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A preparation compound (1r,2s,6s,7s)-4,4-dimethyl-9-benzyl-3,5,8-trioxa-9-azatricyclo[5.2.1.0 2.6 ] decane method

A compound, methanol technology, applied in the direction of organic chemistry, can solve problems such as not suitable for industrial production and poor reproducibility of experimental results

Inactive Publication Date: 2016-08-03
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reproducibility of the experimental results of the method in the literature is also poor, and the post-processing needs to pass through the column to purify the product, which is not suitable for industrial production

Method used

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  • A preparation compound (1r,2s,6s,7s)-4,4-dimethyl-9-benzyl-3,5,8-trioxa-9-azatricyclo[5.2.1.0 <sup>2.6</sup> ] decane method
  • A preparation compound (1r,2s,6s,7s)-4,4-dimethyl-9-benzyl-3,5,8-trioxa-9-azatricyclo[5.2.1.0 <sup>2.6</sup> ] decane method
  • A preparation compound (1r,2s,6s,7s)-4,4-dimethyl-9-benzyl-3,5,8-trioxa-9-azatricyclo[5.2.1.0 <sup>2.6</sup> ] decane method

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preparation example Construction

[0034] Specifically, the compound of formula 4 provided by the invention (1R,2S,6S,7S)-4,4-dimethyl-9-benzyl-3,5,8-trioxa-9-azatricyclic [5.2.1.0 2.6 ] The preparation method of decane comprises steps:

[0035] In the first step, the compound of formula 2 is prepared under the conditions of heating reflux of zinc powder and a protic solvent with the compound of formula 1 as raw material;

[0036] In the second step, the reaction solution in the first step is filtered, and the obtained filtrate containing the compound of formula 2 is reacted with benzyl hydroxylamine or its salt at room temperature in the presence of an inorganic base to prepare the compound of formula 3;

[0037] In the third step, the reaction solution obtained in the second step is filtered and concentrated, and the obtained oil containing the compound of formula 3 is dissolved in chlorobenzene, and heated to reflux in the presence of a certain amount of alkali to prepare the compound of formula 4; or the r...

Embodiment 1

[0064] Take 9.0g of the compound of formula (1), dissolve it in 143ml of 95% ethanol, put it into a 250ml reaction bottle, and stir it mechanically. Add 18.6 g of active zinc prepared in advance to the reaction flask, heat to reflux for 1 h, and TLC monitors that the reaction is complete. The reaction solution was filtered to obtain a light yellow filtrate (Solution A). Add 3.9 g of benzyl hydroxylamine and 15.2 g of sodium carbonate to solution A, stir at room temperature for 1 h, and monitor the completion of the reaction by TLC. The reaction solution was concentrated by rotary evaporation with a water pump at 35°C to obtain a light yellow-green oil containing sodium carbonate. The oil was dissolved in 150ml of chlorobenzene, put into a 250ml reaction bottle, heated to reflux at 105°C, and monitored by TLC for 2 hours to complete the reaction. The reaction solution was filtered, and the filtrate was washed with 50ml×3 water, anhydrous MgSO 4 Dry, filter, and evaporate to ...

Embodiment 2

[0072] Take 24.0g of the compound of formula (1), dissolve it in 380ml of 95% ethanol, put it into a 500ml reaction bottle, and stir it mechanically. Add 75.0 g of active zinc prepared in advance to the reaction flask, heat to reflux for 1 h, and monitor the completion of the reaction by TLC. The reaction solution was filtered to obtain a light yellow filtrate (Solution A). Add 10.3 g of benzylhydroxylamine and 40.5 g of sodium carbonate to solution A, stir at room temperature for 1 h, and monitor the completion of the reaction by TLC. The reaction solution was concentrated by rotary evaporation with a water pump at 35°C to obtain a light yellow-green oil containing sodium carbonate. The oil was dissolved in 380ml of chlorobenzene, put into a 500ml reaction bottle, heated to reflux at 108°C, and the reaction was complete after 3.5 hours of reflux monitored by TLC. The reaction solution was filtered, and the filtrate was washed with 100ml×3 water, anhydrous MgSO 4 Dry, filte...

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Abstract

The invention discloses a method for preparing a compound (1R,2S,6S,7S)-4,4-dimethyl-9-benzyl-3,5,8-trioxa-9-azatricyclo[5.2.1.0<2.6>]decane. The method comprises steps: (1) mixing a compound with the chemical structure shown as a formula 1 and zinc in a protic solvent, so as to obtain a compound with the chemical structure shown as a formula 2; (2) mixing the compound with the chemical structure shown as the formula 2 and benzylhydroxylamine or a salt thereof in a protic solvent in the presence of an inorganic base, so as to obtain a compound with the chemical structure shown as a formula 3, wherein the inorganic base is selected from sodium carbonate, potassium carbonate or sodium bicarbonate; and (3) refluxing the compound with the chemical structure shown as the formula 3 in chlorobenzene in the presence of a base, so as to obtain a compound with the chemical structure shown as a formula 4, wherein the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, pyridine and triethylamine.

Description

technical field [0001] The present invention relates to chemical synthesis, in particular to a compound (1R,2S,6S,7S)-4,4-dimethyl-9-benzyl-3,5,8-trioxa-9-azatri ring [5.2.1.0 2.6 ] The synthetic method of decane and its purification method. Background technique [0002] Compound (1R,2S,6S,7S)-4,4-Dimethyl-9-benzyl-3,5,8-trioxa-9-azatricyclo[5.2.1.0 2.6 The compound of formula (5) can be prepared by hydrogenation and ring-opening of decane. The compound of formula (5) is an important intermediate of the anticoagulant drug ticagrelor, and its synthesis has important economic value. [0003] [0004] Document J.Chem.Soc.PekinTrans.1, 1994, P613-614 has reported the method for synthesizing formula (4) through three-step reaction "one pot method" by formula (1) compound: formula (1) compound and zinc powder Reflux in ethanol for 1 hour, filter, add benzyl hydroxylamine or its hydrochloride, sodium carbonate to the filtrate at room temperature, 15mim complete reaction, then...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/08C07D317/44
CPCC07D317/44C07D498/08
Inventor 郑权单晓燕陈旭东时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD