CN104529951A - Preparation method for natural paclitaxel - Google Patents
Preparation method for natural paclitaxel Download PDFInfo
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- CN104529951A CN104529951A CN201410749059.0A CN201410749059A CN104529951A CN 104529951 A CN104529951 A CN 104529951A CN 201410749059 A CN201410749059 A CN 201410749059A CN 104529951 A CN104529951 A CN 104529951A
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Abstract
A disclosed preparation method for natural paclitaxel comprises the following steps: (1) pretreatment; (2) leaching; (3) concentration; (4) extraction; (5) chromatographic separation, namely, dissolving total terpenoids in a little amount of an organic solvent, mixing with macroporous resin with the volume amount same to that of the extractum, applying the sample to a column in a dry manner, and adding an organic solvent with a certain concentration for elution, so as to obtain corresponding eluate fractions, recovering the solvent at a normal pressure, performing reduced-pressure concentration to obtain a concentrate II, using dichloromethane to perform extraction on the concentrate II, injecting the extraction phase into a concentration tank, and concentrating to obtain an extractum which is a paclitaxel crude extractive;and (6) preparation. The preparation method has the advantages of low cost, operation convenience and high efficiency. A preparation type high performance liquid chromatography separating purifying system further makes up shortage of purification degree of a resin method. A conventional paclitaxel extraction technology restricted to small batch is broken through, the disclosed preparation method guarantees high separation efficiency, and enables the recovery rate to be about 70% and enables the product purity to reach 99.0%.
Description
Technical field
The present invention relates to the extraction process of taxol in field of fine chemical, particularly a kind of preparation method of natural Japanese yew alcohol.
Term implication involved in this patent document:
Than weight average with the density 1g/cm3 of pure water under the normal conditions.
The implication of V/M is volume/mass, specifically represents cm3/g; L/kg; M3/t.
The implication of M/M is mass/mass, specifically represents g/g; Kg/kg; T/t.
The implication of V/V is volume/volume, specifically represents cm3/cm3; L/L; M3/m3;
Normal temperature and pressure is temperature, pressure under the normal conditions;
Except this otherwise noted.
Background technology
Ramulus et folium taxi cuspidatae, has another name called Japanese yew, Taxus.Ramulus et folium taxi cuspidatae has been through the ancient few survivors seeds that quaternary glacier carries over, on earth the history of existing 2,500,000 years.Ramulus et folium taxi cuspidatae is also generally acknowledge endangered natural rare plants for anticancer in the world simultaneously, can extract a kind of bearing taxanes, i.e. taxol from its bark and branches and leaves, has remarkable effect to anticancer division.
Taxol is a kind of diterpenes Taxan, and molecular formula is: C47H51NO14, molecular weight: 853. 9, its chemical structural formula as shown in the formula, be crystallization or the powder of near-white odorless, tasteless in appearance, water insoluble, be soluble in the organic solvents such as acetone, chloroform, ether.
Taxol has unique mechanism of action, Absorbable organic halogens microtubule, prevent microtubule depolymerization, microtubule is no longer separated, the organic cleavage of T suppression cell, cause the tumour cell of division to be fast firmly fixed at mitotic stages, cell capable of blocking is in G2 and the M phase of cell cycle, cancer cells is copied blocked and dead, thus the fissiparity of anticancer.Indicate according to current result of study, taxol has significant curative effect to drug refractory ovarian cancer and metastatic breast cancer, non-small cell carcinoma, also there is better therapeutic action to B16 melanoma, S180 sarcoma and P338, L1210, IIL60, P1534 leukemia, also have certain curative effect to incidence cancer, esophagus cancer.
Due to the anticancer mechanism of taxol uniqueness, cause the special concern of whole world the world of medicine, become the most fast-selling most important PTS with broad spectrum after Zorubicin and cis-platinum, at present tens country's listings.But what be worth emphasis is that taxol content in Ramulus et folium taxi cuspidatae is extremely low, the separation purification method of usual employing is resin column chromatography, lower relative to supercritical extraction cost because of it, and be easier to realize extension production, but its degree of purification is then relatively low in existing technology.
