Method for preparing trandolapril intermediate

A trandolapril and intermediate technology, applied in the field of pharmaceutical intermediates, can solve the problems of difficulty in obtaining, long process route, difficult control of selective hydrogenation, etc., achieves good stereoselectivity, overcomes flammability and explosion, and shortens reaction steps Effect

Inactive Publication Date: 2012-11-14
上海金赛医药化工有限公司
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  • Abstract
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Problems solved by technology

But there are also some problems in the method reported in the literature, such as HENNING R, URBACH H. (Tetrahedron Lett., 1983, 24 (48), 5 34325 346.) Although the steps adopted are less, mercuric nitrate is used, which is not conducive to environmental protection , may also bring impurities in the cis configuration; the patented method [US, 4 933 361] using cyclohexanone as the starting material, the selective hydrogenation step is difficult to control, and the impurities are not easy to separate; the patent [US, 4 879 392 ] The reported starting material trans-hydrogenated isobenzofuranone is difficult to obtain; the patent [WO, 054 194] uses more expensive reagents, and the cost is too high
US20070225505 adopts cheap and easy-to-get cyclohexene and chloramine T as starting materials, but more expensive reagents are used, and the cost is higher
[0008] In summary, the existing preparation methods of (2S, 3aR, 7aS)-octahydroindole-2-carboxylate and its salts have the disadvantages of long technical route, complex operation, etc., and use a large amount of toxic and harmful , Expensive reagents, high cost, not conducive to environmental protection

Method used

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

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Effect test

Embodiment 1

[0033] A preparation method of trandolapril intermediate, the method may further comprise the steps:

[0034] (1) Synthesis of (3aR, 7aS)-octahydro-2-oxo-1-(4-methylbenzenesulfonyl) ethyl 1-H-indole-3-carboxylate (hereinafter referred to as compound 1)

[0035] Chloramine-T (500g, 1.775mol), cyclohexene (164g, 2.0mol), I 2 (28.2g) was added into 1000ml tetrahydrofuran, reacted at room temperature for 24 hours, and placed for later use. At room temperature, add 320 g of diethyl malonate into a solution of 170 g of sodium ethoxide in THF (788 ml), raise the temperature and reflux for 45 minutes, slowly add the previous reaction solution dropwise within 4 hours, reflux for 15 hours, cool down to room temperature, and depressurize Evaporate the solvent, stir and dissolve with 1200ml ethyl acetate and 800ml water, adjust the pH to 6-7 with concentrated hydrochloric acid, separate the layers, extract the aqueous layer with ethyl acetate (400ml×3), combine the organic layers, wash wit...

Embodiment 2

[0047] A preparation method of trandolapril intermediate, the method may further comprise the steps:

[0048] (1) Synthesis of compound 1

[0049] Chloramine-T (500g, 1.775mol), cyclohexene (145g, 1.775mol), I 2 (33g) was added in 533ml tetrahydrofuran, reacted at room temperature for 24 hours, and placed for later use; at room temperature, 284g (1.775mol) diethyl malonate was added in THF (600ml) solution of 239.7g (4.44mol) sodium methylate, Raise the temperature and reflux for 45 minutes, slowly add the previous reaction solution dropwise within 4 hours, reflux for 15 hours, cool down to room temperature, evaporate the solvent under reduced pressure, stir and dissolve with 1000ml ethyl acetate and 600ml water, adjust the pH to 6 with concentrated hydrochloric acid ~7, separate layers, extract the aqueous layer with ethyl acetate (500ml×3), combine the organic layers, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 551.3g of com...

Embodiment 3

[0061] A preparation method of trandolapril intermediate, the method may further comprise the steps:

[0062] (1) Synthesis of Compound 1

[0063] Chloramine-T (500g, 1.775mol), cyclohexene (218g, 2.663mol), I 2 (25g) was added in 1420ml tetrahydrofuran, reacted at room temperature for 24 hours, and placed for later use; at room temperature, 426g (2.663mol) diethyl malonate was added in THF (900ml) solution of 181.2g (2.663mol) sodium ethylate, Raise the temperature and reflux for 45 minutes, slowly add the previous reaction solution dropwise within 4 hours, reflux for 15 hours, cool down to room temperature, evaporate the solvent under reduced pressure, stir and dissolve with 1500ml ethyl acetate and 900ml water, adjust the pH to 6 with concentrated hydrochloric acid ~7, separate layers, extract the aqueous layer with ethyl acetate (300ml×3), combine the organic layers, dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 570.7g of co...

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Abstract

The invention relates to a method for preparing a trandolapril intermediate. Cyclohexene and chloramines T are adopted as starting materials to react to obtain cyclohexane ethylene imine; the cyclohexane ethylene imine reacts with diethyl malonate to obtain to 7-[(4-methyl phenyl)sulfonyl]-7-aza-bicyclo[4.1.0]heptanes. The obtained 7-[(4-methyl phenyl)sulfonyl]-7-aza-bicyclo[4.1.0] heptane reacts with diethyl malonate to obtain (3aR, 7aS)-8H-2-oxo-1-(4-methyl benzenesulfonyl)1-H-indole-3-ethyl formate. Then dl-octahydroindole-2-benzyl carboxylate is obtained through a decarboxylation reaction, a reduction reaction, a cyanation reaction and an alcoholysis reaction. The dl-octahydroindole-2-benzyl carboxylate is split and treated by hydrochloric acid to obtain the trandolapril intermediate (2S, 3aR, 7aS)-octahydroindole-2-benzyl carboxylate hydrochloride. Compared with the prior art, the preparation method of the trandolapril intermediate (2S, 3aR, 7aS)-octahydroindole-2-benzyl carboxylate hydrochloride has the advantages of reasonable process, safe reagent, low cost, no environmental pollution, simple operation, easy separation and the like. Meanwhile, a prepared product is high in both yield and optical purity.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, in particular to a preparation method of a trandapril intermediate. Background technique [0002] Trandolapril (Trandolapril, the structural formula is shown below), the chemical name is (2S, 3aR, 7aS)-[(2S)-[[(1S)-(ethoxycarbonyl)-phenylpropyl]amino]-propyl Acyl]-octahydroindole-2-carboxylic acid, developed by French company Roussel Uclaf, is a long-acting angiotensin-converting enzyme inhibitor that can treat a variety of cardiovascular diseases. Small and other advantages. Further research found that trandolapril can effectively improve peripheral neuropathy in normotensive diabetic patients. [0003] [0004] 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, its side chains (2S, The synthesis of 3aR,7aS)-octahydroindole-2-carbox...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/42
Inventor 朱爱林许振华陈伟铭顾焕
Owner 上海金赛医药化工有限公司
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