CN106632159A - Method for preparing 10-deacetylbaccatin III by utilizing paclitaxel-semisynthesis impurity - Google Patents
Method for preparing 10-deacetylbaccatin III by utilizing paclitaxel-semisynthesis impurity Download PDFInfo
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- CN106632159A CN106632159A CN201611186352.6A CN201611186352A CN106632159A CN 106632159 A CN106632159 A CN 106632159A CN 201611186352 A CN201611186352 A CN 201611186352A CN 106632159 A CN106632159 A CN 106632159A
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- impurity
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- deacetylate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
Abstract
The invention relates to a method for preparing 10-deacetylbaccatin III by utilizing a paclitaxel-semisynthesis impurity. A paclitaxel-semisynthesis impurity raw material is dissolved by using an organic solvent; hydrazine hydrate is added into an obtained first mixture to hydrolyze the first mixture; an acidifying agent is added into hydrolyzed mixed liquor to carry out acidification; acidified liquor is neutralized by using weak base, so that the 10-DAB III (10-deacetylbaccatin III) is obtained. According to the method provided by the invention, the paclitaxel-semisynthesis impurity is used as a raw material, is first hydrolyzed by using the hydrazine hydrate, and then is treated by using the acidifying agent to obtain a 10-DAB III coarse product; the 10-DAB III coarse product is purified by using a silica gel chromatographic column to obtain a 10-DAB III product; the 10-DAB III has a yield which is up to 25.6 to 36.8 percent and a content which is up to 98.2 to 99.1 percent; a new approach of obtaining the 10-DAB III product is exploited; not only is the accumulation problem of the impurity in a paclitaxel semisynthesis process solved, but also the raw material is provided for the semisynthesis of paclitaxel; production equipment used in the method provided by the invention is conventional equipment; the used solvent is a conventional solvent; a production condition is easy to implement; the method is simple to operate and suitable for industrialized production. The product can be used for a synthetic raw material for the paclitaxel and docetaxel and is applied to the field of medicines.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesizes field, concrete one kind relates to the use of semi-synthetic taxol impurity and prepares 10-
The method of acetyl group Bakating III.
Background technology
Taxol (Paclitaxel, trade name Taxol) is that the one kind isolated from Taxus (Taxus) plant is purple
China fir alkane diterpene-kind compound.Taxol chemistry is fully synthetic to succeed, but complex synthetic route, high cost, only with research
Meaning, there is no commercial value fully synthetic with respect to taxol, and it is a kind of preparation method with practical value that taxol is semi-synthetic.It is purple
It is typically all with the 10- deacetylate Bakating III (10- similar with taxol macrocyclic structure that China fir alcohol is semi-synthetic
Deacetylbaccatin III, 10-DAB III) for raw material, docked by the side chain with taxol and taxol is obtained, 10-DAB
III typically extracts from Chinese yew and obtains, due to contents of the 10-DAB III in Chinese yew it is also unusual low, therefore to its 10-
DAB III is made full use of with sizable value.
Impurity can be produced through four reactions steps, each reactions steps by the semi-synthetic taxols of 10-DAB III,
And these impurity great majority have the structures of 10-DAB III, such as《Semi-synthetic taxol process contaminants research》(Wang Yongyi etc., China is existing
Generation apply pharmacy 2014 year 2 month the 2nd phase of volume 31) described in various impurity, especially above-mentioned document Fig. 2 of page 155 remembered
The various impurity for carrying, if these impurity are lost as discarded object, natural 10-DAB III less to yield sheet causes pole
It is big to waste, therefore the impurity containing the structures of 10-DAB III is converted into into another new way that 10-DAB III is acquisition 10-DAB III
Footpath, has no at present the report that the impurity of semi-synthetic taxol is converted into 10- deacetylate Bakating IIIs, enters for the new way
Row research obtains new technical method.
The content of the invention
In order to solve the above problems, the invention provides a kind of high income, product purity are high, be easy to one kind half of industrialization
The preparation method of taxol biosynthesis and its intermediate.