Summary of the invention
For solving the problem, the invention discloses a kind of preparation method of natural Japanese yew alcohol, transformation efficiency is high, and technique is simply rigorous, is easy to expanding production, adopts preparative high performance liquid phase equipment to make to extract the finished product purity height impurity obtained few.And it is simple to have technique, requires low to solvent strength, solvent high-efficiency recycle can be realized aborning, pollution-free, environmentally friendly, effectively reduce production cost.
The preparation method of natural Japanese yew alcohol disclosed by the invention comprises the steps: (1) pre-treatment: Ramulus et folium taxi cuspidatae is broken into meal; (2) leach: meal step (1) obtained leaches 3 times with the alcoholic solvent below appropriate three carbon or the ketones solvent below five carbon and gets leaching liquid respectively, merges three leaching liquids; (3) concentrated: the leaching liquid after step (2) being merged, through being evaporated to striking point, obtains concentrated solution I; (4) extract: repeatedly extract concentrated solution I with methylene dichloride, be concentrated into solvent-free after extraction phase is merged at ambient pressure, and then under vacuo, be evaporated to striking point; Again with normal hexane re-extract, be concentrated into without normal hexane under normal pressure after removing extraction phase, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract; (5) chromatographic separation: by total note medicinal extract with a small amount of organic solvent dissolution, admix the macroporous resin with medicinal extract equal-volume times amount, sample dry method upper prop, add certain density organic solvent and carry out wash-out, obtain normal pressure recycling design after corresponding flow point, concentrating under reduced pressure, obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, be i.e. taxol crude extract; (6) prepare: a small amount of acetone solution of taxol crude extract step (5) obtained, obtained containing taxol flow point by preparative high performance liquid chromatography instrument, concentrating under reduced pressure is drained and is obtained taxol finished product.
The one of the preparation method of natural Japanese yew alcohol disclosed by the invention is improved, in step (1), Ramulus et folium taxi cuspidatae pulverize after granularity be 30-50 order (taxus chinensis powder mince granularity excessive time, because of inadequate with the impregnating depth of solvent, and cause leaching insufficient, affect leaching efficiency; Then easily there is reunion accumulation viscous in a solvent and not easily infiltrated in crushed material undersized, be difficult to fully contact with solvent, and easy knot tying, easy and wall bonds, mix and blend operation easier is large), in crushing process, keep pulverizing room temp must not more than 60 DEG C.
The one of the preparation method of natural Japanese yew alcohol disclosed by the invention is improved, and step (2) extracting solvent is methyl alcohol or ethanol or acetone, and the solvent adding amount of three leachings is 3 ~ 5 times amount (V/M) dropping into raw material, and each leaching time is 24 hours.
The one of the preparation method of natural Japanese yew alcohol disclosed by the invention is improved, and in step (3), concentrating under reduced pressure terminal is the proportion of feed liquid is 1.00-1.02, and the temperature of concentrating under reduced pressure process remains on less than 40 DEG C.
The one of the preparation method of natural Japanese yew alcohol disclosed by the invention is improved, and in step (4), it is 4-6 time that methylene dichloride extracts concentrated solution I number repeatedly; Normal hexane repeatedly extraction times is 2-4 time.
The one of the preparation method of natural Japanese yew alcohol disclosed by the invention is improved, methylene dichloride extracts and after normal hexane extracts repeatedly repeatedly in step (4): the concentrated temperature of normal pressure all remains on less than 55 DEG C, and the temperature of the vacuum-concentrcted after normal pressure concentrates all remains on less than 40 DEG C.
