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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 unfavorable environmental protection, large-scale production, reduced synthesis cost, and small synthesis scale, and achieve solvent recyclability, convenient operation, Simple operation effect

Active Publication Date: 2016-11-02
SHANGHAI JIAO TONG UNIV
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  • Abstract
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Problems solved by technology

Yet, this technique also has some places to be improved: 1) raw material N-p-toluenesulfonyl-7-azabicyclo[4.1.0]heptane is more expensive in this route, if start with cyclohexene Synthesize the compound from raw materials in advance, and the synthesis cost will be further reduced
2) In the synthetic route, the protective group on N is removed using sodium naphthalene as a reagent and separated by a resin column. The synthetic scale is small and the operation is troublesome
[0006] In summary, the existing preparation methods of (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid and its benzyl ester have the disadvantages of long process route, complex operation, etc., and use a large amount of toxic Harmful and expensive reagents, high cost, low overall yield, not conducive to environmental protection and large-scale production

Method used

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  • A kind of preparation method of trandolapril intermediate
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Examples

Experimental program
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Effect test

Embodiment 1

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

[0055] Chloramine-T (500g, 1.775mol), cyclohexene (164.0g, 2.0mol), iodine (28.2g, 0.11mol) and benzyltrimethylammonium bromide (20.4g, 0.088mol) were added to 1000mL tetrahydrofuran and In a mixed solvent of 500 mL of water, react at room temperature for 24 h, distill off tetrahydrofuran, extract the aqueous phase with ethyl acetate (500 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, remove the solvent by rotary evaporation, and use Recrystallized from ethanol to obtain white crystals (326.7g, 65%).

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

[0057] Dissolve cyclohexaneziridine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) in 200mL ether, and allylmagnesium bromide (29.0g, 0.2mol) at -40°C , slowly dropwise, stirring overnight. The reaction was que...

Embodiment 2

[0075] (1) Synthesis of cyclohexaneziridine (hereinafter referred to as compound 2)

[0076] Chloramine T (500.0g, 1.775mol), cyclohexene (164g, 2.0mol), iodine (28.2g, 0.11mol) and benzyltrimethylammonium chloride (16.5g, 0.088mol) were added to 1000mL tetrahydrofuran and 500mL In a mixed solvent of water, react 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 (270.1g ,60%).

[0077] (2) Synthesis of mixed trans-N-p-methylbenzenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3)

[0078] 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 s...

Embodiment 3

[0094] (1) Synthesis of cyclohexaneziridine (hereinafter referred to as compound 2)

[0095] Add 1000 mL of acetonitrile and In a mixed solvent of 500mL water, react 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%).

[0096] (2) Synthesis of mixed trans-N-p-methylbenzenesulfonyl-2-(2-propenyl)-cyclohexylamine (hereinafter referred to as compound 3)

[0097] Cyclohexane aziridine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) were dissolved in 200mL tetrahydrofuran, and allylmagnesium bromide (58.0g, 0.4mol) was , slowly dropwise, stirring overnight. The reaction was quenched with water, extracted with ethyl acetate (250 mL×3), the organic phases were combined, dried over a...

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Abstract

The invention relates to a preparation method of a trandolapril intermediate, that is: cyclohexaneziridine is obtained by reacting cyclohexene and chloramine-T as starting raw materials; cyclohexaneziridine and allyl Grignard reagent Reaction obtains trans-N-p-toluenesulfonyl-2-(2-propenyl)-cyclohexylamine, and under the effect of oxidizing agent, obtains trans-mixed N-p-toluenesulfonyl-octahydro ‑1H‑indole‑2‑carboxylic acid, methyl esterification protects the free carboxyl group to obtain trans-mixed N‑p-methylbenzenesulfonyl‑octahydro‑1H‑indole‑2‑carboxylic acid methyl ester, remove nitrogen After the Ts protecting group and hydrolysis, the benzyl esterification reaction gives the octahydro-1H-indole-2-carboxylic acid benzyl ester which is trans-mixed. After separation and resolution, the key intermediate of trandapril (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylate benzyl ester was obtained. The raw materials of the invention are cheap and easy to obtain, the preparation process is environmentally friendly, and the operation and post-treatment are simple.

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,3aR,7aS)-[(2S)-{[(1S)-(ethoxycarbonyl)-phenylpropyl]amino}]-propionyl]- Octahydro-1H-indole-2-carboxylic acid, developed by France Roussel Uclaf 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), and the difference lies in their side chains. Therefore, when preparing trandolapril, the side chains (2S, 3aR ,7aS)-oc...

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时涛
Owner SHANGHAI JIAO TONG UNIV
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