A kind of purification method of valrubicin

A technology of valrubicin and a purification method, which is applied in the field of purification of valrubicin, can solve problems such as unclear single impurity content, high single impurity content, and large environmental pollution, and achieve simple and easy process, good effect, The effect of little environmental pollution

Active Publication Date: 2021-12-17
SEPAX TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent CN103694291A and patent CN108484689A both involve the purification of crude valrubicin, which are separated and purified by normal phase column chromatography, which adopts normal pressure adsorption and normal pressure elution, which is time-consuming, laborious, complicated to operate, and used in large quantities The organic solvent dichloromethane and ethyl acetate, the environmental pollution is big
Pure valrubicin purified by normal phase column chromatography has acceptable purity, but the content of simple impurities is not clear, and the content of simple impurities is relatively high

Method used

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  • A kind of purification method of valrubicin
  • A kind of purification method of valrubicin
  • A kind of purification method of valrubicin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1 valrubicin crude product purification

[0045] Chromatographic column: valrubicin preparative column (100mm x 250mm) (the filler used is silica gel bonded with octadecylsilane and divinylbenzene)

[0046] mobile phase:

[0047] A: 0.1% formic acid aqueous solution B: Methanol (containing 0.1% formic acid)

[0048] Flow rate: 400ml / min Injection volume: 400ml Column temperature: room temperature

[0049]Sample: 100mg / ml Pressure: 1.2M Pa

[0050] Instrument: Sepax preparative chromatograph

[0051] Detection wavelength: UV@254nm

[0052] Isocratic elution: 75% B

[0053] The specific method is as follows:

[0054] 1. Sample weighing: weigh 40 g (4.8% load) of valrubicin crude product on an analytical balance;

[0055] 2. Solvent preparation: prepare 400ml of 75% methanol aqueous solution containing 0.1% formic acid, measure 328ml of methanol, 72ml of purified water, and measure 400ul of formic acid with a pipette gun. Mix the three together and stir ...

Embodiment 2

[0095] Using the same preparative chromatograph, preparative column and elution method as in Example 1

[0096] Get content 86.09% (m / m) valrubicin crude product 40g, add the 80% methanol aqueous solution (V / V) 400ml that contains 0.1% trifluoroacetic acid, stir and make fully dissolving; Go through 80% methanol (containing 0.1 % trifluoroacetic acid) aqueous solution equilibrated valrubicin chromatography column (100mm * 250mm, about 0.98kg containing filler quality), loading flow rate 200ml / min, with 80% methanol (containing 0.1% trifluoro Acetic acid) and 20% aqueous solution containing 0.1% trifluoroacetic acid elution, elution flow rate 400ml / min, elution 85min altogether, HPLC detects and collects valrubicin component solution, merges qualified components, obtains valrubicin after freeze-drying The pure product of rubicin was 26.67g, the purity detected by HPLC was 99.87%, and the recovery rate was 66.68%.

Embodiment 3

[0098] Get valrubicin crude product 85g (purity 96.5%), add the aqueous solution 800ml that contains the 80% methyl alcohol (V / V) of 0.1% trifluoroacetic acid, stir and make fully dissolving; Trifluoroacetic acid) equilibrated valrubicin preparation column (100mm * 250mm, containing about 0.98kg of filler quality), sample loading flow rate 200ml / min, use 80% methyl alcohol (containing 0.1% trifluoroacetic acid) and 20% aqueous solution containing 0.1% trifluoroacetic acid was eluted, the elution flow rate was 400ml / min, the elution flow rate was 400ml / min, and the total elution was 85min. The valrubicin component solution was collected by HPLC detection, and the data of each component after HPLC detection As shown in Table 4:

[0099] Table 4

[0100] mass (g) Recovery rate(%) Crude 85.00 -- Purity≥99.5 76.37 89.85 Purity ≥ 99.5, and simple impurity 69.15 81.35

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Abstract

The invention provides a method for purifying valrubicin, comprising: purifying and separating the solution containing crude valrubicin through a preparative chromatograph to obtain purified valrubicin, wherein, by purifying and separating The eluent is composed of water, organic phase and acid; and the acid is formic acid, acetic acid, phosphoric acid or trifluoroacetic acid; the organic phase is methanol or ethanol; the elution mode of purification and separation is isocratic elution and the The volume percent content of the organic phase in the eluent is 65%-90%. Furthermore, the purification and separation effect of the present invention is good, and the purity of the obtained purified valrubicin can reach more than 99.8%, the single impurity is less than 0.1%, and the yield can reach more than 66%. Moreover, the preparation by the preparation liquid phase takes short time, and the solvent is easy to recycle, and the environmental pollution is small. Moreover, the method has been scaled up through a pilot test, and the process is simple and easy to implement, and is suitable for industrial scale-up production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for purifying valrubicin. Background technique [0002] Valrubicin, orange-yellow or orange-red powder, is an anthracycline drug for the treatment of BCG-refractory bladder carcinoma in situ. With strong lipophilicity, it is easily soluble in dichloromethane, acetone, methanol, ethyl acetate and absolute ethanol, slightly soluble in n-hexane, n-pentane, heptane and petroleum ether, and almost insoluble in water. Valrubicin molecular formula is: C 34 h 36 f 3 NO 13 , Molecular weight: 723.6, the molecular structure is shown in Formula 1: [0003] [0004] Valrubicin is an anthracycline drug whose main mechanism of action is to interfere with normal DNA division and recombination, thereby affecting various biological functions of cells. The main performance is to interfere with the metabolism of nucleic acids: valrubicin can easily penetrate into cells, and furthe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): B01D15/42G01N30/02G01N30/06G01N30/34G01N30/74
Inventor 贺元康王艺
Owner SEPAX TECH
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