The one of the preparation method of natural Japanese yew alcohol disclosed by the invention is improved, in step (5), dissolving organic solvent used is chloroform-methanol double solvents (chloroform-methanol mixed solution: 100:0 ~ 92:8, or acetone or methyl alcohol V/V), organic solvent add-on is 1-2 times (V/M) of medicinal extract amount, control the every flow point 50mL of gradient elution, flow velocity is every flow point 15min; Concentrating under reduced pressure temperature controls below 60 DEG C, and concentration process must not have precipitate.
The one of the preparation method of natural Japanese yew alcohol disclosed by the invention is improved, in step (6), preparation liquid phase chromatographic column used is industrial preparative liquid chromatography post (4000mm × 200mm), and moving phase is acetone/water=40:60 ~ 58:42 (V/V), and flow velocity is 2L/min.
The preparation method of natural Japanese yew alcohol disclosed by the invention, there is cost low, operate simple and easy and that efficiency is high advantage, the solvent species used in technique is few, all recyclable, and can apply mechanically front and back, reduce production cost, preparative high performance liquid chromatography separation and purification system is adopted to ensure that product purity is high, impurity level.
Accompanying drawing explanation
The process flow sheet of the preparation method of Fig. 1, natural Japanese yew alcohol disclosed by the invention.
Embodiment
Below in conjunction with the drawings and specific embodiments, illustrate the present invention further, following embodiment should be understood and be only not used in for illustration of the present invention and limit the scope of the invention.It should be noted that, the word "front", "rear" of use is described below, "left", "right", "up" and "down" refer to direction in accompanying drawing, word " interior " and " outward " refer to the direction towards or away from particular elements geometric centre respectively.
The preparation method of natural Japanese yew alcohol disclosed by the invention comprises the steps: (1) pre-treatment: Ramulus et folium taxi cuspidatae is broken into meal; (2) leach: meal step (1) obtained leaches 3 times with the alcoholic solvent below appropriate three carbon or the ketones solvent below five carbon and gets leaching liquid respectively, merges three leaching liquids; (3) concentrated: the leaching liquid after step (2) being merged, through being evaporated to striking point, obtains concentrated solution I; (4) extract: repeatedly extract concentrated solution I with methylene dichloride, be concentrated into solvent-free after extraction phase is merged at ambient pressure, and then under vacuo, be evaporated to striking point; Again with normal hexane re-extract, be concentrated into without normal hexane under normal pressure after removing extraction phase, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract; (5) chromatographic separation: by total note medicinal extract with a small amount of organic solvent dissolution, admix the macroporous resin with medicinal extract equal-volume times amount, sample dry method upper prop, add certain density organic solvent and carry out wash-out, obtain normal pressure recycling design after corresponding flow point, concentrating under reduced pressure, obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, be i.e. taxol crude extract; (6) prepare: a small amount of acetone solution of taxol crude extract step (5) obtained, obtained containing taxol flow point by preparative high performance liquid chromatography instrument, concentrating under reduced pressure is drained and is obtained taxol finished product.
Preferred as one, in step (1), Ramulus et folium taxi cuspidatae pulverize after granularity be 30-50 order (taxus chinensis powder mince granularity excessive time, because of inadequate with the impregnating depth of solvent, and cause leaching insufficient, affect leaching efficiency, too small, easily accumulation viscous not easily leaches and fully contacts with solvent), in crushing process, keep pulverizing room temp must not more than 60 DEG C.
Preferred as one, step (2) extracting solvent is methyl alcohol or ethanol or acetone, and the solvent adding amount of three leachings is 3 ~ 5 times amount (V/M) dropping into raw material, and each leaching time is 24 hours.
Preferred as one, in step (3), concentrating under reduced pressure terminal is the proportion of feed liquid is 1.00-1.02, and the temperature of concentrating under reduced pressure process remains on less than 40 DEG C.
Preferred as one, in step (4), it is 4-6 time that methylene dichloride extracts concentrated solution I number repeatedly; Normal hexane repeatedly extraction times is 2-4 time.
