High performance liquid chromatography and chiral mobile phase separated hydrochloric acid daclatasvir and five optical isomers thereof

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

Inactive Publication Date: 2018-08-31
覃叶枫
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] It can be seen that the method provided by Guo Feng et al. requires the use of e

Method used

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  • High performance liquid chromatography and chiral mobile phase separated hydrochloric acid daclatasvir and five optical isomers thereof
  • High performance liquid chromatography and chiral mobile phase separated hydrochloric acid daclatasvir and five optical isomers thereof
  • High performance liquid chromatography and chiral mobile phase separated hydrochloric acid daclatasvir and five optical isomers thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] 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%.

[0114] 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.

[0115] HPLC chromatographic parameters:

[0116] Chromatograph: Waters 2695 high performance liquid chromatograph;

[0117] Chromatographic column: Agilent ZORBAX Extend-C18 (250×4.6mm, 5μm);

[0118] Mobile phase A phase: acetonitrile aqueous solution with a volume percent concentration of 20%, containing 10 mM L-aspartic acid;

[0119] Mobile phase B phase: acetonitrile aqueous solution with a concentration of 80% by volume, conta...

Embodiment 2

[0127] 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%.

[0128] 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.

[0129] HPLC chromatographic parameters:

[0130] Chromatograph: Waters 2695 high performance liquid chromatograph;

[0131] Chromatographic column: Agilent ZORBAX Extend-C18 (250×4.6mm, 5μm);

[0132] Mobile phase A phase: acetonitrile aqueous solution with a concentration of 20% by volume, containing 10 mM (2R, 3R)-bis-n-propyl tartaric acid;

[0133] Mobile phase B phase: acetonitrile aqueous solution with a concentration of 80% b...

Embodiment 3

[0141] 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%.

[0142] 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.

[0143] HPLC chromatographic parameters:

[0144] Chromatograph: Waters 2695 high performance liquid chromatograph;

[0145] Chromatographic column: Agilent ZORBAX Extend-C18 (250×4.6mm, 5μm);

[0146] Mobile phase A phase: the volume percentage concentration is 20% acetonitrile aqueous solution, contains 10mM D-(+)-di-p-methylbenzoyl tartaric acid;

[0147] Mobile phase B phase: a volume percent concentration of 80% acetonitrile in wa...

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Abstract

The invention discloses a high performance liquid chromatography and chiral mobile phase separated hydrochloric acid daclatasvir and five optical isomers thereof. The high performance liquid chromatography and chiral mobile phase separated hydrochloric acid daclatasvir is characterized in that L-asparaginic acid, (2R, 3R)-dipropyl tartaric acid, D-(+)-Di-p-toluoyl-L-tartaric acid, (1R, 2R)-(-)-N-(p-methylphenylsulfonyl)-1, 2-diphenylethanediamine or L-valyl-L-tyrosine is used as an additive and added to the mobile phase, and a common C18 liquid chromatographic column can be utilized to effectively separate hydrochloric acid daclatasvir and five optical isomers thereof, and mutual baseline separation is achieved. The technicians in the field know that the chiral mobile phase is limited andcan only be used for separating limited compounds, and systemic theory guidance is not provided to guide any compound to be separated through the chiral mobile phase, and the chiral mobile phase for separating is only performed by 'trial and error' repeated testing and random exploring. Therefore, the method is not obvious to the technicians in the field and has the creativity as specified by thepatent law.

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 for the treatment of hepatitis C), 5 chiral isomers will be produced during the preparation of 1, 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, cR, dR...

Claims

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Application Information

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IPC IPC(8): G01N30/06
CPCG01N30/06G01N2030/065
Inventor 覃叶枫
Owner 覃叶枫
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