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High performance liquid chromatography resolution method of alkannin raceme and naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivative of alkannin raceme

A technology for nuclear hydroxymethylation of carbonyl oxime and racemate, which is applied in the field of separation of chiral drugs, and can solve problems such as differences in chemical structures and affecting the purity of target compounds.

Active Publication Date: 2021-04-16
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the chemical structure difference between shikonin racemate and its naphthalene mother nucleus hydroxymethylated carbonyl oxime derivative racemate and Boc hydroxyadamantane amino acid cannot be used with the chiral column and Conditions for chromatographic resolution
[0007] In addition, in some methods for HPLC resolution of racemates, acidic and basic reagents, such as diethylamine and trifluoroacetic acid, are often added to the mobile phase. Due to the high boiling point of these reagents, it is difficult to extract from the collected Removed during dehydration, affecting the purity of the target compound
At present, there is no method for efficient resolution and separation and purification of shikonin racemate and shikonin racemate naphthalene nuclei hydroxymethylated carbonyl oxime derivatives

Method used

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  • High performance liquid chromatography resolution method of alkannin raceme and naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivative of alkannin raceme
  • High performance liquid chromatography resolution method of alkannin raceme and naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivative of alkannin raceme
  • High performance liquid chromatography resolution method of alkannin raceme and naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivative of alkannin raceme

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1) Chromatographic separation of shikonin with high optical purity:

[0038] An appropriate amount of shikonin racemate (shikonin racemate was obtained from literature Terada A, Tanoue Y, HatadaA, et al.Synthesis of shikonin(±shikonin) and related compounds[J].Bulletin of the Chemical Society of Japan , 1987,60 (1): prepared by the method reported in 205-213) dissolved in 2mL chromatographic ethanol, the solution concentration is 2.5mg / mL, adopts semi-preparative high performance liquid chromatography to carry out separation and purification, chiral chromatographic column size is Φ20mm×250mm, amylose-tris[(S)-α-methylbenzylcarbamate] filler is a product of Shanghai Daicel Pharmaceutical Chiral Technology Co., Ltd., particle size is 5 μm, shikonin racemate The sample load was 50.0 μg, the mobile phase was n-hexane-isopropanol system (9:1, V / V), isocratic elution, the flow rate was 0.8mL / min, and the elution time was 12min. The detection wavelength of the ultraviolet pho...

Embodiment 2

[0042] 1) Chromatographic separation of shikonin with high optical purity:

[0043] Dissolve an appropriate amount of shikonin racemate in 2 mL of chromatographic ethanol, the solution concentration is 2.5 mg / mL, and use semi-preparative high-performance liquid chromatography for separation and purification. The chiral column size is Φ20mm×250mm, and amylose- Tris[(S)-α-methylbenzylcarbamate] filler is a product of Shanghai Daicel Pharmaceutical Chiral Technology Co., Ltd., with a particle size of 5 μm, and the loading amount of shikonin racemate is 5.0 mg, and the mobile phase It is n-hexane-isopropanol system (9:1, V / V), isocratic elution, flow rate is 18mL / min, elution time is 20min. The detection wavelength of the ultraviolet photometric detector adopted is 516nm, and R-(+)-shikonin is collected.

[0044] 2) Concentration and recrystallization to obtain R-(+)-shikonin with high optical purity

[0045] The collected eluate containing R-(+)-shikonin was concentrated to dry...

Embodiment 3

[0047] 1) Chromatographic resolution of the hydroxymethylated carbonyl oxime derivatives of the parent nucleus of Arkanine naphthalene with high optical purity:

[0048] Dissolve an appropriate amount of shikonin naphthalene alizarin parent nucleus hydroxymethylated carbonyl oxime derivative racemate (mixture of R-(-)-DMSKO-20 and S-(+)-DMAKO-20) with chromatographic ethanol, and prepare into a solution of 600 μg / mL, separated and purified by analytical high-performance liquid chromatography, the size of the chiral chromatographic column is Φ4.6mm×250mm, amylose-tri[(S)-α-methylbenzylcarbamate The ester] filler is a product of Shanghai Daicel Pharmaceutical Chiral Technology Co., Ltd., the particle size is 5 μm, the loading amount of the racemate is 60.0 μg, and the mobile phase is n-hexane-isopropanol system (9:1, V / V). Isocratic elution, flow rate 0.8mL / min, elution time 15min. The detection wavelength of the ultraviolet photometric detector that adopts is 318nm, collects S...

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Abstract

The invention discloses a high performance liquid chromatography resolution method of alkannin raceme and naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivatives thereof, which comprises the following steps: using high performance liquid chromatography, using amylose-tris [(S)-alpha-methyl benzyl carbamate] as a filler and an n-hexane-isopropanol mixed solvent as a mobile phase, separating high-purity R-(+)-alkannin from an alkannin raceme, separating high-purity S-(+)-alkannin naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivatives from an alkannin raceme naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivative, and combining a certain separation and purification means. Therefore, the production efficiency of R-(+)- alkannin is improved, and the efficiency of producing the optically pure alkannin naphthazarin parent nucleus hydroxyl methylated carbonyl oxime derivative by using an intermediate resolution method is improved.

Description

technical field [0001] The invention relates to a resolution method of chiral drugs, in particular to the resolution of shikonin racemate and naphthalene nuclei hydroxymethylated carbonyl oxime derivatives by high performance liquid chromatography. Background technique [0002] Lithospermum erythrorhizon belongs to the perennial medicinal herb of the family Boraginaceae. It grows spontaneously in mountains and fields. Because its flowers, roots and bark are purple, it is named "Lithospermum". Comfrey was first recorded in "Shen Nong's Materia Medica", and was listed as a middle-grade product. It has a "bitter taste and cold nature". Comfrey is also recorded in "Compendium of Materia Medica", "The flowers are purple, the roots are purple, and they can be dyed purple, so it is named." Comfrey is a commonly used clinical traditional Chinese medicine recorded in Pharmacopoeia I. It has the functions of cooling blood, promoting blood circulation, detoxifying and treating rashes....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C46/10C07C50/32C07C249/14C07C251/46C07B57/00
Inventor 丁莉坤崔家华杨燕钱嘉珺
Owner FOURTH MILITARY MEDICAL UNIVERSITY