CN104529951B - A kind of preparation method of natural Japanese yew alcohol - Google Patents
A kind of preparation method of natural Japanese yew alcohol Download PDFInfo
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- CN104529951B CN104529951B CN201410749059.0A CN201410749059A CN104529951B CN 104529951 B CN104529951 B CN 104529951B CN 201410749059 A CN201410749059 A CN 201410749059A CN 104529951 B CN104529951 B CN 104529951B
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Abstract
The preparation method of natural Japanese yew alcohol disclosed by the invention includes the following steps: that (1) pre-processes；(2) it leaches；(3) it is concentrated；(4) it extracts；(5) chromatography: total note medicinal extract is dissolved with a small amount of organic solvent, admix the macroreticular resin measured again in equal volume with medicinal extract, sample dry method upper prop, certain density organic solvent is added to be eluted, obtains normal pressure recycling design after corresponding flow point, is concentrated under reduced pressure, obtain concentrate II, concentrate II is extracted with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract；(6) it prepares.The present invention has at low cost, the simple and high-efficient advantage of operation, and preparative high performance liquid chromatography isolates and purifies the shortage that system has then further compensated for resin method degree of purification, breach the taxol extraction process for being traditionally only limitted to small lot, while guaranteeing high separating efficiency, it enables to the rate of recovery 70% or so, and the purity of finished product is made to reach 99.0%.
Description
Technical field
The present invention relates to the extraction process of taxol in field of fine chemical, especially a kind of preparation side of natural Japanese yew alcohol
Method.
Involved term meaning in this patent document:
Specific gravity is with the density 1g/cm3 of pure water under the status of criterion.
The meaning of V/M is volume/mass, specifically indicates cm3/g；L/kg；m3/t.
The meaning of M/M is mass/mass, specifically indicates g/g；kg/kg；t/t.
The meaning of V/V is volume/volume, specifically indicates cm3/cm3；L/L；m3/m3；
Normal temperature and pressure is temperature, pressure under the status of criterion；
Except this otherwise noted.
Background technique
Chinese yew also known as Japanese yew, Taxus.Chinese yew is the ancient few survivors tree that have passed through quaternary glacier and carry over
Kind, have 2,500,000 years history on earth.Chinese yew is also generally acknowledged endangered natural rare anticancer plant in the world simultaneously
Object can extract a kind of bearing taxanes, i.e. taxol from its bark and branches and leaves, have significantly to inhibition cancer cell division
Effect.
Taxol is a kind of Diterpenes taxane, molecular formula are as follows: C47H51NO14, molecular weight: and 853. 9, chemistry knot
Structure formula such as following formula, the crystallization for near-white odorless, tasteless or powder, not soluble in water in appearance, is soluble in acetone, chloroform, ether etc.
Organic solvent.
Taxol has the unique mechanism of action, can stablize micro-pipe, prevent microtubule depolymerization, keep micro-pipe no longer separated, presses down
The organic cleavage of cell processed causes the tumour cell quickly divided to be firmly fixed in mitotic stages, can block cell in
G2 and the M phase of cell cycle blocks cancer cell duplication and dead, to inhibit the schizogamy of cancer cell.According to current
Result of study indicates that taxol has significant curative effect to drug refractory oophoroma and metastatic breast cancer, non-small cell carcinoma, right
B16 melanoma, S180 sarcoma and P338, L1210, IIL60, P1534 leukaemia also have preferable therapeutic effect, to neck
Portion's cancer, cancer of the esophagus also have certain curative effect.
Due to the unique anticancer mechanism of taxol, the special attention of whole world the world of medicine is caused, is become after adriamycin
And the most important most fast-selling anti-cancer drugs with broad spectrum activity after cis-platinum, at present in tens country's listings.But it is worth note
Weight is that taxol content in Chinese yew is extremely low, and the isolation and purification method generallyd use is resin column chromatography, because it is opposite
In supercritical extract, cost is relatively low, and is easier to realize expanded production, but its degree of purification is then opposite in existing technology
It is lower.