For achieving the above object, the technical solution used in the present invention is：10- is prepared using semi-synthetic taxol impurity go second
The method of acyl group Bakating III includes step：
A. hydrolyze：Semi-synthetic taxol impurity raw material organic solvent is dissolved, hydrazine hydrate hydrolysis is added；
B. it is acidified：Acidulant is added to be acidified in hydrolysis mixture；
C. neutralize：In acidifying solution weak base obtained in step B and 10- deacetylate Bakating IIIs will be obtained final product.
Carrying out that simply hydrolysis, acidifying and neutralization procedure be just obtained by double taxol biosynthesis impurity can effectively utilizes
10- deacetylate Bakating IIIs, this obviously has very practical effect for commercial Application, while can substantially increase
The raw material availability of semi-synthetic taxol, improves the effective rate of utilization of the taxol resource more rare to this.Step A
In semi-synthetic taxol impurity raw material be containing the related impurities of taxol female ring during semi-synthetic taxol.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
The technological parameter of hydrolysis is stirring reaction 4～48 hours at 10～60 DEG C in step A.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
The technological parameter of acidification reaction is reaction 6～24 hours at 10～40 DEG C in step B.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
Weak base is added to adjust pH to 5～7 in mixture in step C.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
Step C gained mixed liquor obtains 10- deacetylate bar card booth crude products Jing after extractant extraction, concentrate drying, by 10- deacetylates
Bar card booth crude product obtains 10- deacetylate Bakating III products after silica gel column chromatography separation.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
Organic solvent is one or more mixing in methyl alcohol, ethanol, tetrahydrofuran, dichloromethane, ethyl acetate.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
Acidulant is one or more mixing in formic acid, acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
Weak base is one or more mixing in sodium acid carbonate, sodium carbonate, saleratus, potassium carbonate, ammoniacal liquor.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
Extractant is one or more mixing in dichloromethane, chloroform, ethyl acetate.
Further, it is above-mentioned to be prepared described in the method for 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity
Organic solvent is 1 with the mass ratio of semi-synthetic taxol impurity：(4～10)；The hydrazine hydrate and semi-synthetic taxol impurity
Mass ratio is 1：(1～3)；Semi-synthetic taxol impurity is 1 with the mass ratio of acidulant：(3～8)；The extractant with it is hemizygous
Mass ratio into taxol impurity is 1：(20～50).
The semi-synthetic taxol impurity of utilization that the present invention is provided prepares the method for 10- deacetylate Bakating IIIs with as follows
Beneficial effect：
1. the inventive method after being first hydrolyzed with hydrazine hydrate, then uses acidulant with semi-synthetic taxol impurity as raw material
Carry out process and obtain the crude products of 10-DAB III, the products of 10-DAB III, 10- are obtained after purification to the crude product silica gel column chromatographies of 10-DAB III
The high incomes of DAB III are up to 98.2%～99.1% up to the contents of 25.6%～36.8%, 10-DAB III.
2. the inventive method opens the new way of an acquisition product of 10-DAB III with semi-synthetic taxol impurity as raw material
Footpath, not only solves the problems, such as the accumulation of impurity during semi-synthetic taxol, also provides raw material for semi-synthetic taxol.
3. production equipment used by the inventive method is conventional equipment, and solvent for use is Conventional solvents, and working condition is easily implemented,
Easy to operate suitable industrialized production.
4. the 10-DAB III for being produced using the inventive method can be used for the synthesis material of taxol, docetaxel, be applied to
During medicine is received.
Specific embodiment
With reference to specific embodiment, the present invention will be further described.It should be noted that the reality described in the present invention
It is only the preferred embodiments of the present invention to apply example, is not limited to the present invention, for a person skilled in the art, this
Invention can have various modifications and variations.All any modifications within the spirit and principles in the present invention, made, equivalent,
Improve etc., should be included within the scope of the present invention.Based on the embodiment in the present invention, those of ordinary skill in the art
The every other embodiment obtained under the premise of creative work is not made, belongs to the scope of protection of the invention.
