Method for synthesizing chiral nicotine from butyrolactone

A technology of nicotine and butyrolactone, applied in the direction of organic chemistry, can solve the problems of long reaction path, high production cost and low yield, and achieve the effects of shortening the reaction steps, mild reaction conditions and low production cost

Active Publication Date: 2021-11-02
SHENZHEN ZINWI BIO-TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(S)-Nicotine is basically obtained by chiral resolution, but chiral resolution reagents are expensive, which is not conducive to industrial production
[0003] The patent with publication number CN104341390A discloses a preparation method of chiral nicotine, which uses cyclic imine as the starting material, requires expensive chiral catalyst, and High-pressure hydrogen equipment is required, the production cost is high, and it is not suitable for large-scale industrial production
The patent with the publication number CN11233829A discloses a preparation method of optically active nicotine, using nitrogen-containing or phosphorus-containing chiral ligands to prepare organometallic catalysts, and using imide salt derivatives as starting materials to prepare (S)- Nicotine, the preparation of organometallic catalysts is more complicated, the production cost is higher, and the productive rate of (S)-nicotine is lower
[0004] The applicant found that the above-mentioned method for synthesizing chiral nicotine from butyrolactone has a defect of relatively long reaction path, resulting in a low yield of (S)-nicotine

Method used

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  • Method for synthesizing chiral nicotine from butyrolactone
  • Method for synthesizing chiral nicotine from butyrolactone
  • Method for synthesizing chiral nicotine from butyrolactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The method for synthesizing chiral nicotine from butyrolactone provided in Example 1, wherein the aminating agent is a methylamine salt-type aminating agent (specifically methylamine hydrochloride), and the synthetic route is shown in Reaction Formula 1, (S) -The specific preparation steps of nicotine are:

[0064] S1, at 0°C, add 86.1g (1mol, 1eq) γ-butyrolactone to 1L DMF, stir at 0°C for 10min, add 48g (2mol, 2eq) NaH, react at 0°C for 0.5h, then add 137.1g (1mol) methyl nicotinate was subjected to condensation reaction at 25°C for 2h, and the reaction was monitored by TCL until the end of the reaction to obtain a condensation product; 0.83L 12mol / L (1mol, 1eq) hydrochloric acid was added to the condensation product, and the reaction was refluxed at 80°C for 1h, Then add saturated brine for extraction, add sodium bicarbonate to make the pH of the system 7, extract 3 times with dichloromethane, combine the organic phases, spin dry to remove the solvent to obtain 4-chl...

Embodiment 2-3

[0068] Example 2-3 differs from Example 1 only in that: in the reaction of step S4, the types of methylamine salt amination reagents are adjusted, as shown in Table 1.

[0069] Table 1 Influence of methylamine salt amination reagent selection on (S)-nicotine yield

[0070] Numbering Methylamine salt amination reagent selection (S)-nicotine yield (%) Example 1 Methylamine hydrochloride 75 Example 2 Methylamine Sulfate 72 Example 3 Methylamine nitrate 70

Embodiment 4-7

[0071] Examples 4-7 differ from Example 1 only in that: in the reaction of step S4, the consumption of methylamine hydrochloride is adjusted, as shown in Table 2.

[0072] The influence of table 2 methylamine hydrochloride dosage selection on (S)-nicotine yield

[0073] Numbering Equivalents of methylamine hydrochloride (eq) (S)-nicotine yield (%) Example 1 3 75 Example 4 1 52 Example 5 2 68 Example 6 4 71 Example 7 5 70

[0074] When the aminating reagent is an amino-based aminating reagent, the synthetic route of the method for synthesizing chiral nicotine from butyrolactone provided by the application is shown in Reaction Formula 2:

[0075]

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PUM

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Abstract

The invention discloses a method for synthesizing chiral nicotine from butyrolactone, which comprises the following steps: condensing nicotinate and gamma-butyrolactone under the action of a basic catalyst, carrying out reflux reaction with hydrochloric acid to obtain 4-chloro-1-(3-pyridine)-1-butanone, inducing the 4-chloro-1-(3-pyridine)-1-butanone by (+)-B-diisopinocampheyl borane to generate chiral hydroxyl so as to obtain (S)-4-chloro-1-(pyridine-3-yl) butyl-1-ol, reacting the material with a chlorination reagent to generate (S)-3-(1, 4-dichlorobutyl) pyridine, carrying out a ring closing reaction on (S)-3-(1, 4-dichlorobutyl) pyridine and an amination reagent under alkaline conditions to obtain (S)-demethylated nicotine or (S)-nicotine, wherein methylation is carried out on (S)-demethylated nicotine to obtain (S)-nicotine. Whether methylation reaction is needed or not can be determined according to the type of the amination reagent, and the yield of the prepared (S)-nicotine is high.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing chiral nicotine from butyrolactone. Background technique [0002] (S)-nicotine, molecular formula C 10 H 14 N 2 , the CAS number is 54-11-5, and the structural formula is At present, there are few studies on the synthesis of chiral nicotine from butyrolactone. (S)-nicotine is basically obtained by the method of chiral resolution, but the chiral resolution reagent is expensive, which is not conducive to industrial production. [0003] The patent with publication number CN104341390A discloses a preparation method of chiral nicotine, which takes cyclic imine as starting material, requires expensive chiral catalyst, and requires high-pressure hydrogen equipment, and the production cost is high, which is not suitable for large-scale industrialization Production. Patent Publication No. CN11233829A discloses a method for preparing optically ac...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 邹军邹阳刘梅森罗维贤
Owner SHENZHEN ZINWI BIO-TECH CO LTD
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