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Synthesis method of lobeline

A synthesis method and compound technology, applied in the synthesis field of lobeline, can solve the problems of low yield, harsh reaction conditions, long route and the like, and achieve the effects of high yield, mild reaction conditions and concise process route

Active Publication Date: 2019-01-18
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Therefore, it is necessary to provide a new synthetic method to change the current situation of long route, low yield and harsh reaction conditions faced by the industrial production of lobeline synthesis.

Method used

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  • Synthesis method of lobeline
  • Synthesis method of lobeline
  • Synthesis method of lobeline

Examples

Experimental program
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preparation example Construction

[0053] This synthetic method comprises the steps:

[0054] (1) Ring-opening reaction: compound 1 is added dropwise to Lewis acid in ethanethiol medium to react to obtain compound 2;

[0055] (2) Oxidation reaction: Compound 2 is added dropwise to phosphoric acid in the medium of dicyclohexylcarbodiimide to obtain compound 3;

[0056] (3) Dehydration reaction: compound 3 is added to the medium of S-tert-butylsulfinamide, and water-absorbing agent anhydrous copper sulfate is added to react to obtain compound 4;

[0057] (4) Addition reaction: compound 4 reacts to obtain compound 5 under the action of acetophenone base;

[0058] (5) Reduction reaction: Compound 5 is stirred and reacted in a reducing agent medium, acid is added dropwise, the pH is adjusted to 2-3, and compound 6 is obtained by reaction;

[0059] (6) Protection reaction: compound 6 is reacted to obtain compound 7 in imidazole and TBSCl in a medium;

[0060] (7) Substitution reaction: Compound 7 was added dropwis...

Embodiment 1

[0065] 1. Pour 3.40kg (40.4mol, 1.0eq) of 3,4-dihydropyran into the cleaned 30-liter reactor, and then pour 6kg of toluene;

[0066] Under the protection of nitrogen, the temperature of ice brine is cooled. When the temperature drops below 10°C, 6.28kg of ethanethiol (101mmol, 2.5eq) is injected, and then 0.8kg of toluene is injected, and the temperature of ice brine is cooled under the protection of nitrogen;

[0067] When the temperature drops below 0°C, slowly add 0.20 kg of boron trifluoride diethyl ether dropwise within 1-2 hours;

[0068] After dropping 0.20kg, slowly drop the remaining 2.90kg of boron trifluoride ether into the reactor, and the temperature during the dropping process should not exceed 5°C;

[0069] After dripping 2.90kg of boron trifluoride diethyl ether, take a sample and submit it for inspection. After confirming that the reaction of the raw materials is complete (3,4-dihydropyran < 1%), the reaction solution is quenched;

[0070] For the configurati...

Embodiment 2

[0122] 1. Pour 34kg of 3,4-dihydropyran into the cleaned 300-liter reactor, and then pour 60kg of toluene into it, and cool it down with ice salt water under the protection of nitrogen. When the temperature drops below 10°C, pour 64kg of ethanethiol (2.5 eq), then inject 8kg of toluene, and cool the ice salt water under the protection of nitrogen;

[0123] When the temperature drops below 0°C, start to slowly add 2kg of boron trifluoride diethyl ether dropwise within 1-2 hours;

[0124] After dropping 2kg, slowly drop the remaining boron trifluoride diethyl ether 29kg (0.5eq) into the reactor, and the temperature during the dropping process should not exceed 5°C;

[0125] After dripping 29kg of boron trifluoride ether, take a sample and submit it for inspection. After confirming that the reaction of the raw materials is complete (3,4-dihydropyran < 1%), the reaction solution is quenched;

[0126] For the configuration of saturated aqueous sodium bicarbonate solution, 9kg of s...

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Abstract

The invention discloses a synthesis method of lobeline and belongs to the technical field of organic synthesis. The synthesis method comprises the following steps: sequentially carrying out ring opening reaction, oxidization reaction, dehydration reaction, addition reaction, reduction reaction, protection reaction, substitution reaction, hydrolysis reaction, coupling reaction and hydrolysis ring closing reaction to prepare 2-[(2R,6S)-6-[(2S)-2-hydroxyl-2-phenethyl]-1-methylpiperidine]-1-acetophenone. According to the synthesis method disclosed by the invention, a whole technological route is simple, raw materials are cheap and easy to obtain, the cost is low, reaction conditions are mild, the operation is simple, the chiral purity is high and the yield is high; a chiral center is synthesized through simple chemical reaction and an expensive chiral catalyst is not used, so that the cost is reduced; in the whole technological route, the raw materials are cheap and easy to obtain, the cost is low, the technology is simple, the reaction conditions are mild, the operation is simple and the total yield is high.

Description

technical field [0001] The invention relates to a method for synthesizing lobeline, belonging to the technical field of organic synthesis. Background technique [0002] Lobeline, also known as lobeline, is an alkaloid extracted from lobelia, chemical name: 2-[(2R,6S)-6-[(2S)-2-hydroxy-2-phenylethyl] -1-methylpiperidine]-1-acetophenone, the structural formula is as follows: [0003] [0004] At present, it has been chemically synthesized, which can stimulate the chemoreceptors of the carotid sinus and aortic body, both of which are N1 receptors, reflexively excite the respiratory center to speed up breathing, but have no direct excitatory effect on the respiratory center, and have no direct excitatory effect on the autonomic nervous system. It is used for neonatal asphyxia, asphyxia caused by carbon monoxide, poisoning of inhaled anesthetics and other central inhibitory drugs, and respiratory failure caused by diseases such as pneumonia and diphtheria. [0005] The most ...

Claims

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Application Information

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IPC IPC(8): C07D211/32
CPCC07B2200/07C07D211/32
Inventor 李文森张文琦
Owner HEADING NANJING PHARMTECH CO LTD
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