Summary of the invention
To solve the above problems, the invention discloses a kind of preparation method of natural Japanese yew alcohol, high conversion efficiency, technique letter
It is single rigorous, it is easily enlarged production, the finished product purity is high impurity for using preparative efficient liquid phase equipment extraction being obtained is few.And
It is low to solvent strength requirement with simple process, it can realize that in production solvent high-efficiency recycles, it is pollution-free, to environment
Close friend is effectively reduced production cost.
The preparation method of natural Japanese yew alcohol disclosed by the invention includes the following steps: that (1) pre-processes: branches and leaves of yew is beaten
At coarse powder；(2) leach: the coarse powder that step (1) is obtained is molten with appropriate three carbon alcohols solvent below or five carbon ketone below
Agent leaches 3 times and takes leaching liquid respectively, merges leaching liquid three times；(3) be concentrated: the leaching liquid after step (2) are merged is by decompression
It is concentrated into striking point, obtains concentrate I；(4) it extracts: concentrate I is extracted repeatedly with methylene chloride, normal after extraction phase is merged
Pressure is concentrated into solvent-free, then again under vacuum, is concentrated under reduced pressure into striking point；It repeats to extract with n-hexane again, removes extraction
It takes and is concentrated into no n-hexane under normal pressure after phase, then again under vacuum, be concentrated under reduced pressure into striking point, obtain total note medicinal extract；(5) layer
Analysis separation: total note medicinal extract being dissolved with a small amount of organic solvent, admixes the macroreticular resin measured again in equal volume with medicinal extract, in sample dry method
Column is added certain density organic solvent and is eluted, and obtains normal pressure recycling design after corresponding flow point, is concentrated under reduced pressure, must be concentrated
Liquid II extracts concentrate II with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract；(6)
Preparation: a small amount of acetone solution of the taxol crude extract that step (5) is obtained is obtained by preparative high performance liquid chromatography instrument
Flow point containing taxol, reduced pressure drain to obtain taxol finished product.
A kind of improvement of the preparation method of natural Japanese yew alcohol disclosed by the invention, in step (1), the smashed grain of Chinese yew
Degree be 30-50 mesh (taxus chinensis powder mince granularity it is excessive when, because inadequate with the impregnating depth of solvent, and lead to leach insufficient, shadow
Ring leaching efficiency；The accumulation that then easily occurs to reunite in a solvent of crushed material undersized viscous is not easy to be infiltrated, it is difficult to fill with solvent
Tap touching, and it is easy knot tying, easily bonded with wall, it is big that operation difficulty be mixed), it keeps crushing in crushing process
Room temperature must not exceed 60 DEG C.
A kind of improvement of the preparation method of natural Japanese yew alcohol disclosed by the invention, step (2) extracting solvent are methanol or second
Alcohol or acetone, the solvent adding amount leached three times are 3 ~ 5 times of amounts (V/M) for putting into raw material, and each leaching time is 24 hours.
A kind of improvement of the preparation method of natural Japanese yew alcohol disclosed by the invention, in step (3), it is material that terminal, which is concentrated under reduced pressure,
The specific gravity of liquid is 1.00-1.02, and the temperature that process is concentrated under reduced pressure is maintained at 40 DEG C or less.
A kind of improvement of the preparation method of natural Japanese yew alcohol disclosed by the invention, in step (4), methylene chloride extracts repeatedly
I number of concentrate is 4-6 times；Extraction times are 2-4 times to n-hexane repeatedly.
A kind of improvement of the preparation method of natural Japanese yew alcohol disclosed by the invention, methylene chloride extracts repeatedly in step (4)
And after n-hexane extracts repeatedly: normal pressure concentration temperature be held in 55 DEG C hereinafter, normal pressure concentration after vacuum-concentrcted
Temperature be held in 40 DEG C or less.
A kind of improvement of the preparation method of natural Japanese yew alcohol disclosed by the invention in step (5), dissolves organic solvent used
For chloroform-methanol double solvents (chloroform-methanol mixed liquor: 100:0 ~ 92:8, V/V) or acetone or methanol, organic solvent is added
Amount is 1-2 times (V/M) of medicinal extract amount, controls the every flow point 50mL of gradient elution, and flow velocity is every flow point 15min；Temperature is concentrated under reduced pressure
Control is at 60 DEG C hereinafter, concentration process must not have precipitate.