Preferred as one, in step (4), methylene dichloride extracts and after normal hexane extracts repeatedly repeatedly: the concentrated temperature of normal pressure all remains on less than 55 DEG C, and the temperature of the vacuum-concentrcted after normal pressure concentrates all remains on less than 40 DEG C.
Preferred as one, in step (5), dissolving organic solvent used is chloroform-methanol double solvents or acetone or methyl alcohol, organic solvent add-on be the 1-2 of medicinal extract amount doubly (V/M), control the every flow point 50mL of gradient elution, flow velocity is every flow point 15min; Concentrating under reduced pressure temperature controls below 60 DEG C, and concentration process must not have precipitate.
Preferred as one, in step (6), preparation liquid phase chromatographic column used is industrial preparative liquid chromatography post (4000mm × 200mm), and moving phase is acetone/water=40:60 ~ 58:42 (V/V), and flow velocity is 2L/min.
Embodiment 1
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 40 object meal at 60 DEG C;
(2) leach: leach 3 times with the methyl alcohol of 90% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 40 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I5 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 50 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 2 times, extraction temperature 40 DEG C, each removing extraction phase, is concentrated into solvent-free normal hexane under normal pressure, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add total note medicinal extract times amount acetone solution, add-on is 2 times (V/M) of medicinal extract amount, admixes the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add the acetone wash-out of 58%, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 40 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 103.0g, purity 98.8%, total yield of products is 70.2%.
Embodiment 2
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 30 object meal at 50 DEG C;
(2) leach: leach 3 times with the ethanol of 95% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 35 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I4 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 55 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 3 times, extraction temperature 30 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add the chloroform-methanol mixed solution (92:8 of total note medicinal extract times amount, V/V) dissolve, add-on is 1.5 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add the methanol-eluted fractions of 59%, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 55 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 100.9g, purity 98.6%, total yield of products is 68.6%.
Embodiment 3
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 50 object meal at 60 DEG C;
(2) leach: leach 3 times with the methyl alcohol of 90% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 30 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I6 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 45 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 4 times, extraction temperature 35 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add the dissolve with methanol of total note medicinal extract times amount, add-on is 1 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add chloroform-methanol mixed solution (100:0) wash-out, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 50 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 102.6g, purity 99.2%, total yield of products is 70.2%.
Embodiment 4
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 40 object meal at 60 DEG C;
(2) leach: leach 3 times with the methyl alcohol of 90% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 40 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I5 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 50 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 2 times, extraction temperature 40 DEG C, each removing extraction phase, is concentrated into solvent-free normal hexane under normal pressure, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add total note medicinal extract times amount chloroform-methanol mixed solution (100:0, i.e. chloroform neat solvent) dissolve, add-on is 2 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add the acetone wash-out of 60%, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 40 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 102.8g, purity 99.0%, total yield of products is 70.2%.
Embodiment 5
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 30 object meal at 50 DEG C;
(2) leach: leach 3 times with the ethanol of 95% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 35 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I4 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 55 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 3 times, extraction temperature 30 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add the chloroform-methanol mixed solution (99:1 of total note medicinal extract times amount, V/V) dissolve, add-on is 1.5 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add the methanol-eluted fractions of 61%, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 60 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 102.6g, purity 98.9%, total yield of products is 70.0%.
Embodiment 6
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 50 object meal at 60 DEG C;
(2) leach: leach 3 times with the methyl alcohol of 90% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 30 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I6 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 45 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 4 times, extraction temperature 35 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add and the chloroform-methanol mixed solution (98:2) of total note medicinal extract times amount is dissolved, add-on is 1 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add chloroform-methanol mixed solution (94:6) wash-out, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 50 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 101.9g, purity 99.3%, total yield of products is 69.8%.
Embodiment 7
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 30 object meal at 50 DEG C;
(2) leach: leach 3 times with the ethanol of 95% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 35 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I4 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 55 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 3 times, extraction temperature 30 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add the chloroform-methanol mixed solution (97:3 of total note medicinal extract times amount, V/V) dissolve, add-on is 1.5 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add the methanol-eluted fractions of 62%, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 60 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 102.6g, purity 99.1%, total yield of products is 70.1%.
