A kind of preparation method of trandolapril intermediate

A technology for trandolapril and intermediates, which is applied in the new field of preparation of key intermediates, can solve the problems of long process route, long reaction time, expensive catalyst, etc., and achieve reasonable preparation process, short preparation method route and good three-dimensional selection sexual effect

Active Publication Date: 2016-01-13
SHANGHAI JIAO TONG UNIV
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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 aftertreatment process, and it is extremely difficult to filter the phenomenon, and the yield is low (32%), resulting in higher cost of the target product
Patent [US20070225505] adopts cheap and easy-to-obtain cyclohexene and chloramine T as starting materials, but expensive reagents are used and the cost is high; patent [CN101597254A] is optimized on the basis of patent [US20070225505], But there are still disadvantages of long route and complicated operation
[0005] In summary, the existing preparation methods of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid and its benzyl ester have the disadvantages of long technical route, complex operation, etc., and use a large amount of toxic and harmful, Expensive reagents, high cost, low total yield, not conducive to environmental protection and large-scale production

Method used

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  • A kind of preparation method of trandolapril intermediate
  • A kind of preparation method of trandolapril intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0038](1) Synthesis of cyclohexaneziridine (hereinafter referred to as compound 2)

[0039] Chloramine T (500g, 1.775mol), cyclohexene (164g, 2.0mol), iodine (28.2g, 0.11mol) and benzyltrimethylammonium bromide (20.4g, 0.088mol) were added to 1000mL tetrahydrofuran and 500mL water In a mixed solvent, react at room temperature for 24 hours, distill off tetrahydrofuran, extract the aqueous phase with ethyl acetate (500mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, remove the solvent by rotary evaporation, and reconstitute the product with ethanol Crystallization gave white crystals (260g, 58%).

[0040] (2) Synthesis of trans-N-p-methylbenzenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3)

[0041] Dissolve cyclohexaneziridine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) in 200mL ether, and allylmagnesium bromide (29g, 0.2mol) at -40°C, Add dropwise slowly and stir overnight. The reaction was q...

Embodiment 2

[0055] (1) Synthesis of cyclohexaneziridine (hereinafter referred to as compound 2)

[0056] Chloramine T (500g, 1.775mol), cyclohexene (164g, 2.0mol), iodine (28.2g) and benzyltrimethylammonium chloride (16.5g, 0.088mol) were added to a mixed solvent of 1000mL tetrahydrofuran and 500mL water In the reaction at room temperature for 24h. The tetrahydrofuran was evaporated, the aqueous phase was extracted with ethyl acetate (500mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, the solvent was removed by rotary evaporation, and the product was recrystallized with ethanol to obtain white crystals (270g, 60%).

[0057] (2) Synthesis of trans-N-p-methylbenzenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3)

[0058] Dissolve cyclohexaneziridine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) in 200mL ether, and allylmagnesium bromide (58g, 0.4mol) at -50°C, Add dropwise slowly and stir overnight...

Embodiment 3

[0072] (1) Synthesis of cyclohexaneziridine (hereinafter referred to as compound 2)

[0073] Chloramine T (500g, 1.775mol), cyclohexene (164g, 2.0mol), iodine (28.2g) and benzyltrimethylammonium chloride (16.5g, 0.088mol) were added to a mixed solvent of 1000mL acetonitrile and 500mL water In the reaction at room temperature for 24h. Acetonitrile was evaporated, the aqueous phase was extracted with ethyl acetate (500mL×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 (275g, 61%).

[0074] (2) Synthesis of trans-N-p-methylbenzenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3)

[0075] Dissolve cyclohexaneziridine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) in 200mL tetrahydrofuran, and place allylmagnesium bromide (58g, 0.4mol) at -50°C, Add dropwise slowly and stir...

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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, chemical name: (2S,3aS,7aS)-[(2S)-{[(1S)-(ethoxycarbonyl)-phenylpropyl]amino}]-propionyl]- Octahydroindole-2-carboxylic acid was developed by France RousselUclaf Company. 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 trandolapril structure is the same as many angiotensin-converting enzyme inhibitors (such as enalapril), the difference lies in their side chains, so when preparing trandolapril, the side chains (2S, 3aS ,7aS)-octahydroindole-...

Claims

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Application Information

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Patent Type & Authority Patents(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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