A kind of improvement of the preparation method of natural Japanese yew alcohol disclosed by the invention in step (6), prepares chromatography used in liquid phase
Column is industrially prepared liquid-phase chromatographic column (4000mm × 200mm), and mobile 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 has at low cost, the simple and high-efficient advantage of operation, work
The solvent type used in skill is few, recyclable, and can front and back apply, production cost is reduced, using preparative efficient liquid phase
Chromatographic separation and purification system ensures product purity height, impurity level.
Detailed description of the invention
The process flow chart of the preparation method of Fig. 1, natural Japanese yew alcohol disclosed by the invention.
Specific embodiment
With reference to the accompanying drawings and detailed description, the present invention is furture elucidated, it should be understood that following specific embodiments are only
For illustrating the present invention rather than limiting the scope of the invention.It should be noted that word " preceding " used in the following description,
" rear ", "left", "right", "up" and "down" refer to that the direction in attached drawing, word "inner" and "outside" refer respectively to direction or remote
Direction from geometric center of specific component.
The preparation method of natural Japanese yew alcohol disclosed by the invention includes the following steps: that (1) pre-processes: branches and leaves of yew is beaten
At coarse powder；(2) leach: the coarse powder that step (1) is obtained is molten with appropriate three carbon alcohols solvent below or five carbon ketone below
Agent leaches 3 times and takes leaching liquid respectively, merges leaching liquid three times；(3) be concentrated: the leaching liquid after step (2) are merged is dense through depressurizing
It is reduced to striking point, obtains concentrate I；(4) it extracts: concentrate I is extracted repeatedly with methylene chloride, in normal pressure after extraction phase is merged
Under be concentrated into solvent-free, then again under vacuum, be concentrated under reduced pressure into striking point；It repeats to extract with n-hexane again, removes extraction
No n-hexane is concentrated into after phase under normal pressure, then again under vacuum, is concentrated under reduced pressure into striking point, obtains total note medicinal extract；(5) it chromatographs
Separation: total note medicinal extract is dissolved with a small amount of organic solvent, admixes the macroreticular resin measured again in equal volume with medicinal extract, in sample dry method
Column is added certain density organic solvent and is eluted, and obtains normal pressure recycling design after corresponding flow point, is concentrated under reduced pressure, must be concentrated
Liquid II extracts concentrate II with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract；(6)
Preparation: a small amount of acetone solution of the taxol crude extract that step (5) is obtained is obtained by preparative high performance liquid chromatography instrument
Flow point containing taxol, reduced pressure drain to obtain taxol finished product.
As a preference, in step (1), the smashed granularity of Chinese yew is that (taxus chinensis powder minces granularity mistake 30-50 mesh
When big, because inadequate with the impregnating depth of solvent, and cause to leach insufficient, influence leaching efficiency, it is too small, easily accumulate it is viscous not
Easily leaching comes into full contact with solvent), keep crushing room temperature to must not exceed 60 DEG C in crushing process.
As a preference, step (2) extracting solvent is methanol or ethyl alcohol or acetone, the solvent adding amount leached three times are
3 ~ 5 times of amounts (V/M) of raw material are put into, each leaching time is 24 hours.
As a preference, it is 1.00-1.02 that the specific gravity that terminal is feed liquid, which is concentrated under reduced pressure, in step (3), it was concentrated under reduced pressure
The temperature of journey is maintained at 40 DEG C or less.
As a preference, it is 4-6 times that methylene chloride extracts I number of concentrate repeatedly in step (4)；N-hexane is repeatedly
Extraction times are 2-4 times.
As a preference, methylene chloride extracts repeatedly and after n-hexane extracts repeatedly in step (4): normal pressure concentration
Temperature is held in 55 DEG C hereinafter, the temperature of the vacuum-concentrcted after normal pressure concentration is held in 40 DEG C or less.
