CN1696135A

CN1696135A - Method for purifying Vinorelbine Bitartrate

Info

Publication number: CN1696135A
Application number: CN 200510009928
Authority: CN
Inventors: 祖元刚; 付玉杰; 张琳; 史权; 刘君星; 李庆勇; 祖柏实; 曹玉杰
Original assignee: Northeast Forestry University
Current assignee: Northeast Forestry University
Priority date: 2005-04-26
Filing date: 2005-04-26
Publication date: 2005-11-16
Anticipated expiration: 2025-04-26
Also published as: CN100374445C

Abstract

A process for purifying vinorelbine includes preparing silica gel column, negative-pressure chromatography by filling liquid from its bottom, segmental cutting, eluting, filtering, low-temp vacuum concentrating, dripping it in water to obtain crystals, centrifugal depositing, and drying the deposit.

Description

A kind of method of purifying Vinorelbine Bitartrate

Affiliated technical field:

The present invention relates to a kind of Vinorelbine purifying process.Be particularly related to a kind of method of utilizing negative pressure ascending chromatography mode purifying Vinorelbine Bitartrate.

Background technology:

Vinorelbine is treatment nonsmall-cell lung cancer in late period (NSCLC) patient's of U.S. food Drug Administration (FDA) approval a medicine, the Vinorelbine of single preparation and cis-platinum share becomes the lung cancer in non-cellule type in unresectable late period patient's first-line treatment medicine, also be choice drug aspect treatment mammary cancer, lymphatic cancer, the ovarian cancer, its market value costliness.The existing market source mainly obtains by the chemosynthesis approach, and purity is not very high, the present invention is directed to this problem, has sought out a kind of purification process that carries out scale operation, therefore has good DEVELOPMENT PROSPECT.

1974, Vinorelbine was synthetic by French scholar Potier, tries out in clinical treatment in 1985.According to the literature, Mangeney P, Andriamialisoa RZ etc. synthesize Vinorelbine and salt thereof with different methods, and the research of its separation and purification aspect does not appear in the newspapers.At present, the study on the synthesis of China's Vinorelbine has also had very big breakthrough, and the synthesis technique that Lin Yongjiang etc. will abroad report improves, and makes operation be more suitable for producing; Professor You Qidong of China Medicine University waits " Vinorelbine new synthetic process and industrialization research " project of bearing to obtain Jiangsu Province's scientific and technological progress third prize.The separation and purification aspect, Lin Yongjiang etc. carry out the malleation column chromatography for separation twice with synthetic Vinorelbine crude product, get product HPLC normalization method purity and reach more than 98%, but it exists the purifying amount few, and efficient is low, and shortcomings such as cycle length can't be carried out suitability for industrialized production.

The present invention adopts, and the up column chromatography method of quick, simple, easy-operating negative pressure comes the purifying Vinorelbine Bitartrate crude product, the higher part of purity is cut the back wash-out obtain the higher Vinorelbine of purity.This purification process can shorten the purifying cycle greatly, saves solvent load, can remedy long, deficiency such as solvent load is big of descending column chromatography cycle of traditional malleation.

Summary of the invention:

The object of the invention is to provide the Vinorelbine that a kind of technical process is simple, with short production cycle, cost is low, purity is high new technology for purifying.

In order to achieve the above object, the technical solution used in the present invention is: the Vinorelbine crude product is after dried silicagel column carries out the negative pressure ascending development, carry out segmentation cutting, wash-out, elutriant after filtration, concentrate concentrated solution, concentrated solution is splashed into crystallization in the water, centrifugal, get highly purified Vinorelbine after the drying.

Advantage of the present invention:

1, it is simple, with short production cycle to have a technical process, and solvent load is few, can carry out advantages such as suitability for industrialized production;

2, Vinorelbine purity is more than 95%;

3, replaced purification process such as traditional normal pressure is descending, decompression is descending, the descending column chromatography of pressurization, application of negative pressure concussion collumn-pouring machine dried preparation silicagel column and the up column chromatography method of negative pressure carry out purifying to the Vinorelbine crude product.

