High performance liquid chromatography chiral mobile phase method for separation of daclatasvir hydrochloride and five optical isomers thereof

A technology of high performance liquid chromatography and optical isomers, which is applied in the field of drug analysis, separation of daclatasvir hydrochloride and its five optical isomers by high performance liquid chromatography chiral mobile phase method, can solve the problem of high cost and applicable sexual inferiority

Inactive Publication Date: 2018-12-07
覃叶枫
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] It can be seen that the method provided by Guo Feng et al. requires the help ...

Method used

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  • High performance liquid chromatography chiral mobile phase method for separation of daclatasvir hydrochloride and five optical isomers thereof
  • High performance liquid chromatography chiral mobile phase method for separation of daclatasvir hydrochloride and five optical isomers thereof
  • High performance liquid chromatography chiral mobile phase method for separation of daclatasvir hydrochloride and five optical isomers thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] 1 (aS, bS, cS, dS type), 2 (aR, bS, cS, dS type), 3 (aS, bS, cR, dS type), 4 (aR, bS, cS, dR type), 5 ( aS, bR, cR, dS type) and 6 (aR, bR, cR, dR type) reference substances are self-made or purchased, and the purity is not less than 98%.

[0116] Preparation of mixed reference substance solution: Accurately weigh 10 mg each of 1-6 reference substances, put them in a 20ml measuring bottle, dissolve with acetonitrile and constant volume, and shake well to obtain a mixed control with a concentration of 0.5 mg / ml for 1-6 product solution.

[0117] HPLC chromatographic parameters:

[0118] Chromatograph: Waters 2695 high performance liquid chromatograph;

[0119] Chromatographic column: Agilent ZORBAX Extend-C18 (250×4.6mm, 5μm);

[0120] Mobile phase A phase: acetonitrile aqueous solution with a volume percent concentration of 20%, containing 10 mM L-aspartic acid;

[0121] Mobile phase B phase: acetonitrile aqueous solution with a concentration of 80% by volume, conta...

Embodiment 2

[0129] 1 (aS, bS, cS, dS type), 2 (aR, bS, cS, dS type), 3 (aS, bS, cR, dS type), 4 (aR, bS, cS, dR type), 5 ( aS, bR, cR, dS type) and 6 (aR, bR, cR, dR type) reference substances are self-made or purchased, and the purity is not less than 98%.

[0130] Preparation of mixed reference substance solution: Accurately weigh 10 mg each of 1-6 reference substances, put them in a 20ml measuring bottle, dissolve with acetonitrile and constant volume, and shake well to obtain a mixed control with a concentration of 0.5 mg / ml for 1-6 product solution.

[0131] HPLC chromatographic parameters:

[0132] Chromatograph: Waters 2695 high performance liquid chromatograph;

[0133] Chromatographic column: Agilent ZORBAX Extend-C18 (250×4.6mm, 5μm);

[0134] Mobile phase A phase: acetonitrile aqueous solution with a concentration of 20% by volume, containing 10 mM (2R, 3R)-bis-n-propyl tartaric acid;

[0135] Mobile phase B phase: acetonitrile aqueous solution with a concentration of 80% b...

Embodiment 3

[0143]1 (aS, bS, cS, dS type), 2 (aR, bS, cS, dS type), 3 (aS, bS, cR, dS type), 4 (aR, bS, cS, dR type), 5 ( aS, bR, cR, dS type) and 6 (aR, bR, cR, dR type) reference substances are self-made or purchased, and the purity is not less than 98%.

[0144] Preparation of mixed reference substance solution: Accurately weigh 10 mg each of 1-6 reference substances, put them in a 20ml measuring bottle, dissolve with acetonitrile and constant volume, and shake well to obtain a mixed control with a concentration of 0.5 mg / ml for 1-6 product solution.

[0145] HPLC chromatographic parameters:

[0146] Chromatograph: Waters 2695 high performance liquid chromatograph;

[0147] Chromatographic column: Agilent ZORBAX Extend-C18 (250×4.6mm, 5μm);

[0148] Mobile phase A phase: acetonitrile aqueous solution with a volume percentage concentration of 20%, containing 10mM D-(+)-di-p-toluyl tartaric acid;

[0149] Mobile phase B phase: acetonitrile aqueous solution with a concentration of 80%...

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Abstract

The invention discloses a high performance liquid chromatography chiral mobile phase method for separation of daclatasvir hydrochloride and five optical isomers thereof. The daclatasvir hydrochlorideand the five optical isomers thereof can be effectively separated by adding of L-aspartic acid, (2R, 3R) bis-n-propyl tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, and (1R, 2R)-(-)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine or L-valyl-L-tyrosine as additives to a mobile phase by use of a common C18 liquid chromatography column, and baseline resolution of every two of the daclatasvir hydrochloride and the five optical isomers thereof can be achieved. Persons skilled in the art know that a chiral mobile phase method is very limited in that and only a limited number of compounds can beseparated, no systematic theory can guide which compounds can be separated by the chiral mobile phase method, and only a trial-and-error method can be used for repeatedly trying and groping without rules. Accordingly, the high performance liquid chromatography chiral mobile phase method has obvious creativity prescribed by the patent law for the persons skilled in the art.

Description

technical field [0001] The invention belongs to the field of medicine and relates to drug analysis, in particular to a high-performance liquid chromatography chiral mobile phase method for separating daclatasvir hydrochloride and five optical isomers thereof. Background technique [0002] Daclatasvir dihydrochloride (1), chemical name N, N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl -(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-1,2-ethanediyl]]]dicarbamic acid dimethyl Ester dihydrochloride is a non-structural protein 5A (NS5A) inhibitor and an anti-hepatitis C virus drug. [0003] 1 (type aS, bS, cS, dS) contains 4 chiral centers. According to literature reports (Chinese patent, CN101778841A, method for synthesizing compounds used to treat hepatitis C), 5 chiral isomers will be produced during the preparation of 1, which are respectively 2(aR, bS, cS, dS type), 3 (type aS, bS, cR, dS), 4 (type aR, bS, cS, dR), 5 (type aS, bR, cR, dS) and 6 (type aR, bR,...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06B01D15/38
CPCG01N30/02B01D15/3833G01N30/06G01N2030/065
Inventor 覃叶枫
Owner 覃叶枫
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