As a preference, dissolving organic solvent used is chloroform-methanol double solvents or acetone or first in step (5)
Alcohol, organic solvent additional amount are 1-2 times (V/M) of medicinal extract amount, control the every flow point 50mL of gradient elution, and flow velocity is every flow point
15min；Temperature control is concentrated under reduced pressure at 60 DEG C hereinafter, concentration process there must not be precipitate.
As a preference, preparing chromatographic column used in liquid phase is industrially prepared liquid-phase chromatographic column (4000mm in step (6)
× 200mm), mobile phase is acetone/water=40:60 ~ 58:42 (V/V), flow velocity 2L/min.
Embodiment 1
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 40 mesh at 60 DEG C；
(2) it leaches: being leached 3 times with 90% methanol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 40 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I5 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 50 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts 2 times again, 40 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: being added and total note medicinal extract is measured into acetone solution again, additional amount is 2 times (V/M) of medicinal extract amount, admixes and soaks
The macroreticular resin of cream equimultiple, sample dry method upper prop are added 58% acetone elution, gradient elution every flow point are controlled when elution
50mL, flow velocity are every flow point 15min；After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into concentration
(it is 40 DEG C that temperature control, which is concentrated under reduced pressure ,) is concentrated under reduced pressure in tank at 60 DEG C or less, obtains concentrate II, is extracted and be concentrated with methylene chloride
Extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract by liquid II, and concentration process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 103.0g, and purity 98.8% produces
Product total recovery is 70.2%.
Embodiment 2
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 30 mesh at 50 DEG C；
(2) it leaches: being leached 3 times with 95% ethyl alcohol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 35 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I4 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 55 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 3 times, 30 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (92:8, V/V) for measuring total note medicinal extract again is added and dissolves, additional amount is leaching
1.5 times (V/M) of cream amount, admix the macroreticular resin with medicinal extract equimultiple, and sample dry method upper prop is added 59% methanol elution, washes
Gradient elution every flow point 50mL is controlled when de-, flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, by eluted fraction
Normal pressure recycling design, after squeeze into concentration tank (it is 55 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less, must be concentrated
Liquid II extracts concentrate II with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, dense
Compression process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 100.9g, and purity 98.6% produces
Product total recovery is 68.6%.
Embodiment 3
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 50 mesh at 60 DEG C；
(2) it leaches: being leached 3 times with 90% methanol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 30 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I6 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 45 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 4 times, 35 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) chromatograph: the methanol for measuring total note medicinal extract again be added and dissolves, additional amount is 1 times (V/M) of medicinal extract amount, admix with
Chloroform-methanol mixed liquor (100:0) elution is added in the macroreticular resin of medicinal extract equimultiple, sample dry method upper prop, control ladder when elution
Degree elutes every flow point 50mL, and flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, eluted fraction normal pressure is recycled molten
Agent, after squeeze into concentration tank (it is 50 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less, concentrate II is obtained, with two
Chloromethanes extracts concentrate II, and extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, concentration process is not
There must be precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 102.6g, and purity 99.2% produces
Product total recovery is 70.2%.
Embodiment 4
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 40 mesh at 60 DEG C；
(2) it leaches: being leached 3 times with 90% methanol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 40 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I5 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 50 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts 2 times again, 40 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: being added and total note medicinal extract is measured into chloroform-methanol mixed liquor (100:0, i.e. chloroform pure solvent) dissolution again, add
Enter 2 times (V/M) that amount is medicinal extract amount, admixes the macroreticular resin with medicinal extract equimultiple, 60% acetone is added in sample dry method upper prop
Elution, gradient elution every flow point 50mL is controlled when elution, and flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, it will wash
The separation of flow divides normal pressure recycling design, after squeeze into concentration tank (it is 40 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less,
Concentrate II is obtained, concentrate II is extracted with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol coarse extraction
Object, concentration process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 102.8g, and purity 99.0% produces
Product total recovery is 70.2%.
