Analysis method for chiral purity of 1-naphthylethylamine

A technology of chiral purity and analysis method, applied in the field of analysis of chiral purity of 1-naphthylethylamine, which can solve problems such as low detection efficiency, increased reaction time, and difficulty in synthesis

Pending Publication Date: 2021-09-03
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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Problems solved by technology

Although the above two methods use reversed-phase chromatography to determine the chiral purity of 1-NEA after the derivatization reaction, the detection time of the derivative product is too long and the detection efficiency is low.
Mochizuki (Analytica Chimica Acta, 2013, 773: 76-82) etc. used L-PGA as a chiral derivatization reagent to carry out derivatization reaction with 1-NEA, and used ACQUITY UPLC BEH C18 chromatographic column (1.7μm, 100mm×2.1 mm), acetonitrile and water were used as the mobile phase, and the retention times of the derivative products were 8.58min and 9.03min respectively. Although the retention time of the derivative products was shortened, the derivatization process used EDC and HOBt as condensation agents, and the atom economy was poor. problem, while UPLC is expensive
[0006] The derivatization process is also disclosed in the existing patent technology, for example, the enantiomers of 3-aminopiperidine and 2-aminobutanol are disclosed in patent numbers ZL201610043272.9, ZL201610043273.3, ZL201610043277.1 and ZL201610043270.X However, due to the different target substrates, the corresponding specific chiral derivatization reagent is the key technology, and the choice of chiral reagent is not obvious or deduced. The reasons are as follows: (1) some chiral derivatives Reagents are difficult to purchase and synthesize. For example, the chiral derivatization reagent (R)-(+)-1-phenylethanesulfonyl chloride used in previous patents is not easy to purchase. If you first synthesize (R)-(+)-1- Phenylethanesulfonic acid, and then the chiral derivatization reagent (R)-(+)-1-phenylethanesulfonyl chloride is obtained through chlorination reaction, which not only increases the detection cost, but also greatly increases the detection time, and the process is no longer convenient. sex
[0007] (2) Although some compounds such as (S)-COXA-Osu, OTPTHE, etc. can be directly used as chiral derivatization reagents, their prices are relatively expensive, which increases the detection cost
[0008] (3) In addition, common chiral amino acids, such as (D)-phenylglycine and (D)-p-hydroxyphenylglycine, will generate by-products during the conventional chlorination reaction, so they are not suitable for use as chiral Derivative reagent; if a condensing agent is used to condense directly with 1-NEA, it will not only greatly increase the reaction time, but also be unfavorable for atom economy
Not suitable as a chiral derivatization reagent

Method used

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  • Analysis method for chiral purity of 1-naphthylethylamine
  • Analysis method for chiral purity of 1-naphthylethylamine
  • Analysis method for chiral purity of 1-naphthylethylamine

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Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1: the liquid chromatography analysis of (D)-camphorsulfonyl chloride and 1-NEA derivative

[0040] 1-1: Liquid chromatography analysis of (D)-camphorsulfonyl chloride and (R)-1-NEA derivatives

[0041] Take (R)-1-NEA 5g (0.029mol), triethylamine 12mL (0.087mol) dissolved in 15g (11.32mL) of dichloromethane, stirred at 25 ° C, (D)-camphorsulfonyl chloride 6g (0.024 mol) was dissolved in 10g (7.55mL) of dichloromethane, stirred evenly, transferred to a constant pressure dropping funnel, slowly added dropwise to the system, TLC monitored the reaction, and evaporated to dryness after the reaction to obtain a yellow viscous liquid. The solid product can be better extracted, and further, a white solid (D)-camphorsulfonyl·(R)-1-naphthylethylamine derivative is precipitated by soaking in n-heptane, and the pure product is obtained by toluene recrystallization.

[0042] The (D)-camphorsulfonyl·(R)-1-naphthylethylamine derivative was dissolved in mobile phase at a co...

