Method for preparing trandolapril intermediate

A technology for trandolapril and intermediates, which is applied in the field of new preparation of key intermediates, can solve the problems of unfavorable environmental protection and large-scale production, high cost of target products, expensive catalysts, etc., and achieve low cost, high yield and easy separation Effect

Active Publication Date: 2013-01-23
SHANGHAI JIAO TONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The catalyst used in the above method is relatively expensive, and the reaction time is longer, and the emulsification is serious with ethanol extraction in the post-treatment process, which is extremely difficult for suction filtration, and the yield is low (32%), resulting in higher cost of the target product
Patent [US 20070225505] adopts cheap and easy-to-obtain cyclohexene and chloramine T as starting materials, but expensive reagents are used and the cost is high; patent [CN 101597254A] is carried out on the basis of patent [US 20070225505] has been optimized, but there are still disadvantages of long routes and complicated operations
[0005]In summary, the existing (2S,3aS,7aS)-octahydroindole-2-carboxylic acid and benzyl ester thereof has the disadvantages of long operational route and complex operation, and uses a large amount of toxic and harmful, expensive reagents, high cost and low overall yield. Low, not conducive to environmental protection and mass production

Method used

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  • Method for preparing trandolapril intermediate
  • Method for preparing trandolapril intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1) Cyclohexaneziridine (hereinafter referred to as compound 2 )Synthesis

[0038] Chloramine T (500 g, 1.775 mol), cyclohexene (164 g, 2.0 mol), iodine (28.2 g, 0.11 mol) and benzyltrimethylammonium bromide (20.4 g, 0.088 mol) were added to 1000 mL tetrahydrofuran and 500 mL of water in a mixed solvent, react at room temperature for 24 h, distill off THF, extract the aqueous phase with ethyl acetate (500 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, and remove the solvent by rotary evaporation , the product was recrystallized from ethanol to obtain white crystals (260 g, 58 %).

[0039] (2) trans-N-p-toluenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3 )Synthesis

[0040] Dissolve cyclohexaneziridine (25.1 g, 0.1 mol) and copper bromide (2.23 g, 0.01 mol) in 200 mL of ether, and allylmagnesium bromide (29 g, 0.2 mol) at -40 °C Slowly added dropwise and stirred overnight. The reaction was...

Embodiment 2

[0054] (1) Cyclohexaneziridine (hereinafter referred to as compound 2 )Synthesis

[0055] Chloramine T (500 g, 1.775 mol), cyclohexene (164 g, 2.0 mol), iodine (28.2 g) and benzyltrimethylammonium chloride (16.5 g, 0.088 mol ) were added to 1000 mL tetrahydrofuran and 500 mL In a mixed solvent of water, react at room temperature for 24 h. The tetrahydrofuran was evaporated, the aqueous phase was extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, and the solvent was removed by rotary evaporation, and the product was recrystallized with ethanol to obtain white crystals (270 g, 60%).

[0056] (2) trans-N-p-toluenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3 )Synthesis

[0057] Dissolve cyclohexaneziridine (25.1 g, 0.1 mol) and copper bromide (2.23 g, 0.01 mol) in 200 mL of ether, and allylmagnesium bromide (58 g, 0.4 mol) at -50 °C Slowly added dropwise and s...

Embodiment 3

[0071] (1) Cyclohexaneziridine (hereinafter referred to as compound 2 )Synthesis

[0072] Add 1000 mL of acetonitrile and 500 mL In a mixed solvent of water, react at room temperature for 24 h. Acetonitrile was evaporated, the aqueous phase was extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, and the solvent was removed by rotary evaporation, and the product was recrystallized with ethanol to obtain white crystals (275 g, 61%).

[0073] (2) trans-N-p-toluenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3 )Synthesis

[0074] Dissolve cyclohexaneziridine (25.1 g, 0.1 mol) and copper bromide (2.23 g, 0.01 mol) in 200 mL tetrahydrofuran, and allylmagnesium bromide (58 g, 0.4 mol) at -50 °C Slowly added dropwise, stirring overnight. The reaction was quenched with water, extracted with ethyl acetate (250 mL×3), the organic phases were combined, dried over anhydr...

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Abstract

The invention relates to a method for preparing a trandolapril intermediate in the field of biomedicines, i.e. a method for synthesizing (2S, 3aR, 7aS)-octahydroindole-2-carboxyl benzyl ester. Firstly, cyclohexene and chloramine T are taken as initial raw materials to react so that cyclohexane ethylene imine is obtained; cyclohexane ethylene imine and allylmagnesium bromide are reacted with each other to obtain trans-N-(p-toluene sulphonyl)-2-(2-allyl)-cyclohexylamine which is peroxidized so as to obtain racemic N-protecting octahydroindole-2-carboxylic acid under the action of an oxidizing agent; after a protecting group on nitrogen is removed, racemic octahydroindole-2-carboxyl benzyl ester is obtained through esterification reaction; and the racemic octahydroindole-2-carboxyl benzyl ester is recrystallized and separated to obtain the trandolapril key intermediate (2S, 3aR, 7aS)-octahydroindole-2-carboxyl benzyl ester. According to the method, raw materials are low in cost and easy to obtain, the preparation process is environmental-friendly, the operation and post-treatment are simple, separation and purification are easy and the like.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a novel preparation method of a key intermediate of trandolapril in cardiovascular drugs. Background technique [0002] Trandolapril (Trandolapril), chemical name: (2 S ,3 s ,7 s )-[(2 S )-{[(1 S )-(ethoxycarbonyl)-phenylpropyl]amino}]-propionyl]-octahydroindole-2-carboxylic acid, developed by French company Roussel Uclaf. It is a long-acting angiotensin-converting enzyme inhibitor, which can treat a variety of cardiovascular diseases, and has the advantages of significant curative effect, long acting time, and small side effects. Further research found that trandolapril can effectively improve peripheral neuropathy in normotensive diabetic patients. [0003] The main part of the structure of trandolapril is the same as that of many angiotensin-converting enzyme inhibitors (such as enalapril), and the difference lies in their side chains. Therefore, when preparing trandolapril, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42
CPCY02P20/55
Inventor 张万斌刘德龙申杰峰
Owner SHANGHAI JIAO TONG UNIV
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