Embodiment 5
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 30 mesh at 50 DEG C；
(2) it leaches: being leached 3 times with 95% ethyl alcohol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 35 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I4 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 55 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 3 times, 30 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (99:1, V/V) for measuring total note medicinal extract again is added and dissolves, additional amount is leaching
1.5 times (V/M) of cream amount, admix the macroreticular resin with medicinal extract equimultiple, and sample dry method upper prop is added 61% methanol elution, washes
Gradient elution every flow point 50mL is controlled when de-, flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, by eluted fraction
Normal pressure recycling design, after squeeze into concentration tank (it is 60 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less, must be concentrated
Liquid II extracts concentrate II with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, dense
Compression process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 102.6g, and purity 98.9% produces
Product total recovery is 70.0%.
Embodiment 6
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 50 mesh at 60 DEG C；
(2) it leaches: being leached 3 times with 90% methanol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 30 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I6 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 45 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 4 times, 35 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (98:2) for measuring total note medicinal extract again is added and dissolves, additional amount is medicinal extract amount
1 times (V/M), admix the macroreticular resin with medicinal extract equimultiple, sample dry method upper prop is added chloroform-methanol mixed liquor (94:6)
Elution, gradient elution every flow point 50mL is controlled when elution, and flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, it will wash
The separation of flow divides normal pressure recycling design, after squeeze into concentration tank (it is 50 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less,
Concentrate II is obtained, concentrate II is extracted with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol coarse extraction
Object, concentration process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 101.9g, and purity 99.3% produces
Product total recovery is 69.8%.
Embodiment 7
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 30 mesh at 50 DEG C；
(2) it leaches: being leached 3 times with 95% ethyl alcohol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 35 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I4 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 55 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 3 times, 30 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (97:3, V/V) for measuring total note medicinal extract again is added and dissolves, additional amount is leaching
1.5 times (V/M) of cream amount, admix the macroreticular resin with medicinal extract equimultiple, and sample dry method upper prop is added 62% methanol elution, washes
Gradient elution every flow point 50mL is controlled when de-, flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, by eluted fraction
Normal pressure recycling design, after squeeze into concentration tank (it is 60 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less, must be concentrated
Liquid II extracts concentrate II with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, dense
Compression process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 102.6g, and purity 99.1% produces
Product total recovery is 70.1%.
Embodiment 8
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 50 mesh at 60 DEG C；
(2) it leaches: being leached 3 times with 90% methanol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 30 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I6 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 45 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 4 times, 35 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (96:4) for measuring total note medicinal extract again is added and dissolves, additional amount is medicinal extract amount
1 times (V/M), admix the macroreticular resin with medicinal extract equimultiple, sample dry method upper prop is added chloroform-methanol mixed liquor (97:3)
Elution, gradient elution every flow point 50mL is controlled when elution, and flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, it will wash
The separation of flow divides normal pressure recycling design, after squeeze into concentration tank (it is 50 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less,
Concentrate II is obtained, concentrate II is extracted with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol coarse extraction
Object, concentration process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 103.3g, and purity 98.7% produces
Product total recovery is 70.3%.
Embodiment 9
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 30 mesh at 50 DEG C；
(2) it leaches: being leached 3 times with 95% ethyl alcohol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 35 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I4 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 55 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 3 times, 30 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (95:5, V/V) for measuring total note medicinal extract again is added and dissolves, additional amount is leaching
1.5 times (V/M) of cream amount, admix the macroreticular resin with medicinal extract equimultiple, and sample dry method upper prop is added 63% methanol elution, washes
Gradient elution every flow point 50mL is controlled when de-, flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, by eluted fraction
Normal pressure recycling design, after squeeze into concentration tank (it is 45 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less, must be concentrated
Liquid II extracts concentrate II with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol crude extract, dense
Compression process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 103.4g, and purity 99.3% produces
Product total recovery is 70.8%.
Embodiment 10
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 50 mesh at 60 DEG C；
(2) it leaches: being leached 3 times with 90% methanol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 30 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I6 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 45 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 4 times, 32 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (94:6) for measuring total note medicinal extract again is added and dissolves, additional amount is medicinal extract amount
1 times (V/M), admix the macroreticular resin with medicinal extract equimultiple, sample dry method upper prop is added chloroform-methanol mixed liquor (95:5)
Elution, gradient elution every flow point 50mL is controlled when elution, and flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, it will wash
The separation of flow divides normal pressure recycling design, after squeeze into concentration tank (it is 55 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less,
Concentrate II is obtained, concentrate II is extracted with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol coarse extraction
Object, concentration process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 102.0, purity 98.9%, product
Total recovery is 69.6%.
