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2-[(2R, 6S)-6-[(2S)-2-hydroxy-2-phenethyl]-1-pipecoline]-1-hypnone synthesis method

A synthesis method and a technology for methyl piperidine, applied in the field of organic synthesis, can solve the problems of low yield, difficult industrial production and the like, and achieve the effects of high yield, easy operation and high chiral purity

Active Publication Date: 2017-03-15
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In 2006, Franz-Dietrich et al. used double-coordinated phosphine ligands for asymmetric reduction to synthesize the key intermediate for the preparation of Lobeline: 2-[(2R,6S)-6-[(2S)-2- Hydroxy-2-phenethyl]-1-methylpiperidine]-1-acetophenone, this step requires a high pressure condition of 15-20bar, and the yield is low, it is difficult to be used in industrial production (US20060014791)

Method used

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  • 2-[(2R, 6S)-6-[(2S)-2-hydroxy-2-phenethyl]-1-pipecoline]-1-hypnone synthesis method

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Experimental program
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Effect test

Embodiment 1

[0034]

[0035] Add (1S,2S)-1,2-diphenylethylenediamine (1.0g, 4.7mmol) into 10mL DCM, stir to dissolve and clarify, add 5mL 2N NaOH aqueous solution, cool down to 0°C, add p-toluenesulfonate dropwise Acyl chloride (0.84g, 4.4mmol) in dichloromethane (10mL) solution was maintained at 0°C for 1 hour, then heated to room temperature for 2 hours, and the reaction was completed by HPLC detection. The reaction solution was poured into saturated sodium chloride solution (10 mL), stirred for 10 minutes, and the aqueous phase was extracted once with DCM (10 mL), and the organic phase was combined, dried, and dichloromethane was distilled off under reduced pressure to obtain a crude product. Recrystallization from petroleum ether / ethyl acetate system gave compound I (1.4 g, 80.9%) as a yellow solid.

[0036] 1 H NMR (CDCl 3 400MHz): δ2.335(s, 1H), 4.160-4.172(d, 1H), 4.400-4.413(d, 1H), 6.978-6.998(d, 2H), 7.119-7.191(m, 10H), 7.318- 7.339(d, 2H).

[0037]

[0038] Add 3-(1,...

Embodiment 2

[0050] The procedure was the same as in Example 1, except that (1S, 2S)-1,2-diphenylethylenediamine (3.0 g, 14.1 mmol) was added to 50 mL of DCM, stirred to dissolve and clarified, and then 15 mL of 2N NaOH aqueous solution was added , cooled to 0°C, a solution of p-toluenesulfonyl chloride (2.65g, 14.1mmol) in dichloromethane (30mL) was added dropwise, maintained at 0°C for 1 hour, then raised to room temperature for 2 hours, and HPLC detected that the reaction was complete. The reaction solution was poured into saturated sodium chloride solution (30 mL), stirred for 10 minutes, and the aqueous phase was extracted once with DCM (30 mL), and the organic phase was combined, dried, and dichloromethane was distilled off under reduced pressure to obtain a crude product. Recrystallization from petroleum ether / ethyl acetate system gave compound I as a yellow solid (4.48g, 82.3%)

Embodiment 3

[0052] 3-Phenylpropanol (2.1g, 15.3mmol) was added to pyridine (2.4g, 30.6mmol), under nitrogen protection, cooled to 0°C, stirred for 30 minutes, slowly added trifluoromethanesulfonic anhydride (4.57g , 16.2mmol), after the dropwise addition was completed, maintain 0°C, react for 30 minutes, then rise to room temperature, and react for 1 hour; then continue to cool the reaction solution to 0°C, add compound I (3.5g, 9.55mmol) and TEA (2.3 g, 23.0 mmol) in dichloromethane solution, maintain this temperature for 1 hour, remove the ice bath, and stir at room temperature overnight until the HPLC detection reaction ends. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, and the layers were separated. The organic phase was washed once with water, dried, and concentrated to obtain a crude product, which was recrystallized by ethanol as a white solid compound II (3.68 g, 80.1%).

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Abstract

The invention discloses a 2-[(2R, 6S)-6-[(2S)-2-hydroxy-2-phenethyl]-1-pipecoline]-1-hypnone synthesis method, and belongs to the field of organic synthesis. (1S, 2S)-1, 2-diphenyl diaminoethane serving as a raw material is subjected to acylation, substitution and the like to prepare chiral amine catalysts. A main route totally includes two steps: synthesizing glutaraldehyde, benzoyl acetic acid and methylamine hydrochloride to form cis-lobelanine; performing asymmetric selective reduction synthesis of 2-[(2R, 6S)-6-[(2S)-2-hydroxy-2-phenethyl]-1-pipecoline]-1-hypnone under mild reaction conditions and under the action of the catalysts. The raw material in the whole process route is cheap and easy to obtain, the catalysts can be recycled and can continue to be used, and the synthesis method is low in cost, simple in process, mild in reaction condition, convenient in operation and high in total yield.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to 2-[(2R, 6S)-6-[(2S)-2-hydroxyl-2-phenethyl]-1-methylpiperidine]-1-acetophenone resolve resolution. Background technique [0002] 2-[(2R,6S)-6-[(2S)-2-Hydroxy-2-phenethyl]-1-methylpiperidine]-1-acetophenone is the key intermediate in the synthesis of lobeline hydrochloride Lobeline, also known as lobeline, is an alkaloid extracted from lobelia, which can be chemically synthesized. Stimulates chemoreceptors in the carotid sinus and aortic body (both N 1 receptors), reflexively excites the respiratory center to accelerate breathing, but has no direct excitatory effect on the respiratory center, and first excites the autonomic ganglion and then blocks it. It is used for neonatal asphyxia and asphyxia caused by carbon monoxide. It has a large safety range and is not easy to convulse. [0003] From the structure of 2-[(2R,6S)-6-[(2S)-2-hydroxyl-2-phenethyl]-1-methylpiperidine]-1-ac...

Claims

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Application Information

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IPC IPC(8): C07D211/32B01J31/12
CPCB01J31/122B01J2231/643C07D211/32
Inventor 李文森
Owner HEADING NANJING PHARMTECH CO LTD
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