Specific embodiments:

Below embodiment of the present invention are described in further detail:

With negative pressure vibration collumn-pouring machine dried preparation silicagel column, column length is 45cm～55cm, diameter is 3cm～5cm, the post material is hollow PVC post, and up and down or horizontal negative pressure vibration perfusion silica gel, the concussion frequency is 50～100 times/min, negative pressure is 0.06～0.1MPa, silica gel is 400～800 orders activated silica gels, and activation method is the high fire activation of baking oven 105 ℃ of activation, 1～5h or microwave oven 3 times, each 3min; This silicagel column is carried out the negative pressure ascending development, the bottom feed liquor, with difference of altitude or self-priming mode ascending development, negative pressure is 0.06～0.1MPa, developping agent is a trichloromethane: methyl alcohol=250: 18～325: 18 or tetracol phenixin: methyl alcohol=100: 15～50: 15; With purity is that 50～80% Vinorelbine crude product is dissolved in the developping agent of 0.3～0.7ml, with automatic sampling valve or syringe from the column bottom sample injection; After opening up capital, 8～15cm upwards cuts in 4～8cm place portion at the bottom of the post; With anhydrous propanone, anhydrous methanol or dehydrated alcohol is ultrasonic or stir wash-out 2～5 times, the eluent consumption is 150～500ml/ time with the silica gel section, and elution time is 5～30min/ time; Elutriant carries out negative pressure leaching with tubular fibre or the millipore filtration of 0.22 μ m, and the employing negative pressure is 0.06～0.1MPa; Elutriant is carried out low-temperature negative-pressure concentrate, temperature is 30～50 ℃, and negative pressure is 0.06～0.1MPa; Then concentrated solution is splashed in its distilled water or distilled water of 3～15 times, separates out white cotton-shaped crystallization, after centrifugal white precipitate; This white precipitate is carried out lyophilize or vacuum-drying, get white cotton-shaped Vinorelbine.

Embodiment 1

The hollow PVC post of getting long 50cm, diameter and be 3cm pours into activated silica gel with negative pressure vibration collumn-pouring machine dry method, concussion up and down, and frequency is 70 times/min, the silica gel activating mode is 105 ℃ of activation of baking oven 1.5h; The silicagel column upper end is connected the zone of negative pressure analysis apparatus, the lower end connects the developping agent device, the developping agent container is hung in the post upper end, produce difference of altitude, carry out the negative pressure ascending development, developping agent is a trichloromethane: methyl alcohol=300: 18, bottom injector to inject sample introduction, sample are that the Vinorelbine crude product of 0.4g70% is dissolved in the solution in the developping agent of 0.4ml; After opening up capital, cut apart from 8cm place, post bottom upwards 10cm part, use the ultrasonic wash-out of 250ml dehydrated alcohol 3 times, each 10min merges elutriant; After elutriant carries out negative pressure leaching with the tubular fibre of 0.22 μ m, under 40 ℃, carry out negative pressure and concentrate, concentrated solution 3ml splashes in the 30ml distilled water, separate out white flocks, centrifugal postlyophilization, purity is 98% Vinorelbine 112mg.

Embodiment 2

The hollow PVC post of getting long 45cm, diameter and be 3cm pours into activated silica gel with negative pressure vibration collumn-pouring machine dry method, adds the level concussion up and down, and frequency is 80 times/min, and activation method is 105 ℃ of activation of baking oven 3h; The silicagel column upper end is connected the zone of negative pressure analysis apparatus, the lower end connects the developping agent device, the developping agent container is hung in the post upper end, produce difference of altitude, carry out the negative pressure ascending development, developping agent is a trichloromethane: methyl alcohol=250: 18, bottom automatic sampling valve injection, sample are that the Vinorelbine crude product of 0.3g77% is dissolved in the solution in the developping agent of 0.3ml; After opening up capital, cut apart from 4cm place, post bottom upwards 10cm part, use the ultrasonic wash-out of 300ml anhydrous methanol 2 times, each 20min merges elutriant; After elutriant carries out negative pressure leaching with the tubular fibre of 0.22 μ m, under 35 ℃, carry out negative pressure and concentrate, concentrated solution 3ml splashes in the 40ml distilled water, separate out white flocks, centrifugal postlyophilization, purity is 96% Vinorelbine 99mg.

