, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (eluent EA:PE=1:4 +2.5% triethylamine) to give intermediate (S)-2-(2-bromoacetyl)-N-(4-methoxyphenyl)-N-methyl-3-phenylpropanamide (4) 190 mg, white oil, 68% yield.

[0057] Spectral data: 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 benzothiadiazine-3-ketone 1,1-dioxide and a preparation method and application thereof. The derivative has the structure shown in the following general formula I. The invention also relates to a preparation method of the derivatives and their application as HIV-1 inhibitors in the preparation of anti-AIDS drugs.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and in particular relates to a phenylalanine derivative containing benzothiadiazine-3-one 1,1-dioxide and 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) that endangers human life and health. Currently, 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 their different targets. "Highly Active Antiretroviral Therapy" (HAART) prolongs the survival time of patients to a large extent and improves the quality of life of patients, but the problems of drug resistance, drug side effects, latent infection and long...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/078C07K5/02A61K38/05A61P31/18
CPCY02P20/55
Inventor 刘新泳孙林展鹏黄天广巩志伟李国雄陈阳中慧
Owner SHANDONG UNIV
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