Embodiment 2

[0050] Example 2: 1-NEA and (D)-camphorsulfonyl chloride derivatization reaction conditions investigation test

[0051] 2-1: Dissolve (RS)-1-NEA 5g (0.029mol), triethylamine 4mL (0.029mol) in 25g (27.78mL) ethyl acetate, stir at 25°C, and (D)-camphorsulfonic acid Dissolve 7.3g (0.029mol) of acid chloride in 25g (27.78mL) of ethyl acetate, stir evenly, transfer to a constant pressure dropping funnel, slowly add it dropwise to the system, monitor the reaction by TLC, and evaporate to dryness to obtain a yellow Viscous liquid, soaked in n-heptane to precipitate a white solid (D)-camphorsulfonyl·(RS)-1-naphthylethylamine derivative.

[0052] The (D)-camphorsulfonyl·(RS)-1-naphthylethylamine derivative was dissolved in mobile phase at a concentration of 30 μg / mL, and detected and analyzed by high performance liquid chromatography. Liquid chromatography conditions: Agilent C18 chromatographic column, mobile phase is acetonitrile-potassium dihydrogen phosphate solution (40mmol / L, K ...

Embodiment 3

[0061] Embodiment 3: chromatographic condition investigation test

[0062] (1) Derivatization

[0063] Take (RS)-1-NEA 5g (0.029mol), triethylamine 12mL (0.087mol) dissolved in 15g (11.32mL) of dichloromethane, stirred at 25 ° C, (D)-camphorsulfonyl chloride 6g (0.024 mol) was dissolved in 10g (7.55mL) of dichloromethane, stirred evenly, transferred to a constant pressure dropping funnel, slowly added dropwise to the system, TLC monitored the reaction, evaporated to dryness after the reaction to obtain a yellow viscous liquid, normal Soak in heptane to precipitate a white solid (D)-camphorsulfonyl·(RS)-1-naphthylethylamine derivative.

[0064] (2) Separation and detection of (D)-camphorsulfonyl chloride and (RS)-1-NEA derivatives using the following different chromatographic conditions

[0065] 3-1: The (D)-camphorsulfonyl·(RS)-1-naphthylethylamine derivative was dissolved in mobile phase at a concentration of 50 μg / mL, and detected and analyzed by high performance liquid ch...

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Abstract

The invention relates to analysis method for the chiral purity of 1-naphthylethylamine. The analysis method comprises the following two steps of (1) derivatization and (2) separation and detection. The method is mild in condition, convenient and low in price. According to the analysis method, (D)-camphor sulfonyl chloride is taken as a derivatization reagent to carry out derivatization reaction with 1-NEA, the chiral purity of the D-camphor sulfonyl chloride and the derivative of the 1-NEA is analyzed through the combination of reversed-phase high performance liquid chromatography and an ultraviolet detector, so that the chiral purity of the 1-NEA is analyzed.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, in particular to a method for analyzing the chiral purity of 1-naphthylethylamine. Background technique [0002] 1-Naphthylethylamine (1-NEA) is an important chiral drug raw material, for example (R)-1-NEA is an important chiral intermediate of cinacalcet hydrochloride. Cinacalcet hydrochloride is a new type of oral calcimimetic agent developed by NPS Pharmaceuticals in the United States. It is the first calcimimetic agent approved by the FDA. Cinacalcet hydrochloride acts on the calcium receptors present on the surface of parathyroid cell membranes. Inhibition of parathyroid hormone secretion and serum Ca 2+ The concentration is similar when the concentration is increased. It is clinically used to treat secondary hyperparathyroidism in patients with chronic kidney disease (CKD) undergoing dialysis, and is also used to treat hypercalcemia in patients with parathyroid cancer. Since (R)-1-N...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/89G01N30/06G01N30/74
CPCG01N30/89G01N30/06G01N30/74
Inventor 陈梦孙凤霞孙玉娟王玉春杨浩
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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