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Synthetic method for aromatic ring bisamide spiro drug template

A technology for the synthesis of cyclobisamide spiro compounds, which is applied in the field of synthesis of aromatic ring bisamide spiro drug templates, can solve the problems of cumbersome methods, lack of feasibility and selectivity of aromatic ring bisamide spiro compounds, etc. Achieve the effect of simple process, few reaction steps and mild conditions

Active Publication Date: 2009-09-02
WUXI APPTEC SUZHOU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is relatively cumbersome, and there is a problem of selectivity, and it does not have the feasibility of large-scale preparation of 3-substituted aromatic ring bisamide spiro compounds

Method used

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  • Synthetic method for aromatic ring bisamide spiro drug template
  • Synthetic method for aromatic ring bisamide spiro drug template
  • Synthetic method for aromatic ring bisamide spiro drug template

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] 1. Synthesis of 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile

[0043]Dissolve 2 indanoxine (10g, 0.076mol) and propylamine hydrochloride (8g, 0.084mol) in water (120mL) and stir at room temperature for 30 minutes; then add sodium cyanide (4.1g, 0.084mol) and continue to Stir for 15 hours. The reaction system was extracted with dichloromethane (200mL), washed with saturated brine, and the organic phase was washed with Na 2 SO 4 Drying, removal of solvent to obtain 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product 10g, MS (m / z): 201 (M+1); without purification, directly used in the following step.

[0044] 2. Synthesis of 3-propyl-1′,3′-dihydrospiro[imidazoline-4,2′-indene]-2,5-dione

[0045] Dissolve 4 g (purity 50%, 0.01 mol) of 2-(propylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product obtained in step 1 in 200 mL of dichloromethane, and add isocyanate dropwise at room temperature Dichloromethane solution (50mL) of sulf...

Embodiment 2

[0051]

[0052] 1. Synthesis of 2-(cyclopropylamine)-2,3-dihydro-1H-indene-2-carbonitrile

[0053] 2-Indanone (10g, 0.076mol) and cyclopropylamine hydrochloride (7.8g, 0.084mol) were dissolved in water (120mL), stirred at room temperature for 30 minutes; then sodium cyanide (4.1g, 0.084mol) was added, Stirring was continued at room temperature for 15 hours. The reaction system was extracted with dichloromethane (200mL), washed with saturated brine, and the organic phase was washed with Na 2 SO 4 Drying and removal of the solvent gave 11 g of crude product 2-(cyclopropylamine)-2,3-dihydro-1H-indene-2-carbonitrile, MS (m / z): 199 (M+1); directly applied to Next step.

[0054] 2. Synthesis of 3-cyclopropyl-1′,3′-dihydrospiro[imidazoline-4,2′-indene]-2,5-dione

[0055] Dissolve 3.5 g (purity 45%, 0.008 mol) of 2-(cyclopropylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product obtained in step 1 in 150 mL of dichloromethane, drop it at room temperature Add a dichloromet...

Embodiment 3

[0058]

[0059] 1. Synthesis of 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile

[0060] 2-Indanone (3g, 0.023mol) and benzylamine hydrochloride (3.6g, 0.025mol) were dissolved in water (60mL), stirred at room temperature for 30 minutes; then sodium cyanide (1.35g, 0.025mol) was added, Stirring was continued at room temperature for 15 hours. The reaction system was extracted with dichloromethane (120mL), washed with saturated brine, and the organic phase was washed with Na 2 SO 4 Drying and removal of the solvent gave 5 g of crude product 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile, MS (m / z): 249 (M+1); directly applied to Next step.

[0061] 2. Synthesis of 3-benzyl-1′,3′-dihydrospiro[imidazoline-4,2′-indene]-2,5-dione

[0062] 3 g (purity 55%, 0.007 mol) of 2-(benzylamine)-2,3-dihydro-1H-indene-2-carbonitrile crude product obtained in step 1 were dissolved in 150 mL of dichloromethane, and added dropwise at room temperature Isocyanate sulfonyl chloride ...

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Abstract

The invention relates to a synthetic method for an aromatic ring bisamide spiro drug template, which solves the technical problems that the original synthetic method has more reaction steps and low efficiency and is not beneficial to synthesis on a large scale. The technique comprises the following steps of: firstly carrying out cyanation and amination on 2-indenone (n=1) or 2-tetralone (n=2) compound A by a one-pot mode; then utilizing isocyanate sulfonic chloride and hydrochloric acid to close the ring directly and obtaining the substituted aromatic ring bisamide spiro drug template with 3 bit N; and then easily obtaining the substituted aromatic ring bisamide spiro drug template with 1 bit N and 3 bit N doubly by alkylation reaction of 1 bit N. The method has less reaction steps and is a synthetic method for an aromatic ring bisamide spiro drug template with large-scale preparation.

Description

Technical field: [0001] The invention relates to a synthesis method of an aromatic ring bisamide spirocyclic drug template. Background technique: [0002] As early as the 1970s, spirocyclic compounds were found to have biological activity. After more than 30 years of research and development, a variety of spirocyclic derivatives have been confirmed to have promising therapeutic effects, such as anti-depression, inhibition of angiogenesis (anti-tumor), anti-platelet aggregation (anti-thrombosis), and anti-alheian Merz disease (senile dementia), etc. The aromatic ring bisamide spiro ring structure 1 contains both hydrogen bond acceptors and donors (R 2 = H). The simultaneous presence of hydrogen bond acceptors and donors can increase the chance of interaction between the substrate and the target, and thus may increase the degree of binding between the substrate and the protein target to increase the activity of the substrate. It has been widely proven that it has various S...

Claims

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Application Information

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IPC IPC(8): C07D233/72
Inventor 李建源王倩倩柏祝季丽肖贻崧贺海鹰陈曙辉李革
Owner WUXI APPTEC SUZHOU
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