Preparation method of optically pure lobeline hydrochloride and enantiomer thereof

A technology of lobeline hydrochloride and enantiomers, which is applied in the field of preparation of optically pure lobeline hydrochloride and its enantiomers, can solve the problems of complex preparation of chiral catalysts, low yield of enzymatic reactions, and ligand Expensive and other issues, to achieve the effect of being suitable for large-scale industrial production, saving process costs, and high optical purity of products

Pending Publication Date: 2021-11-02
GUANGDONG PHARMA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved in the present invention is to overcome the defects and deficiencies of existing methods for synthesizing Lobeline hydrochloride, such as complicated preparation

Method used

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  • Preparation method of optically pure lobeline hydrochloride and enantiomer thereof
  • Preparation method of optically pure lobeline hydrochloride and enantiomer thereof
  • Preparation method of optically pure lobeline hydrochloride and enantiomer thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1 A kind of preparation method of optically pure lobeline hydrochloride and its enantiomer

[0042] The preparation method of the optically pure lobeline hydrochloride and its enantiomers, the reaction scheme is as follows:

[0043]

[0044] Specifically include the following steps:

[0045] (1) Condensation reaction: Dissolve 13.12g (0.08mol) of benzoylacetic acid, 2.72g (0.04mol) of methylamine hydrochloride, and 8.0mL (0.04mol) of 50% glutaraldehyde aqueous solution in 600mL of citric acid buffer solution (0.05M, pH=4.0), stirred and reacted at room temperature for 48 hours, washed with n-hexane (500mL×2) after the reaction, then cooled the water phase to below 0°C, acidified to pH with 4mol / L HCl aqueous solution =1~2, and stirred to form a white precipitate, the white precipitate was filtered out with a Buchner funnel and the filter cake was washed with a small amount of water, dried in vacuo to obtain behenone hydrochloride Ⅰ (8.2g, yield: 55.1%) ;...

Embodiment 2

[0060] Embodiment 2 A kind of preparation method of optically pure lobeline hydrochloride and its enantiomer

[0061] Compared with the preparation method of Example 1, the difference of the preparation method of Example 2 is that the step (4) splits and specifically adopts the following steps:

[0062] Dissolve compound III (racemate) (3.95g, 0.01mol) obtained in step (3) in 40mL ethanol at room temperature, stir and heat to 80°C, after dissolving, add resolving agent (-)-camphor- 10-sulfonic acid (1.28g, 0.0055mol), continue to stir until dissolving and cool down, until white solid is separated out, after stirring for 30 minutes, suction filtration obtains the salt 2.10g that compound III (a) forms with resolving agent, yield is 33.5%, ee value is close to 100% (the HPLC analysis spectrogram of obtained product III (a) sees Figure 4 , wherein, the peak time of Ⅲ(a) is 14.2min).

[0063] Refer to Example 1 for other operations and parameters.

Embodiment 3

[0064] Embodiment 3 A kind of preparation method of optically pure lobeline hydrochloride and its enantiomer

[0065] Compared with the preparation method of Example 1, the difference of the preparation method of Example 3 is that the step (4) splitting specifically adopts the following steps:

[0066] Dissolve compound III (racemate) (3.95g, 0.01mol) obtained in step (3) in 30mL toluene at room temperature, stir and heat to 80°C, after dissolving, add the resolving agent di-p-methoxybenzene Formyl-L-tartaric acid (2.30g, 0.0055mol), continued to stir until dissolved and then cooled until a white solid was precipitated. After stirring for 60 minutes, suction filtered to obtain 2.59g of the salt formed by compound III (a) and a resolving agent. The rate is 31.9%, and the ee value is 87% (the HPLC analysis spectrogram of gained product III (a) sees Figure 5 , wherein, the peak time of III(a) is 13.9min, and the peak time of III(b) is 9.5min).

[0067] Refer to Example 1 for o...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of optically pure lobeline hydrochloride and an enantiomer of the optically pure lobeline hydrochloride. According to the method, benzoylacetic acid, methylamine hydrochloride and glutaraldehyde are used as raw materials, and a target product can be prepared through condensation, reduction, acylation, resolution, oxidation and hydrolysis reactions in sequence. According to the method, meso-racemic lobeline is derived into raceme through acylation by adopting a desymmetry strategy, so that conditions are created for further resolution, and the use of a chiral catalyst which is high in price and tedious in preparation is avoided. In the splitting step, the product is filtered, the obtained filtrate is subjected to hydrolysis and other treatments to obtain an intermediate compound II, and the intermediate compound II can be recycled, so that the process cost is greatly saved; and moreover, the whole preparation process flow is simple to operate, mild in condition, high in optical purity of the product and very suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis. More specifically, it relates to a preparation method of optically pure lobeline hydrochloride and its enantiomers. Background technique [0002] Lobeline is also known as lobeline, its chemical name is 2-[(2R,6S)-6-[(S)-2-hydroxy-2-phenylethyl]-1-methylpiperidine]-1-benzene Ethyl ketone is the main alkaloid component of a plant native to North America - Beetroot. It can stimulate carotid sinus and aortic body chemoreceptors (both N1 receptors), reflexively excite the respiratory center and accelerate breathing. It also has a reflex excitatory effect on the vagus nerve center and vasomotor center, so it can be used for central respiratory depression caused by various reasons. Its prodrug lobeline hydrochloride has been used as an adjunct to asthma, expectorant, respiratory stimulant and smoking cessation. [0003] However, there are some methods of using chiral reagents or auxiliary...

Claims

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Application Information

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IPC IPC(8): C07D211/32
CPCC07D211/32C07B2200/07Y02P20/55
Inventor 宣宜宁储仕林
Owner GUANGDONG PHARMA UNIV
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