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Preparation method for (2S, 3aR, 7aS)-octahydro indole-2-benzyl formate

A technology of benzyl formate and indoline, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of carry-in, difficult separation of impurities, severe selective hydrogenation reaction, etc., and achieves high yield, good optical activity, and improved reaction. effect of speed

Active Publication Date: 2012-01-18
ANHUI TOPSUN PHARMA
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Problems solved by technology

Patent US4933361 discloses a preparation method using cyclohexanone as a raw material, adding acrylonitrile to cyclization, reducing formic acid / sodium formate, chlorination, selective hydrogenation, dechlorination, rearrangement, resolution, and esterification. However, the selective hydrogenation reaction is violent and difficult to control, and the impurities are not easy to separate, and the product purity is difficult to guarantee
? Disclosed is a method that uses cyclohexene as a raw material, adds mercuric nitrate and acetonitrile, reacts with 2-chloroacrylonitrile and sodium borohydride, cyclizes under the action of sodium hydride, removes acyl and cyano groups under acidic conditions, The preparation method of esterification and resolution, but although this method has fewer reaction steps, it uses mercury nitrate, which is not conducive to environmental protection, and may also bring in cis-configured impurities

Method used

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  • Preparation method for (2S, 3aR, 7aS)-octahydro indole-2-benzyl formate
  • Preparation method for (2S, 3aR, 7aS)-octahydro indole-2-benzyl formate
  • Preparation method for (2S, 3aR, 7aS)-octahydro indole-2-benzyl formate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1. Cis-addition reaction:

[0036] Chloramine-T (1.775mol), cyclohexene (4.4mol), I 2 (0.11mol) was added in 1491ml of acetonitrile, reacted at natural room temperature for 24 hours, and evaporated the solvent under reduced pressure to obtain 453.5g of the red oily product of this step, yield: 102%, 1 H NMR (CDCl 3 , 300MHz) δ(ppm): 1.16~1.26(m, 2H); 1.33~1.45(m, 2H); 2.42(s, 3H); 2.96(s, 2H); 7.46~7.57(m, 3H); 7.31 (d, 2H, J=7.78Hz); 7.80(d, 2H, J=6.7Hz);

[0037] 2. Closed-loop hydrolysis reaction:

[0038] Diethyl malonate (2.72mol) was added into a solution of tetrahydrofuran (1650ml) dissolved with sodium ethoxide (3.48mol), heated to reflux for 45 minutes, and slowly added dropwise to tetrahydrofuran (1767ml) of the product (453.5g) obtained in step (1). ) solution, reflux reaction for 15 hours, down to room temperature, and decompression to remove the solvent; add ethyl acetate to dissolve the resulting product, add 1256ml of water, stir and dissolve, adjust ...

Embodiment 2

[0052] 1. Cis-addition reaction:

[0053] Chloramine-T (1.775mol), cyclohexene (3.55mol), I 2 (0.10mol) was added in 1491ml of acetonitrile, reacted at natural room temperature for 24 hours, and evaporated the solvent under reduced pressure to obtain 444.6g of the red oily product of this step, yield: 100%, 1 H NMR (CDCl 3 , 300MHz) δ(ppm): 1.16~1.26(m, 2H); 1.33~1.45(m, 2H); 2.42(s, 3H); 2.96(s, 2H); 7.46~7.57(m, 3H); 7.31 (d, 2H, J=7.78Hz); 7.80(d, 2H, J=6.7Hz);

[0054] 2. Closed-loop hydrolysis reaction:

[0055] Diethyl malonate (2.7mol) was added into a solution of tetrahydrofuran (1345ml) dissolved with sodium ethoxide (3.3mol), heated to reflux for 30 minutes, and slowly added dropwise to tetrahydrofuran (1732ml) of the product (444.6g) obtained in step (1). ) solution, reflux reaction for 15 hours, down to room temperature, and evaporate the solvent under reduced pressure; add ethyl acetate to dissolve the resulting product, then add 1112ml of water, stir and diss...

Embodiment 3

[0069] 1. Cis-addition reaction:

[0070] Chloramine-T (1.775mol), cyclohexene (5.3mol), I 2 (0.14mol) was added in 1491ml of acetonitrile, and the natural room temperature was reacted for 24 hours under the condition of 25° C., and the solvent was evaporated under reduced pressure to obtain 462.4 g of the red oily product of step (1), yield: 104%, 1 HNMR (CDCl 3 , 300MHz) δ(ppm): 1.16~1.26(m, 2H); 1.33~1.45(m, 2H); 2.42(s, 3H); 2.96(s, 2H); 7.46~7.57(m, 3H); 7.31 (d, 2H, J=7.78Hz); 7.80(d, 2H, J=6.7Hz);

[0071] 2. Closed-loop hydrolysis reaction:

[0072] Diethyl malonate (3.2mol) was added into a solution of tetrahydrofuran (2000ml) dissolved with sodium ethoxide (4.8mol), heated to reflux for 2h, and slowly added dropwise to tetrahydrofuran (1800ml) of the product (462.4g) obtained in step (1) solution, reflux reaction for 18 hours, down to room temperature, and evaporate the solvent under reduced pressure; add 1800ml of ethyl acetate, 1380ml of water, stir and dissolv...

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Abstract

The invention relates to a preparation method for a medicine intermediate and aims to provide a preparation method for (2S, 3aR, 7aS)-octahydro indole-2-benzyl formate. The method is high in yield and steps are reduced. The method comprises the following steps of: performing cis-form addition on cyclohexene and chloramines-T under the condition of adding a catalyst I2; heating and refluxing diethyl malonate and the product of the cis-form addition to perform ring-closure reaction; hydrolyzing the product of the ring-closure reaction; heating the hydrolysate to perform decarboxylation; performing sodium borohydride reducing chlorination on the decarboxylate; adding trimethyl cyano silane into the product of the reducing chlorination to perform substitution reaction; performing acidolysis on the substitution product by using concentrated hydrochloric acid and acetic acid as catalysts under the condition of heating and refluxing; performing refluxing water distribution on the product of the acidolysis and benzyl alcohol under the action of a strong acid catalyst to perform esterification; and further purifying the esterification product by using a resolving agent.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate. Background technique [0002] Cardiovascular disease is one of the most serious diseases in the world, and its morbidity and mortality have surpassed tumor diseases to rank first in the world. In recent years, the long-acting angiotensinase inhibitor trandolapril has attracted the attention of many researchers because of its ability to treat a variety of cardiovascular diseases. The drug has the advantages of significant curative effect, long duration of action, and few side effects. Recently, it has also been found that trandolapril can effectively improve peripheral neuropathy in normotensive patients. (2S, 3aR, 7aS)-benzyl octahydroindole-2-carboxylate (structural formula is shown below) is the key intermediate of trandolapril, which can be synthesized through two-step reaction. There are three chiral centers in the structure, and its optical purity directly affects th...

Claims

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Application Information

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IPC IPC(8): C07D209/42
Inventor 王佩义黄梅李文新
Owner ANHUI TOPSUN PHARMA
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