Embodiment 8
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 50 object meal at 60 DEG C;
(2) leach: leach 3 times with the methyl alcohol of 90% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 30 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I6 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 45 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 4 times, extraction temperature 35 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add and the chloroform-methanol mixed solution (96:4) of total note medicinal extract times amount is dissolved, add-on is 1 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add chloroform-methanol mixed solution (97:3) wash-out, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 50 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 103.3g, purity 98.7%, total yield of products is 70.3%.
Embodiment 9
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 30 object meal at 50 DEG C;
(2) leach: leach 3 times with the ethanol of 95% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 35 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I4 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 55 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 3 times, extraction temperature 30 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add the chloroform-methanol mixed solution (95:5 of total note medicinal extract times amount, V/V) dissolve, add-on is 1.5 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add the methanol-eluted fractions of 63%, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 45 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 103.4g, purity 99.3%, total yield of products is 70.8%.
Embodiment 10
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 50 object meal at 60 DEG C;
(2) leach: leach 3 times with the methyl alcohol of 90% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 30 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I6 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 45 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 4 times, extraction temperature 32 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add and the chloroform-methanol mixed solution (94:6) of total note medicinal extract times amount is dissolved, add-on is 1 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add chloroform-methanol mixed solution (95:5) wash-out, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 55 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 102.0, purity 98.9%, total yield of products is 69.6%.
Embodiment 11
(1) pre-treatment: 500kg Ramulus et folium taxi cuspidatae is broken into 50 object meal at 55 DEG C;
(2) leach: leach 3 times with the methyl alcohol of 90% of Ramulus et folium taxi cuspidatae meal 3-5 times amount (V/M), three times solvent adding amount is followed successively by 2500L, 2000L, 1500L, and each leaching time is 24 hours, merges three leaching liquids;
(3) concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is evaporated to former leaching liquid, concentrating under reduced pressure temperature is 37 DEG C, more successively to squeeze into the proportion being evaporated to feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrated solution I;
(4) extract: repeatedly extract concentrated solution I6 time with methylene dichloride, extraction phase is merged, solvent-free by being concentrated under the feed liquid layer normal pressure obtained, thickening temperature 48 DEG C, and then under vacuo, be evaporated to striking point, then with normal hexane re-extract 4 times, extraction temperature 37 DEG C, all remove extraction phase at every turn, under normal pressure, be concentrated into solvent-free normal hexane, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract;
(5) chromatography: add and the chloroform-methanol mixed solution (93:7) of total note medicinal extract times amount is dissolved, add-on is 1 times (V/M) of medicinal extract amount, admix the macroporous resin with medicinal extract equimultiple, sample dry method upper prop, add chloroform-methanol mixed solution (92:8) wash-out, control gradient elution every flow point 50mL during wash-out, flow velocity is every flow point 15min; After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into inherent less than the 60 DEG C concentrating under reduced pressure of concentration tank (it be 57 DEG C that concentrating under reduced pressure temperature controls,), obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate;
(6) prepare liquid phase separation: a small amount of acetone solution of taxol crude extract chromatographic separation obtained, put into preparative high performance liquid chromatography instrument, prepare taxol flow point, concentrating under reduced pressure is drained, obtain finished product 100.9g, purity 99.0%, total yield of products is 68.9%.
The preparation method of natural Japanese yew alcohol disclosed by the invention, there is cost low, operate simple and easy and that efficiency is high advantage, the solvent species used in technique is few, all recyclable, and can apply mechanically front and back, reduce production cost, preparative high performance liquid chromatography separation and purification system is adopted to ensure that product purity is high, impurity level.
The non-limit part of technical scope mid point value that this place embodiment is protected application claims, equally all in the scope of protection of present invention.
