Determination method of excess rate of 1-NEA enantiomers

Abstract

The invention relates to a method for determining the excess rate of 1-NEA enantiomers. The method comprises the following steps of: (1) derivatization, and (2) separation and detection. According to the method, (S)-naproxen acyl chloride is adopted as a derivatization reagent to be subjected to a rapid derivatization reaction with the 1-NEA, and then the (S)-naproxen acyl-1-NEA is subjected to qualitative analysis, quantitative analysis and enantiomer excess rate determination by using common reversed-phase HPLC-UV. The method is simple, fast, effective and low in cost.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, and in particular relates to a method for measuring the excess rate of 1-NEA enantiomer. Background technique [0002] 1-Naphthylethylamine (1-NEA) is an important chiral intermediate of the new oral calcimimetic agent cinacalcet hydrochloride, and (R)-1-NEA is the only chiral intermediate of (R)-cinacalcet hydrochloride Therefore, the determination of the enantiomeric excess ratio of 1-NEA has important theoretical and practical significance for the preparation of cinacalcet hydrochloride with high optical purity. [0003] Chiral chromatographic column analysis is the main method for determining the enantiomer excess rate of 1-NEA, and the result of this method is accurate and reliable. Zhang Feng et al. (West China Pharmaceutical Journal, 2014,29(01):75-76) adopted Daicel Chirlcel OJ-H (250mm×4.6mm, 5μm) chiral chromatographic column, mobile phase was 95% n-hexane+5% ethanol+ 0.1% ethan...

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Problems solved by technology

(Analytica Chimica Acta, 2013,773:76-82) such as Mochizuki adopts L-PGA as chiral derivatization reagent, uses acetonitrile and water as mobile phase on UPLC, and the retention time of derivative product is respectively 8.58min and 9.03min, although The retention time of the derivative product is shortened, but the derivatization process uses EDC and HOBt as condensing agents, which has the problem of poor atom economy

[0005] 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

[0006] (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

[0007] (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 reagents; 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

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