Embodiment 3

The hollow PVC post of getting long 55cm, diameter and be 3cm pours into activated silica gel with the negative pressure vibration collumn-pouring machine in method, concussion up and down, and frequency is 90 times/min, activation method is the high fire activation of microwave oven 3 times, each 3min; The silicagel column upper end is connected the zone of negative pressure analysis apparatus, the lower end connects the developping agent device, developping agent container and silicagel column are in same level, automatically suck developping agent by suction function, carry out the negative pressure ascending development, developping agent is a tetracol phenixin: methyl alcohol=100: 20, bottom automatic sampling valve injection, sample are that the Vinorelbine crude product of 0.5g70% is dissolved in the solution in the developping agent of 0.5ml; After opening up capital, cut apart from 6cm place, post bottom upwards 12cm part, stir wash-out 2 times with the 350ml anhydrous methanol, each 15min gets elutriant; After elutriant carries out negative pressure leaching with the millipore filtration of 0.22 μ m, under 45 ℃, carry out negative pressure and concentrate, concentrated solution 3ml splashes in the 50ml distilled water, separate out white flocks, centrifugal final vacuum drying, temperature are 40 ℃, purity is 95% Vinorelbine 158mg.

Claims

1, a kind of the Vinorelbine crude product is carried out the novel method of purifying, it is characterized in that:, this silicagel column is carried out the negative pressure ascending development, from the column bottom feed liquor with negative pressure vibration collumn-pouring machine dried preparation silicagel column; Sample injection after opening up capital, carries out the segmentation cutting; Use the eluent wash-out for silica obtained section, elutriant filters; Get filtrate and carry out concentrating under reduced pressure, concentrated solution splashes in the water, separates out crystallization, and is centrifugal; Precipitation is carried out the dry white powder that gets.

2, be meant that according to the described negative pressure vibration collumn-pouring machine of claim 1 dried preparation silicagel column column length is that 45cm～55cm, diameter are the hollow PVC post of 3cm～5cm, through up and down or horizontal oscillator carry out negative pressure vibration perfusion 400～800 orders activated silica gel, the concussion frequency is 50～100 times/min, the employing negative pressure is 0.06～0.1MPa, the silica gel activating method is the high fire activation of baking oven 105 ℃ of activation, 1～5h or microwave oven 3 times, each 3min.

3, be meant that according to the described negative pressure ascending development of claim 1 the silicagel column upper end connects the zone of negative pressure analysis apparatus, the employing negative pressure is 0.06～0.1MPa; The lower end connects the developping agent device, and the bottom feed liquor carries out ascending development with difference of altitude or self-priming mode; Developping agent is a trichloromethane: methyl alcohol=250: 18～325: 18 or tetracol phenixin: methyl alcohol=100: 15～50: 15.

4, be meant according to the described column bottom of claim 1 sample injection 0.3～0.6g Vinorelbine crude product be dissolved in the developping agent of 0.3～0.7ml that with automatic sampling valve or injector to inject sample introduction, Vinorelbine crude product purity is 50～80%.

5, be that 8～15cm is upwards cut at 4～8cm place, span post bottom according to the described segmentation cutting of claim 1.

6, be meant ultrasonic according to the described eluent wash-out of claim 1 or the stirring wash-out, eluent is anhydrous propanone, anhydrous methanol or dehydrated alcohol, and the eluent consumption is 150～500ml/ time, and elution time is 5～30min/ time, and the wash-out number of times is 2～5 times.

7, be meant that according to the described filtration of claim 1 tubular fibre or millipore filtration with 0.22 μ m carry out negative pressure leaching, the employing negative pressure is 0.06～0.1MPa.

8, be that temperature is 30～50 ℃ according to the described concentrated condition of claim 1, negative pressure is 0.06～0.1MPa.

9, be meant according to the described crystallization of claim 1 concentrated solution splashed in its distilled water or distilled water of 3～15 times, after centrifugal white precipitate.

10, according to described dry the white powder of claim 1 for to carry out cryodrying with freeze drier or vacuum drying oven.