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1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative, preparation method and application in resisting aggregation of thrombocyte

A technology of methoxycarbonylmethyltetrahydroisoquinoline and methoxycarbonylmethyl, which is applied in the field of pharmaceutical synthesis and achieves the effects of correct structure, simple and easy preparation method and low cost

Active Publication Date: 2015-12-09
DALIAN UNIV OF TECH
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  • 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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  • 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative, preparation method and application in resisting aggregation of thrombocyte
  • 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative, preparation method and application in resisting aggregation of thrombocyte
  • 1-benzyl-6-carbomethoxy methyl tetrahydroisoquinoline derivative, preparation method and application in resisting aggregation of thrombocyte

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0041] Example 12 Preparation of-[(1,1'-biphenyl)-4-yl]-N-(4-methoxyphenethyl)acetamide (Compound 9)

[0042] Weigh 1 mmol p-methoxyphenethylamine hydrochloride and 1.0-1.2 mmol felbinac, in a 25 mL single-neck round bottom flask, dissolve the raw material in 5 mL acetonitrile, add 4.2 mmol 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 completed in 15-60 minutes. The 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), and washed with 50 mL of saturated brine. The dichloromethane layer was dried with anhydrous sodium sulfate, filtered with suction, and rotated under reduced pressure. The solvent was evaporated to obtain a white solid. Column chromatography separation (dichloromethane: petroleum ether: ethyl acetate=100:25:4) to obtain 0...

Embodiment 22

[0043] Example 22-[(1,1'-Biphenyl)-4-yl]-N-(3-phenylmercaptomethoxycarbonylmethyl-4-methoxyphenethyl)acetamide (Compound 10) preparation

[0044] (1) Preparation of methyl 2-phenylmercaptoacetate (Compound 7). Measure 2054 μL (20.0 mmol) of thiophenol in a 100 mL three-necked flask, add 30 mL of toluene, cut 0.5060 g (22.0 mmol) of sodium metal into small pieces and add to the bottle, reflux the reaction at 110° C., and monitor the progress of the reaction by TLC. After the reaction is complete, 20.0-30.0 mmol of methyl chloroacetate are added dropwise with a constant pressure dropping funnel, and the reaction is monitored by TLC. The reaction is complete after 1 to 2 hours. 70 mL of ethyl acetate and 100 mL of deionized water were added to wash 3 times, the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and the solvent was removed by rotary evaporation under reduced pressure to obtain a pale yellow oily liquid 1. Column chromatography separation ...

Embodiment 32

[0047] Example 32 Preparation of-[(1,1'-biphenyl)-4-yl]-N-(3-methoxycarbonylmethyl-4-methoxyphenethyl)acetamide (Compound 11)

[0048] Weigh 3.9813 g (7.6 mmol) of the compound into a 250 mL single-necked flask, and dissolve 80 mL of ethanol. The Raney nickel was washed with ethanol to remove water, 11.4 g of Raney nickel was added, and hydrogen was replaced 3 times. Under hydrogen, the reaction was completed under a water bath at 25°C and magnetically vigorously stirred for 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 white solid with a yield of 97%. 1 HNMR(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'),6.68(d,J=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, and specifically relates 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 deep vein thrombosis of the lower extremities, coronary artery thrombosis and cerebral artery thrombosis, etc., which have caused serious impact and distress on people's lives. Antiplatelet drugs are an important part of antithrombotic drugs, which mainly act by blocking the signal transduction of membrane receptors related to thrombosis or interfering with intracellular signal pathways. ADP is an important platelet promoter, which induces and accelerates the activation of platelets thr...

Claims

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Application Information

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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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