Technique means disclosed in the present invention program is not limited only to the technique means disclosed in above-mentioned technique means, also comprises the technical scheme be made up of above technical characteristic arbitrary combination.The above is the specific embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Claims (8)
1. a preparation method for natural Japanese yew alcohol, is characterized in that, the preparation method of described natural Japanese yew alcohol comprises the steps: (1) pre-treatment: Ramulus et folium taxi cuspidatae is broken into meal; (2) leach: meal step (1) obtained leaches 3 times with the alcoholic solvent below appropriate three carbon or the ketones solvent below five carbon and gets leaching liquid respectively, merges three leaching liquids; (3) concentrated: the leaching liquid after step (2) being merged, through being evaporated to striking point, obtains concentrated solution I; (4) extract: repeatedly extract concentrated solution I with methylene dichloride, be concentrated into solvent-free after extraction phase is merged at ambient pressure, and then under vacuo, be evaporated to striking point; Again with normal hexane re-extract, be concentrated into without normal hexane under normal pressure after removing extraction phase, and then under vacuo, be evaporated to striking point, obtain total note medicinal extract; (5) chromatographic separation: by total note medicinal extract with a small amount of organic solvent dissolution, admix the macroporous resin with medicinal extract equal-volume times amount, sample dry method upper prop, add certain density organic solvent and carry out wash-out, obtain normal pressure recycling design after corresponding flow point, concentrating under reduced pressure, obtain concentrated solution II, with dichloromethane extraction concentrated solution II, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, be i.e. taxol crude extract; (6) prepare: a small amount of acetone solution of taxol crude extract step (5) obtained, obtained containing taxol flow point by preparative high performance liquid chromatography instrument, concentrating under reduced pressure is drained and is obtained taxol finished product.
2. the preparation method of natural Japanese yew alcohol according to claim 1, is characterized in that, in described step (1), the granularity after Ramulus et folium taxi cuspidatae pulverizing is 30-50 order, and in crushing process, keep pulverizing room temp must not more than 60 DEG C.
3. the preparation method of natural Japanese yew alcohol according to claim 1, it is characterized in that, described step (2) extracting solvent is methyl alcohol or ethanol or acetone, and the solvent adding amount of three leachings is 3 ~ 5 times amount (V/M) dropping into raw material, and each leaching time is 24 hours.
4. the preparation method of natural Japanese yew alcohol according to claim 1, is characterized in that, in described step (3), concentrating under reduced pressure terminal is the proportion of feed liquid is 1.00-1.02, and the temperature of concentrating under reduced pressure process remains on less than 40 DEG C.
5. the preparation method of natural Japanese yew alcohol according to claim 1, is characterized in that, in described step (4), it is 4-6 time that methylene dichloride extracts concentrated solution I number repeatedly; Normal hexane repeatedly extraction times is 2-4 time.
6. the preparation method of natural Japanese yew alcohol according to claim 1 or 5, it is characterized in that, methylene dichloride extracts and after normal hexane extracts repeatedly repeatedly in described step (4): the concentrated temperature of normal pressure all remains on less than 55 DEG C, and the temperature of the vacuum-concentrcted after normal pressure concentrates all remains on less than 40 DEG C.
7. the preparation method of natural Japanese yew alcohol according to claim 1, it is characterized in that, in described step (5), dissolving organic solvent used is chloroform-methanol double solvents or acetone or methyl alcohol, organic solvent add-on is 1-2 times (V/M) of medicinal extract amount, control the every flow point 50mL of gradient elution, flow velocity is every flow point 15min; Concentrating under reduced pressure temperature controls below 60 DEG C, and concentration process must not have precipitate.
8. the preparation method of natural Japanese yew alcohol according to claim 1, it is characterized in that, in described step (6), preparation liquid phase chromatographic column used is industrial preparative liquid chromatography post (4000mm × 200mm), moving phase is acetone: water=40:60 ~ 58:42 (V/V), and flow velocity is 2L/min.
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