Embodiment 11
(1) it pre-processes: 500kg branches and leaves of yew is broken into the coarse powder of 50 mesh at 55 DEG C；
(2) it leaches: being leached 3 times with 90% methanol of 3-5 times of Chinese yew coarse powder amount (V/M), solvent adding amount is successively three times
For 2500L, 2000L, 1500L, each leaching time is 24 hours, merges leaching liquid three times；
(3) it is concentrated: leaching liquid is squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, be concentrated under reduced pressure
Temperature be 37 DEG C, then successively squeeze into be concentrated under reduced pressure into scraper evaporator and treatment tank feed liquid specific gravity be 1.00-1.02, i.e., it is dense
Contracting liquid I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I6 times, extraction phase is merged, the feed liquid layer obtained is normal
Pressure is concentrated into solvent-free, 48 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then with n-hexane weight
It extracts again 4 times, 37 DEG C of extraction temperature, removes extraction phase every time, solvent-free n-hexane is concentrated under normal pressure, then again in vacuum
Under, it is concentrated under reduced pressure into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor (93:7) for measuring total note medicinal extract again is added and dissolves, additional amount is medicinal extract amount
1 times (V/M), admix the macroreticular resin with medicinal extract equimultiple, sample dry method upper prop is added chloroform-methanol mixed liquor (92:8)
Elution, gradient elution every flow point 50mL is controlled when elution, and flow velocity is every flow point 15min；After obtaining corresponding eluted fraction, it will wash
The separation of flow divides normal pressure recycling design, after squeeze into concentration tank (it is 57 DEG C that temperature control, which is concentrated under reduced pressure ,) be concentrated under reduced pressure at 60 DEG C or less,
Concentrate II is obtained, concentrate II is extracted with methylene chloride, extraction phase is squeezed into concentration tank and is concentrated into medicinal extract, i.e. taxol coarse extraction
Object, concentration process must not have precipitate；
(6) prepare liquid phase separation: a small amount of acetone solution of the taxol crude extract that chromatography is obtained is put into preparation
Taxol flow point is prepared in type high performance liquid chromatograph, and reduced pressure is drained, and obtains finished product 100.9g, and purity 99.0% produces
Product total recovery is 68.9%.
The preparation method of natural Japanese yew alcohol disclosed by the invention has at low cost, the simple and high-efficient advantage of operation, work
The solvent type used in skill is few, recyclable, and can front and back apply, production cost is reduced, using preparative efficient liquid phase
Chromatographic separation and purification system ensures product purity height, impurity level.
Claimed midpoint of technical range is not exhaustive in this place embodiment, equally all wants in the present invention
In the range of asking protection.
The technical means disclosed in the embodiments of the present invention is not limited to the technical means disclosed in the above technical means, and further includes
Technical solution consisting of any combination of the above technical features.The foregoing is a specific embodiment of the present invention, should refer to
Out, for those skilled in the art, without departing from the principle of the present invention, can also make several
Improvements and modifications, these modifications and embellishments are also considered to be within the scope of the present invention.
