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A kind of 1-benzyl-6-methoxycarbonylmethyl tetrahydroisoquinoline derivative, its preparation method and its anti-platelet aggregation application

A technology of methoxycarbonyltetrahydroisoquinoline and methoxycarbonylmethyl, which is applied in the field of drug synthesis to achieve the effects of low cost, simple and easy preparation method, and correct structure

Active Publication Date: 2018-04-10
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the structure of 1-benzyltetrahydroisoquinoline that has been studied more at present, the 6 and 7 substituents of isoquinoline are mostly H, MeO, PhCH 2 O or 6,7-OCH 2 O, little research on 6-methoxycarbonylmethyl substitution

Method used

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  • A kind of 1-benzyl-6-methoxycarbonylmethyl tetrahydroisoquinoline derivative, its preparation method and its anti-platelet aggregation application
  • A kind of 1-benzyl-6-methoxycarbonylmethyl tetrahydroisoquinoline derivative, its preparation method and its anti-platelet aggregation application
  • A kind of 1-benzyl-6-methoxycarbonylmethyl tetrahydroisoquinoline derivative, its preparation method and its anti-platelet aggregation application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Preparation of 2-[(1,1'-biphenyl)-4-yl]-N-(4-methoxyphenethyl)acetamide (compound 9)

[0042] Weigh 1 mmol of p-methoxyphenethylamine hydrochloride, 1.0-1.2 mmol of felbinac, dissolve the raw materials in 5 mL of acetonitrile in a 25 mL single-necked round bottom flask, add 4.2 mmol of triethylamine, and stir magnetically in a water bath at 25 °C. After 5 minutes, 0.4930 g (1.3 mmol) of peptide coupling agent HBTU was added, and the reaction was complete in 15 to 60 minutes. Acetonitrile was removed by rotary evaporation under reduced pressure to obtain a yellow solid, which was dissolved in 50 mL of dichloromethane, washed with deionized water (50 mL×3), washed with 50 mL of saturated brine, and the dichloromethane layer was dried with anhydrous sodium sulfate, suction filtered, and spun under reduced pressure. The solvent was evaporated to give a white solid. Column chromatography separation (dichloromethane:petroleum ether:ethyl acetate=100:25:4) gave 0.33...

Embodiment 2

[0043] Example 2 2-[(1,1'-biphenyl)-4-yl]-N-(3-phenylmercaptomethoxycarbonylmethyl-4-methoxyphenethyl)acetamide (Compound 10) preparation of

[0044] (1) Preparation of methyl 2-phenylthioglycolate (compound 7). Measure 2054 μL (20.0 mmol) of thiophenol into a 100 mL three-neck flask, add 30 mL of toluene, cut 0.5060 g (22.0 mmol) of sodium metal into small pieces and add it to the bottle, reflux at 110 ° C, and monitor the progress of the reaction by TLC. After the reaction is complete, add 20.0 to 30.0 mmol of methyl chloroacetate dropwise with a constant pressure dropping funnel, monitor the reaction by TLC, and the reaction is complete after 1 to 2 hours. Add 70 mL of ethyl acetate, wash with 100 mL of deionized water three times, dry the organic phase with anhydrous sodium sulfate, filter with suction, and remove the solvent by rotary evaporation under reduced pressure to obtain a light yellow oily liquid 1. Column chromatography (ethyl acetate:petroleum ether=1:40) gav...

Embodiment 3

[0047] Example 3 Preparation of 2-[(1,1'-biphenyl)-4-yl]-N-(3-methoxycarbonylmethyl-4-methoxyphenethyl)acetamide (compound 11)

[0048] Weigh 3.9813g (7.6mmol) of compound 10 into a 250mL single-necked flask, and dissolve in 80mL of ethanol. Wash the Raney nickel with ethanol to remove water, add 11.4g of Raney nickel, replace with hydrogen 3 times, put the hydrogen in a water bath at 25°C and stir vigorously with magnetic force, and the reaction is complete in 2 to 4 hours. The reaction solution was suction-filtered with diatomaceous earth, the filter cake was washed with dichloromethane, and the filtrate was rotary evaporated under reduced pressure to remove the solvent to obtain 3.0500 g of a white solid with a yield of 97%. 1 H NMR (CDCl 3 ,400MHz)δ:7.59(d,J=7.2Hz,2H,H-2",6"),7.55(d,J=8.0Hz,2H,H-4,8),7.44(dd,J 1 =7.2Hz,J 2 =7.2Hz, 2H, H-3”, 5”), 7.35(t, 1H, J=7.2Hz, 1H, H-4”), 7.26(d, J=8.0Hz, 2H, H-5,7 ),6.90(d,J=1.4Hz,H-4'),6.89(dd,1H,J 1 =1.4Hz,J 2 =8.0Hz, H-8'), ...

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Abstract

The invention belongs to the field of medicine synthesis, and provides a 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative, a preparation method and an application in resisting aggregation of thrombocyte, and particularly relates to a novel 1-substituted-benzyl-N-alkyl (acyl)-6-carbomethoxy methyl-7-methoxyl-1,2,3,4-tetrahydroisoquinoline derivative as shown in the formula (see the specification), a preparation method and an application for resisting the aggregation activity of the thrombocyte. According to the derivative, the in-vitro thrombocyte aggregation-resisting activity is tested by virtue of a Born turbidimetry, a test result shows that the derivative has the thrombocyte aggregation resisting activity, and the activity is obviously higher than positive reference clopidogrel sulfate. The nitrogen decoration of the 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative is favorable for improving the thrombocyte aggregation resisting activity. The 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative can be used for further preparing an antithrombus drug and has a good practical value and application prospect.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a 1-benzyl-6-methoxycarbonylmethyltetrahydroisoquinoline derivative, a preparation method and its anti-platelet aggregation application, in particular to a 1-substituted benzyl- N-Alkyl (acyl)-6-methoxycarbonylmethyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline derivative, preparation method and application of anti-platelet aggregation. Background technique [0002] Common thrombotic diseases include lower extremity deep vein thrombosis, coronary artery thrombosis, and cerebral artery thrombosis, which have seriously affected and troubled people's lives. Antiplatelet drugs are an important part of antithrombotic drugs, which mainly function by blocking the signal transduction of membrane receptors related to thrombosis or interfering with intracellular signaling pathways. ADP is an important platelet motility agent, which induces and accelerates the activation of platelets through two G-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02C07D217/06C07D217/04A61P7/02
CPCC07D217/02C07D217/04C07D217/06
Inventor 李悦青赵伟杰宋其玲杨菲秦秋燕王柳孙滨滨
Owner DALIAN UNIV OF TECH
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