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1,2-dihydroisoquinoline derivative and preparation thereof

A technology of dihydroisoquinoline and derivatives, applied in organic chemistry and other fields, can solve the problems of low yield and long steps, and achieve the effects of convenient operation, mild reaction conditions and easy preparation

Inactive Publication Date: 2009-08-12
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Chen, J; Chen, X; Michele, B.C., and Zhu J (J.Am.Chem.Soc.2006, 128, 87) reported the synthetic route of the following structural formula ecteinascidin 743 (marine anticancer drug), wherein in the synthetic route The tetrahydroisoquinoline structure is prepared by the secondary amine compound with aryl group through acid-catalyzed cyclization reaction. The reaction is five steps to synthesize the tetrahydroisoquinoline structure. The steps are long and the yield is not very high.

Method used

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  • 1,2-dihydroisoquinoline derivative and preparation thereof
  • 1,2-dihydroisoquinoline derivative and preparation thereof
  • 1,2-dihydroisoquinoline derivative and preparation thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Preparation of 2-(1,2-dihydro-2,3-diphenylisoquinolin-1-yl)-2-hydroxy-2-phenylacetic acid methyl ester

[0029] The preparation of mixed solution is: take by weighing 2-phenylethynyl-N-phenylbenzaldimine (87.1mg, 0.31mmol), measure water (6.3 μ l, 0.35mmol) with microsampler, then weigh rhodium acetate ( 1.50mg, 0.0035mmol), silver trifluoromethanesulfonate (4.4mg, 0.017mmol), put them into a 25ml two-necked bottle, and add 8ml of anhydrous dichloromethane.

[0030] Preparation of diazo solution: Weigh ethyl phenyldiazoacetate (61.6 mg, 0.35 mmol) and add 4 ml of anhydrous dichloromethane.

[0031] Draw up the diazo solution with a 5ml syringe, inject it into the mixed solution with the control of a peristaltic pump for 1 hour, remove dichloromethane by rotary evaporation at 40°C, and then pass column chromatography (eluent is petroleum ether:ethyl acetate=50:1 volume than) isolate the target product pure product (a mixture of diastereoisomers, column chromatography ca...

Embodiment 2

[0036] Preparation of methyl 2-(1,2-dihydro-2,3-diphenylisoquinolin-1-yl)-2-hydroxy-2-(4-methoxyphenyl)acetate

[0037] The preparation of the mixed solution was the same as in Example 1.

[0038] Preparation of diazo solution: Weigh 4-methoxyphenyl ethyl diazoacetate (72.2 mg, 0.35 mmol) and add 4 ml of anhydrous dichloromethane.

[0039] Draw up the diazo solution with a 5ml syringe, inject it into the mixed solution for 1 hour under the control of a peristaltic pump, remove dichloromethane by rotary evaporation at 40°C, and then pass column chromatography (eluent: petroleum ether: ethyl acetate = 30:1 volume ratio) to isolate the target product pure product (a mixture of diastereomers, column chromatography can not be separated) as shown in the structure of 4b;

[0040]

[0041] 0.4H), 3.83(s, 1.2H), 3.77(s, 1.8H), 3.53(s, 1.2H), 3.49(s, 0.6H)

[0042] Yield: 90%, d.r. value: 56:44

Embodiment 3

[0044] Preparation of methyl 2-(1,2-dihydro-2,3-diphenylisoquinolin-1-yl)-2-hydroxy-2-(4-methylphenyl)acetate

[0045] The preparation of the mixed solution was the same as in Example 1.

[0046] Preparation of diazo solution: Weigh 4-methylphenyldiazoacetate ethyl ester (66.6mg, 0.35mmol) and add 4ml of anhydrous dichloromethane. Draw up the diazo solution with a 5ml syringe, inject it into the mixed solution for 1 hour under the control of a peristaltic pump, remove the dichloromethane by rotary evaporation at 40°C, and then pass column chromatography (eluent: petroleum ether: ethyl acetate = 40:1 volume ratio) to isolate the target product pure product (a mixture of diastereoisomers, which cannot be separated by column chromatography) of the structure shown in 4c;

[0047]

[0048] 0.4H), 3.94(s, 1.8H), 3.85(s, 0.4H), 3.53(s, 1.2H), 3.47(s, 0.6H), 2.38(s, 1.2H), 2.32(s, 1.8H) )

[0049] Yield: 84%, d.r. value: 58:42

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Abstract

The invention discloses a 1,2-dihydroisoquinolin derivative and a preparation method thereof, relating to a midbody which can be used for synthesizing natural alkaloid and a preparation method thereof. The 1,2-dihydro-isoquinolin derivative has a structure of formula (I). In the formula, R1 is meta-position or ortho-position substituted electron donating or weak electron-withdrawing aromatic group or H; R2 is methyl or ethyl; R3 is hydrogen or alkyl; and R4 is meta-position or ortho-position substituted aromatic group. The mol ratio of diazonium, alcohol (or water), imine, rhodium acetate and silver trifloromethanesulfonate is 1.2:1.2:1:0.01:0.05. A solvent, the alcohol (or water), the imine and a catalyst are used for preparing a mixed solution. Then, the diazonium is evenly mixed with another solvent to prepare diazonium solution which is then infused into the mixed solution. The solvent is removed by reduced pressure distillation at a temperatre of 40-70 DEG C. Column chromatographic separation is carried out to obtain the pure product of the 1,2-dihydro-isoquinolin derivative. When the 1,2-dihydro-isoquinolin undergoes reduction reaction, a tetrahydroisoquinoline derivative with pharmaceutical activity can be generated. The 1,2-dihydroisoquinolin derivative is an important structural unit of a great number of natural products and can be used as a midbody which can be used for synthesizing natural alkaloid.

Description

technical field [0001] A 1,2-dihydroisoquinoline derivative and a preparation method thereof relate to an intermediate that can be used as a synthetic natural alkaloid and a preparation method thereof. The invention belongs to the technical field of pharmaceutical chemical synthesis. Background technique [0002] Isochorine alkaloids are the main alkaloids in Chestnut plants. They have a similar mother nucleus structure and have various activities including antibacterial, anti-tumor, analgesic, anti-platelet aggregation, anti-arrhythmia, etc. Isocarine alkaloids have been receiving much attention in cardiovascular drugs, and they have been found to have significant therapeutic effects on arrhythmia, myocardial ischemia, hypertension and heart failure. [0003] At present, the research on derivatives based on tetrahydroisocarines is a hot spot at home and abroad, especially the structural modification of tetrahydroisocarine derivatives, and then the development of drugs has ...

Claims

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Application Information

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IPC IPC(8): C07D217/16
Inventor 胡文浩蔡媚郭震球杨琍苹
Owner EAST CHINA NORMAL UNIV
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