Claims (1)
1. a kind of preparation method of natural Japanese yew alcohol, which is characterized in that the preparation method of the natural Japanese yew alcohol includes following step
It is rapid: (1) to pre-process: branches and leaves of yew is broken into the coarse powder of 50 mesh at 60 DEG C；
(2) leach: 90% methanol for measuring V/M with 3-5 times of Chinese yew coarse powder leaches 3 times, and solvent adding amount is followed successively by three times
2500L, 2000L, 1500L, each leaching time are 24 hours, merge leaching liquid three times；
(3) it is concentrated: leaching liquid being squeezed into the half volume that outer circulation concentration tank is concentrated under reduced pressure into former leaching liquid, temperature is concentrated under reduced pressure
It is 30 DEG C, then successively squeezes into that be concentrated under reduced pressure into the specific gravity of feed liquid in scraper evaporator and treatment tank be 1.00-1.02, i.e. concentrate
I；
(4) it extracts: being extracted repeatedly with methylene chloride concentrate I 6 times, extraction phase is merged, it will be dense under obtained feed liquid layer normal pressure
It is reduced to solvent-free, 45 DEG C of thickening temperature, then again under vacuum, is concentrated under reduced pressure into striking point, then extraction 4 is repeated with n-hexane
It is secondary, 35 DEG C of extraction temperature, extraction phase is removed every time, is concentrated into solvent-free n-hexane under normal pressure, then again under vacuum, decompression
It is concentrated into striking point, obtains total note medicinal extract；
(5) it chromatographs: the chloroform-methanol mixed liquor 98:2 dissolution of one times of total note medicinal extract amount V/M is added, admixes and total note medicinal extract equivalent
Macroreticular resin, sample dry method upper prop is added chloroform-methanol mixed liquor 94:6 elution, gradient elution every flow point controlled when elution
50mL, flow velocity are every flow point 15min；After obtaining corresponding eluted fraction, by eluted fraction normal pressure recycling design, after squeeze into concentration
It is concentrated under reduced pressure at 50 DEG C in tank, obtains concentrate II, concentrate II is extracted with methylene chloride, extraction phase is squeezed into concentration tank concentration
To medicinal extract, i.e. taxol crude extract, concentration process must not have precipitate；
(6) prepare liquid phase separation: the taxol crude extract acetone solution that chromatography is obtained is put into the efficient liquid of preparative
Taxol flow point is prepared in chromatography, and reduced pressure is drained, and obtains taxol finished product.
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| CN105669603A (en) * | 2016-03-03 | 2016-06-15 | 重庆市碚圣医药科技股份有限公司 | Method for preparing ultrahigh-purity paclitaxel from raw material low-purity paclitaxel |
| CN105837534A (en) * | 2016-05-24 | 2016-08-10 | 福建紫杉园生物有限公司 | Soaking extraction method for extracting paclitaxel from taxus chinensis |
| CN107602511A (en) * | 2017-10-21 | 2018-01-19 | 厦门翼翔缘生物科技有限公司 | A kind of extraction process of natural taxol |
| CN108047169A (en) * | 2018-01-12 | 2018-05-18 | 重庆市碚圣医药科技股份有限公司 | A kind of method that low pure Japanese yew raw polyol is prepared into high-purity taxol |
| CN110857289A (en) * | 2018-08-22 | 2020-03-03 | 台江县吉阳生物科技有限公司 | Paclitaxel extraction method |
| CN111393390A (en) * | 2019-01-02 | 2020-07-10 | 贵州罗贝罗生物科技有限公司 | Method for efficiently extracting paclitaxel from taxus chinensis |
| CN110003143A (en) * | 2019-04-15 | 2019-07-12 | 云南汉德生物技术有限公司 | A method of extracting natural Japanese yew alcohol |
| CN110845451A (en) * | 2019-11-28 | 2020-02-28 | 云南皓瑞逸生物科技有限公司 | Method for extracting paclitaxel from taxus chinensis |
| CN112409300A (en) * | 2020-11-06 | 2021-02-26 | 巢湖学院 | Extraction process of paclitaxel |
| CN112521349B (en) * | 2020-11-11 | 2023-04-07 | 福建齐衡科技有限公司 | Method for purifying paclitaxel |
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| CN101560197B (en) * | 2009-06-01 | 2011-07-06 | 西北农林科技大学 | Extraction method of taxol from branches and leaves of artificially cultivated yew |
| CN102212045A (en) * | 2010-04-08 | 2011-10-12 | 常山曼地亚红豆杉科技开发有限公司 | Method for simultaneously extracting taxol and 10-DABIII (10-deacetyl baccatine III) from branches and leaves of Taxus media |
| CN103193735B (en) * | 2013-03-26 | 2015-07-15 | 安徽和华生物医药科技有限公司 | Extraction method for taxus chinensis taxol activity extract |
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