Synthesizing method of aromatic ring ureas loop-coil medicament template

A synthesis method and an aromatic ring technology, applied in the direction of organic chemistry, etc., can solve the problems of unsuitable large-scale derivative synthesis, long reaction steps, low efficiency, etc., and achieve the effects of few reaction steps, mild conditions and simple process.

Inactive Publication Date: 2009-10-14
WUXI APPTEC (TIANJIN) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reaction steps are long, the efficiency is low, and it is not suitable for large-scale derivative synthes...

Method used

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  • Synthesizing method of aromatic ring ureas loop-coil medicament template
  • Synthesizing method of aromatic ring ureas loop-coil medicament template
  • Synthesizing method of aromatic ring ureas loop-coil medicament template

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]

[0044] 1. Synthesis of 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile

[0045] 2-Indanone (4 g, 30.3 mmol) and propylamine hydrochloride (3.1 g, 32.6 mmol) were dissolved in water (60 mL) and stirred at room temperature for 60 minutes; then sodium cyanide (1.62 g, 33.1 mmol) was added, and continued Stir at room temperature for 15 hours. The reaction system was extracted with dichloromethane (120 mL), washed with saturated brine (3×100 mL), and the organic phase was washed with Na 2 SO 4 Dry and remove the solvent to obtain 5.6 g of crude 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile, MS(m / z): 201(M+1); directly applied to without purification Next step.

[0046] 2. Synthesis of 2-(aminomethyl)-N-propyl-2,3-dihydro-1H-indene-2-amine

[0047] 5.6 g (purity 30%, 12.6 mmol) of the crude 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile obtained in step 1 was dissolved in 150 mL of anhydrous ether, and cooled in an ice bath to Below 5 degrees, ad...

Embodiment 2

[0052]

[0053] 1. Synthesis of 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile

[0054] 2-Indanone (3.58 g, 27 mmol) and benzylamine hydrochloride (4.27 g, 29.7 mmol) were dissolved in water (350 mL) and stirred at room temperature for 60 minutes; then sodium cyanide (1.46 g, 29.7 mmol) was added, Stirring was continued at room temperature for 15 hours. The reaction system was extracted with dichloromethane (1000 mL), washed with saturated brine (3×100 mL), and the organic phase was washed with Na 2 SO 4 Dry and remove the solvent to obtain 7g crude product of 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile, MS (m / z): 249 (M+1); directly applied to without purification Next step.

[0055] 2. Synthesis of 2-(aminomethyl)-N-benzyl-2,3-dihydro-1H-inden-2-amine

[0056] 7 g (purity 31%, 12.1 mmol) of the crude 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile obtained in step 1 was dissolved in 200 mL of anhydrous ether, and cooled in an ice bath to Below 5...

Embodiment 3

[0061]

[0062] 1. Synthesis of 2-(aniline)-2,3-dihydro-1H-indene-2-carbonitrile

[0063] 2-Indanone (10 g, 0.075 mol) and aniline hydrochloride (7.67 g, 82.5 mmol) were dissolved in water (120 mL), and stirred at room temperature for 30 minutes; then sodium cyanide (4.04 g, 82.5 mmol) was added, and continued Stir at room temperature for 15 hours. The reaction system was extracted with dichloromethane (250 mL), washed with saturated brine, and the organic phase was washed with Na 2 SO 4 Dry and remove the solvent to obtain 2-(isopropylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product 14.71g, MS(m / z): 235(M+1); used directly without purification in the next step.

[0064] 2. Synthesis of 2-(aminomethyl)-N-phenyl-2,3-dihydro-1H-inden-2-amine

[0065] 14.71 g (purity 70%, 63 mmol) of the crude 2-(aniline)-2,3-dihydro-1H-indene-2-carbonitrile obtained in step 1 was dissolved in 250 mL of anhydrous ether, and cooled to 5 in an ice bath. Below the temperature, add...

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Abstract

The invention relates to a synthesizing method of an aromatic ring ureas loop-coil medicament template, which mainly solves the technical problems of massive reaction steps, low efficiency and no favorability for large-scale synthesis in prior methods. In the synthesizing method, a 2-indenone (n=1) type or 2-tetralone (n=2) type compound undergoes cyanation and amination by means of one-pot boiling; then, cyano-group is reduced into amino-group, and finally N-N'carbonyl diimidazole is used for direct ring closing so as to obtain an aromatic ring ureas loop-coil medicament template with substitution on 3-position N; and then, an aromatic ring ureas loop-coil medicament template with double-substitution on 1,3-position N can be easily obtained by means of alkylation or acylation reaction on 1-position N. The synthesizing method is capable of the large-scale preparation of the aromatic ring ureas loop-coil medicament template.

Description

Technical field: [0001] The invention relates to a method for synthesizing an aromatic ring urea spiro ring drug template. Background technique: [0002] As early as the 1970s, spiro compounds were found to be biologically active. After more than 30 years of research and development, a variety of spiro derivatives have been proved to have promising therapeutic effects, such as anti-depression, inhibition of angiogenesis (anti-tumor), anti-platelet aggregation (anti-thrombosis), anti-Alhai Mertz disease (senile dementia), etc. Aromatic urea spiro structure 1 contains both hydrogen bond acceptors and donors. The simultaneous existence of hydrogen bond acceptors and donors can increase the chance of interaction between the substrate and the target, so it may improve the binding degree of the substrate and the protein target, and achieve the effect of increasing the activity of the substrate. It has been widely proved that it has various physiological effects. Activity, has r...

Claims

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Application Information

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IPC IPC(8): C07D235/02C07D405/06
Inventor 季丽李建源蔡怡然吴安树柏祝贺海鹰陈曙辉
Owner WUXI APPTEC (TIANJIN) CO LTD
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