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Method for preparing (3aS,6aR)-1,3-substituted benzyl-tetrahydro-1H-thieno[3,4-d]imidazole derivatives

An imidazole derivative, 4-d technology, applied in organic chemistry and other directions, can solve the problems of flammability and explosion, difficult catalyst separation and recovery operations, harsh reaction conditions, etc., and achieves cheap and safe recovery, good application prospects, easy to use. The effect of recycling

Inactive Publication Date: 2011-05-04
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of this method is the use of anhydrous ether, which is flammable, explosive and cannot be recycled, and the cost is high
Chinese patent (CN1445229) discloses that compound (II) carries out Grignard reaction with 1,4-dimagnesium halobutane (double Grignard reagent) formed by magnesium chips and 1,4-dihalobutane in an organic solution, Subsequent feed into carbon dioxide to carry out the method of carboxylation reaction and make I, but this reaction condition is harsh, side reaction is many
SeKi M et al. (Tetrahedron Lett, 2004, 45, 1635) reported the Fukuyanma coupling reaction catalyzed by palladium on carbon, but it is difficult to separate and recover the catalyst, and the palladium is easy to lose.

Method used

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  • Method for preparing (3aS,6aR)-1,3-substituted benzyl-tetrahydro-1H-thieno[3,4-d]imidazole derivatives
  • Method for preparing (3aS,6aR)-1,3-substituted benzyl-tetrahydro-1H-thieno[3,4-d]imidazole derivatives
  • Method for preparing (3aS,6aR)-1,3-substituted benzyl-tetrahydro-1H-thieno[3,4-d]imidazole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1, put zinc powder (0.8g, 12.4mmol) and iodine (39mg) plus tetrahydrofuran (1.3ml) and toluene (0.8ml) in a dry reaction flask, heat and stir at 40°C until the purple color disappears, and the temperature rises to Slowly add bromovalerate (1.3g, 6.2mmol) dropwise to the mixed solution at 50°C, drop it within 1.0~1.5h, continue heating and stirring until the reaction of bromovalerate is complete (about 2.5~3h) . Then the mixture was transferred to ion exchange resin palladium (9g, 0.9mmol) and compound II (1.0g, 3.0mmol) were dissolved in toluene (6ml), in the mixed system of N,N-dimethylformamide (0.8ml), Lower the temperature to 35-40°C for 10 hours, add water, filter, separate the organic layer, extract the aqueous phase with toluene (3×30mL), combine the organic layers, recover the solvent under reduced pressure, pass through a silica gel column (mobile phase: ethyl acetate / Petroleum ether = 2 / 1) to isolate pale yellow oil I (1.2 g, 85%). IR(KBr): v=2961, ...

Embodiment 2

[0022] Example 2, zinc powder (0.8g, 12.4mmol) and iodine (39mg) plus tetrahydrofuran (2ml) were placed in a dry reaction bottle, heated and stirred at 25°C until the purple color disappeared, the temperature rose to 50°C, and slowly added dropwise Bromovalerate (1.8g, 8.6mmol) was dropped in the mixed solution within 1.5h, and continued to heat and stir until the reaction of bromovalerate was complete (about 3-3.5h). Then the mixture was transferred to ion exchange resin palladium (9g, 0.76mmol) and compound II (1.0g, 3.0mmol) were dissolved in toluene (6ml), in the mixed system of N,N-dimethylacetamide (1.5ml), Lower the temperature to 40-45°C for 8 hours, add water, filter, separate the organic layer, extract the aqueous phase with toluene (3×30mL), combine the organic layers, recover the solvent under reduced pressure, pass through a silica gel column (mobile phase: ethyl acetate / Petroleum ether = 2 / 1) to isolate a pale yellow oil I (1.3 g, 92.8%). IR, 1 H NMR and MS ar...

Embodiment 3

[0023]Example 3, zinc powder (0.8g, 12.4mmol) and iodine (39mg) plus tetrahydrofuran (2ml) and toluene (2ml) were placed in a dry reaction flask, heated and stirred at 30°C until the purple color disappeared, and the temperature rose to 40°C , slowly added bromovalerate (1.3g, 6.2mmol) dropwise into the mixed solution, the drop was completed within 1.5h, and continued heating and stirring until the reaction of bromovalerate was completed (about 3.5-4h). Then the mixture was transferred to ion exchange resin palladium (10g, 1.2mmol) and compound II (1.0g, 3.0mmol) were dissolved in toluene (10ml), in the mixed system of N,N-dimethylformamide (0.8ml), Lower the temperature to 35-40°C for 10 hours, add water, filter, separate the organic layer, extract the aqueous phase with toluene (3×30mL), combine the organic layers, recover the solvent under reduced pressure, pass through a silica gel column (mobile phase: ethyl acetate / Petroleum ether = 2 / 1) to isolate pale yellow oil I (1....

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Abstract

The invention relates to the organic chemistry technology field, in particular to a process for preparing (3aS, 6aR)-1, 3-substituted aryl-tetrahydrochysene-1H-thiofuran and [3, 4-d] imidazoles derivation, which particularly comprises conducting the fukuyama coupling reaction of (3aS, 6aR)-1,3-substitute aryl-tetrahydrochysene-4H-thiofuran and [3, 4-d] imidazoles-2,4(1H)- diketone and zinc-halogen reagent which is formed by zinc powder and halogenated carboxylate under the catalysis of nanometer palladium catalyst which is dispersed by anion exchange resin, introducing multiple carbon side-chains at one time, further adding water, and then obtaining target compound after filtered, and the output rate is larger than 85%. The invention has wider diversity of raw material, mild reaction condition, simple operation, easy recovering, which is convenient for preparing at large scale. And the catalyst has excellent stability and activity.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and relates to a method for preparing (3aS, 6aR)-1,3-substituted benzyl-tetrahydro-1H-thieno[3,4-d]imidazole-derivatives shown in formula I. [0002] [0003] where R 1 is hydrogen, C 1 ~C 6 Alkyl, phenyl, p-tolyl, p-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, p-chlorophenyl, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxy phenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl or naphthyl; R 2 for C 1 ~C 6 Alkyl, phenyl, substituted aryl; n=1-4. Background technique [0004] It is known that (3aS, 6aR)-1,3-substituted benzyl-tetrahydro-1H-thieno[3,4-d]imidazole derivatives shown in formula I are synthetic (+)-biotin ((+ )-Biotin, vitamin H, key intermediate of coenzyme R). Japanese Patent Publication No. 3-45077 discloses the process of compound II and the Witt...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
Inventor 陈芬儿戴惠芳黄建盛浩
Owner FUDAN UNIV