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Method for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide

A technology of dicarboximide and formamide, which is applied in the field of preparing cis-exo-bicyclo[2.2.1]heptane-2, can solve the problems of difficult industrialization and harsh equipment requirements, and achieve simple operation and high reaction efficiency. The effect of low temperature and high purity

Inactive Publication Date: 2012-03-21
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires high-temperature sealing reaction, which has strict requirements on equipment and is difficult to realize industrialization

Method used

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  • Method for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide
  • Method for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide
  • Method for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (II) (93g, 0.56mol) and urea (67.9g, 1.12mol) were ground and stirred uniformly, then heated to 145°C, It was molten and kept stirring for 4h. Then cool to 100-110°C, add water for recrystallization. After cooling to room temperature, filter, and vacuum dry (80°C, 4h) to obtain pure white cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide (I) (79.33g, yield 85%): mp150-152°C; 1 HNMR (CDCl 3 )δ7.6-8.0 (br s, 1H), 2.6-2.8 (s, 4H), 1.6-1.8 (t, 2H), 1.2-1.4 (m, 4H); HPLC purity 99.78%.

Embodiment 2

[0050] After grinding and stirring cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (II) (10 g, 0.06 mol) and urea (14.46 g, 0.24 mol) uniformly, heat to 145°C, It was molten and kept stirring for 4h. Then cool to 100-110°C, add water for recrystallization. After cooling to room temperature, filter, and vacuum dry (80°C, 4h) to obtain pure white cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide (I) (8.32g, yield 84%): mp146-151°C; 1 HNMR (CDCl 3 )δ7.6-8.0 (br s, 1H), 2.6-2.8 (s, 4H), 1.6-1.8 (t, 2H), 1.2-1.4 (m, 4H); HPLC purity 99.41%.

Embodiment 3

[0052] After grinding and stirring cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (II) (10 g, 0.06 mol) and urea (3.62 g, 0.06 mol) uniformly, heat to 145°C, It was molten and kept stirring for 4h. Then cool to 100-110°C, add water for recrystallization. After cooling to room temperature, filter, and vacuum-dry (80°C, 4h) to obtain pure white cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide (I) (7.23g, yield 71%): mp146-149°C; 1 HNMR (CDCl 3 )δ7.6-8.0 (br s, 1H), 2.6-2.8 (s, 4H), 1.6-1.8 (t, 2H), 1.2-1.4 (m, 4H); HPLC purity 98.52%.

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Abstract

The invention discloses a method for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, comprising the steps of mixing one of cis-exo-bicyclo [2.2.1] heptane-2, 3-dimethyl anhydride, cis-exo-bicyclo [2.2.1] heptane-3-formamide-2-ammonium formate and cis-exo-bicyclo [2.2.1] heptane-3-formamide-2-formic acid with urea, heating till fusing, reacting and obtaining. The preparation method has the advantages of simpleness and convenience for operation, relatively lower reaction temperature, incapability of carbonization caused by overhigh reaction temperature, no need for pipe sealing so as to reduce the requirements for equipment, high yield and purity and is more suitable for large-scale industrialized production.

Description

technical field [0001] The present invention relates to a method for preparing cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide. Background technique [0002] Cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboximide (as shown in formula I) is an important pharmaceutical intermediate, such as for the synthesis of antipsychotic lurasidone hydrochloride and the anti-anxiety drug tandospirone. [0003] Its preparation method is obtained by ammonolysis of cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (as shown in formula II). The reaction formula is as follows: [0004] [0005] Using ammonia water or ammonia gas as a nitrogen source, Morgan et al. reacted with cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (II) at 210°C to obtain cis-exo-bicyclo[2.2 .1] Heptane-2,3-dicarboximide (I), yield 20% (Morgan MS, et al. J Am Chem Soc, 1944, 66:404-407). At high temperature, cis-exo-bicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride (II) is easily charred. Therefore, the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/56
Inventor 唐飞张庆文王正雄安定国
Owner SHANGHAI INST OF PHARMA IND CO LTD