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Preparation method of anti-anxiety drug pagoclone or pazinaclone

A Patazin cloning and anti-anxiety technology, applied in the field of drug synthesis, can solve the problems of complex raw materials, insufficient preparation process, and insufficient universality of substrates, etc., and achieve the effect of simple operation

Active Publication Date: 2019-03-19
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this work has broadened the substrate category, and has good applicability to heterocycles such as thiophene, furan, and pyridine, and the reaction conditions have become milder, the universality of the substrate is still not wide enough, and the raw materials More complicated, the preparation process is not simple enough

Method used

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  • Preparation method of anti-anxiety drug pagoclone or pazinaclone
  • Preparation method of anti-anxiety drug pagoclone or pazinaclone
  • Preparation method of anti-anxiety drug pagoclone or pazinaclone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] In a 25mL Schlenk bottle, weigh 22mg (0.2mmol) p-tolualdehyde (1.0eq), Cu(OAc) 2 65mg (2.0eq), 2-amino-1,8-naphthalene 54mg (1.5eq), [Cp*RhCl 2 ] 2 6 mg (5%). Then it was vacuumized and nitrogen gas was introduced. After three operations, 2 mL of acetonitrile and 50 mg (2.0 eq) of unsaturated carbonyl compound were added, and the mixture was stirred at 80° C. in a nitrogen atmosphere. After about 10 hours, TLC detected that the reaction was complete. A little silica gel was added, the solvent was evaporated, solidified, and the solid was loaded as a sample for column chromatography. Pagolon (cas: 133737-32-3) can be prepared in a total yield of about 15%.

[0031]

[0032] Product NMR data: 1 H NMR (CDCl 3 ,600MHz), δ:8.98(d,J=9.0Hz,1H),8.23(d,J=8.4Hz,1H),8.11(d,J=8.4Hz,1H),7.95(d,J=7.2Hz ,1H),7.67–7.60(m,2H),7.55–7.50(m,1H),7.43(d,J=8.4Hz,1H),6.18(dd,J 1 =7.8Hz,J 2 =3.0Hz,1H),3.64(dd,J 1 =16.8Hz,J 2 =3.6Hz,1H),3.09(dd,J 1 =17.2Hz,J 2 =7.8Hz, 1H), 2.40–2...

Embodiment 2

[0035] According to the same steps as in Example 1, replacing the following reactants, Patazin clone can be prepared with a yield of 20%. And if the intermediate butamide generated in the reaction is firstly prepared (condensed by acid chloride and amine), both the following second reaction formula can obtain pazin clone with higher efficiency, and the yield can reach 68%. Specifically, in a 25mL Schlenk bottle, weigh 56.6mg (0.2mmol) amide (1.0eq), Cu(OAc) 2 65mg (2.0eq), [Cp*RhCl 2 ] 2 6 mg (5%). Then it was subjected to vacuum treatment and nitrogen gas was introduced. After three operations, 2 mL of acetonitrile and 78 mg (2.0 eq) of unsaturated amide compound were added, and stirred at 80° C. under a nitrogen atmosphere at constant temperature. After about 10 hours, TLC detected that the reaction was complete, added a little silica gel, evaporated the solvent, solidified, loaded the solid, and carried out column chromatography (the volume ratio of ethyl acetate to pet...

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Abstract

The invention discloses a method for catalytically synthesizing an anti-anxiety drug pagoclone or pazinaclone and analogues thereof by utilizing Rh(III). The method comprises the following steps: reacting benzaldehyde and 2-aminopyridine compounds in a solvent in the presence of a rhodium catalyst and acetate, and producing an effective guide group in situ; and reacting the guide group and substituted olefin under rhodium catalysis, and performing after-treatment after the reaction is completed, thereby obtaining a compound having a nitrogen heterocyclic framework. According to the preparationmethod, two independent reactions (amide formation and carbon-hydrogen activation) are catalyzed by using rhodium, and a synthetic strategy of self-assembling high-efficiency guide groups is successfully realized. The reaction is carried out based on simple raw materials, an isoindoxone skeleton having substitution characteristics is synthesized in a simple and mild catalytic system by utilizinga 'one-pot process', the operation is simple and convenient, the reaction conditions are mild, the yield is high, and atom economy is high.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of an anti-anxiety drug Pagolon or Patazinone. Background technique [0002] Isoindolinone (γ-lactam) is a more common and important mother nucleus, which is reflected in many biologically active molecules, as shown in the figure below. [0003] [0004] Since the α position is an N atom with a strong complexing force, there have been many reports on the use of the nitrogen atom in benzamide as the guiding atom and its participation in the formation of γ-lactam. Li Xingwei's research group first tried to use N-phenyl substituted aromatic formamide as a substrate in 2010 to react with acrylate to construct an isoindolinone skeleton (Org. Lett., 2010, 12, 5430). In the reaction, the Heck product intermediate is firstly generated, and then Michael addition occurs and cyclization occurs. However, if the aromatic ring in the substrate is a heterocycl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61P25/22
CPCA61P25/22C07D471/04C07D519/00
Inventor 张岩林心如黄玉婷胡琪胡博跃何宇朱钢国
Owner ZHEJIANG NORMAL UNIVERSITY