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11-replaced oxoisoaporphine derivatives as well as synthetic method and application thereof

A technology of isoaporphine and a synthesis method, which is applied in the field of 11-substituted oxidized isoapophthene derivatives and the synthesis fields thereof, can solve the problems that have not been seen before, and achieve the effects of good medicinal value and strong inhibitory activity.

Inactive Publication Date: 2014-07-16
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the reports on it in recent years are all limited to extraction and separation, and there are few reports on its transformation and activity research. So far, there has been no synthesis of drugs using oxidized isoapofil as the parent and the acid chloride compound connected with piperidine. Related reports

Method used

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  • 11-replaced oxoisoaporphine derivatives as well as synthetic method and application thereof
  • 11-replaced oxoisoaporphine derivatives as well as synthetic method and application thereof
  • 11-replaced oxoisoaporphine derivatives as well as synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Synthesis of 4-chloro-2-phenylisoindoline-1,3-dione (compound 1)

[0037] Add 57g (0.1mol) of 3-chlorophthalic anhydride and 45g (0.1mol) of phenethylamine into a 1L three-hole round bottom flask, then add 500ml of toluene, reflux for 6 hours, pour it out while it is hot, and cool it down. Crystals were precipitated and filtered by suction to obtain compound 1 (white flaky crystals) with a yield of about 98%.

[0038] Compound 1 is analyzed, and its spectral characteristics are as follows:

[0039] 1 H NMR (CDCl 3 ,500MHz): δ3.00~3.04(m,2H),3.94~3.97(m,2H),7.23~7.34(m,5H),7.65(d,J=1.7,1H),7.66(s,1H) ,7.78(dd,J 1 =5.0andJ 2 =3.2,1H);ESI-MS(m / z):287[M+H] + .

[0040] Therefore, it can be determined that the above-mentioned compound 1 is 4-chloro-2-phenylisoindoline-1,3-dione, and its structural formula is as follows:

[0041]

Embodiment 2

[0042] Embodiment 2: Synthesis of 10-Cl-1-azabenzanthrone (compound 2)

[0043] Add 75g (0.56mol) of anhydrous aluminum trichloride and 15g of sodium chloride into a 1L three-hole round-bottomed flask, mix and heat to 140°C for melting, then slowly add 53g (0.2mol) of compound 1 in batches After the addition, the temperature was raised to 220°C, and the reaction was stirred for 3 hours, poured into a mortar while heating, cooled, and crushed to obtain a reddish-brown solid, which was placed in a dry vessel.

[0044] Take 600ml of concentrated sulfuric acid and add it to a 2L three-hole round bottom flask. When the temperature rises to 80°C, start adding the reddish-brown solid obtained in the previous step in batches. into about 600g of ice water, adjust the pH of the system to about 2-3 with NaOH, a large amount of solids precipitated, filtered with suction, and washed with water to obtain a crude product. The crude product was purified by silica gel column chromatography (p...

Embodiment 3

[0049] Example 3: Synthesis of 11-amino-10-chloro-7H-dibenzoquinolin-7-one (compound 3)

[0050] Take 6mL of concentrated sulfuric acid, slowly add 4g of compound 2, after it is completely dissolved, then add 3mL of fuming nitric acid, stir at room temperature for 20min, then react at 50°C for 4h, stop the reaction. After cooling, pour it into about 150mL of ice water, filter it with suction, and dry it. A yellow 11-position nitrated product was obtained with a yield of about 85%.

[0051] Take the nitration product obtained in the previous step, 6.7g of sodium sulfide nonahydrate and 2.6g of NaOH in a 250mL round bottom flask, then add 200mL of ethanol solution (ethanol: water (volume ratio) = 7:3), stir and reflux for 4.5h. After stopping the reaction, cool down, distill ethanol off under reduced pressure, wash with water, and filter with suction to obtain compound 3 (dark red solid), with a yield of about 35%.

[0052] Compound 3 was analyzed, and its spectral characteris...

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Abstract

The invention discloses a series of 11-replaced oxoisoaporphine derivatives as well as a synthetic method and an application thereof. The synthetic method comprises the following steps: (1) carrying out ring closing reaction on 3-chlorophthalic anhydride and phenylethylamine as raw materials so as to construct a 10-Cl-1-azabenzanthrone parent body; (2) nitrating the parent body compound so as to obtain a 11-site nitrated product, and reducing the 11-site nitrated product so as to obtain 11-amino-10-chlorine-7H-dibenzoquinoline-7-ketone; and (3) reacting the 11-amino-10-chlorine-7H-dibenzoquinoline-7-ketone with an acyl chloride compound connected with piperidine so as to obtain a corresponding target product. Through study, the applicant finds that the series of derivatives have very strong inhibitory activity on acetylcholin esterase and are expected to be used for treating AD (Alzheimer Disease), cerebrovascular dementia and related diseases caused by cholinergic neurotransmitter reduction. The structural formula of the 11-replaced oxoisoaporphine derivatives is shown in descriptions.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to 11-substituted oxidized isoapofil derivatives and their synthesis methods and applications. Background technique [0002] Acetylcholinesterase (acetylcholinesterase, AChE, EC3.1.1.7.), also known as acetylcholine hydrolase (acetylcholine hydrolase), its main biological function is to rapidly hydrolyze the neurotransmitter acetylcholine ( ACh), so as to stop the transmission of nerve impulses. Its reaction formula is as follows: [0003] [0004] Butyrylcholinesterase (butyrylcholinesterase, BChE, EC3.1.1.8), also known as pseudo or non-specific cholinesterase, is an enzyme that hydrolyzes butyrylcholine. It belongs to the serine esterase family, mainly distributed in serum and liver, and also exists in a small amount in muscle and brain tissue. BChE can hydrolyze many esters, peptides and amides in life activities, participate in the metabolic process of some dr...

Claims

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Application Information

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IPC IPC(8): C07D221/18A61K31/473A61P25/28A61P27/06A61P21/04
CPCC07D221/18
Inventor 唐煌
Owner GUANGXI NORMAL UNIV
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