The semi-synthetic taxol impurity raw material for using in embodiment one to three is as follows in taxol biosynthesis
The various waste liquid set containing taxanes：
(1) raw materials of 10-DAB III are weighed, dry pyridine stirring and dissolving is added, triethyl group chlorine is then added dropwise under nitrogen protection
Silane, time for adding is maintained at 30min, and dropping temperature is controlled at 10 DEG C, and after being added dropwise to complete, controlling reaction temperature is 10 DEG C, when
Stopping reaction when the residuals of 10-DAB III are less than 0.2% in reactant liquor, water is added dropwise carries out that reaction is quenched, and then neutralizes through concentrated hydrochloric acid
Pyridine, dichloromethane extraction, concentrate drying obtains intermediate compound I.Wherein, the mass ratio of each reactive component is that 10-DAB III is former
Material：Dry pyridine=1：3,10-DAB III raw materials：Chlorotriethyl silane=1：0.8.
(2) intermediate compound I is weighed, dry pyridine stirring and dissolving is added, chloroacetic chloride is then added dropwise under nitrogen protection, during dropwise addition
Between be maintained at 30min, dropping temperature is controlled at -15 DEG C, and after being added dropwise to complete, controlling reaction temperature is -15 DEG C, in reactant liquor
Mesosome I residuals for 5% when stop reaction, water is added dropwise carries out that reaction is quenched, and then in concentrated hydrochloric acid and pyridine, dichloromethane extracts
Take, concentrate drying obtains intermediate II.Wherein, the mass ratio of each reactive component is, intermediate compound I：Dry pyridine=1：3, it is middle
Body I：Chloroacetic chloride=1：0.5.
(3) intermediate II is weighed, with organic solvent dissolving, is filtered, then Jing preparative liquid chromatographies are separated to collect respectively and contained
There is the eluent of intermediate compound I, intermediate II, the eluent containing intermediate compound I, intermediate II is concentrated respectively to be dried to obtain centre
Body I, intermediate II, intermediate compound I is used as the raw material of synthetic intermediate II, and intermediate II is former as the reaction of synthetic intermediate III
Material.Wherein, organic solvent is methyl alcohol, and the mass ratio of each reactive component is, intermediate II：Organic solvent=1：2, prepare liquid phase color
Spectrum is detached to prepare the octadecylsilane chemically bonded silica that filler used by post is 5um, and mobile phase is the methyl alcohol of 50vol%.
(4) intermediate II is weighed, side chain group compound, DMAP is added, dry toluene dissolving is added,
Condensing agent is added dropwise under nitrogen protection in the case where temperature is for 10 DEG C, is reacted to intermediate II in the case where reaction temperature is for 10 DEG C after being added dropwise to complete
Raw material residual obtains reactant liquor less than less than 0.2% stopping reaction, adds n-hexane stirred crystallization 1 hour in reactant liquor, mistake
Filter is dried to obtain intermediate III.Wherein, side-chain radical compound be (4S, 5R) -3- benzoyl -2- (4- methoxyphenyls) -
4- phenyl -5- oxazole dicarboxylic acid moieties, condensing agent is dicyclohexylcarbodiimide, and the mass ratio of each reactive component is, intermediate III：Side
Chain group compound=1：0.63, intermediate III：DMAP=1：0.05, intermediate III：Toluene=1：4, it is middle
Body III：Condensing agent=1：0.2, intermediate III：N-hexane=1：8.
(5) intermediate III is weighed, acetic acid, water stirring and dissolving is added, trifluoroacetic acid is added, is reacted in the case where temperature is for 10 DEG C
To the raw material of intermediate III residual for 5% when stop reaction, add weak base adjust pH to 6, with dichloromethane extraction after, Jing washing,
Concentrate, be dried to obtain taxol crude product.Wherein, weak base is sodium acid carbonate, and the mass ratio of each reactive component is, intermediate III：Second
Acid=1：2, mesosome III：Water=1：0.1, intermediate III：Trifluoroacetic acid=1：0.5.
(6) taxol crude product is weighed, with organic solvent dissolving, is filtered, then Jing preparative liquid chromatographies are separated and collected respectively
Eluent containing taxol, intermediate III, the eluent containing taxol, intermediate III is concentrated respectively to be dried to obtain Japanese yew
Alcohol product, intermediate III, reaction raw materials of the intermediate III as taxol biosynthesis.Wherein, organic solvent is methyl alcohol, prepares liquid phase
Chromatographic isolation prepare filler used by post be 5um octadecylsilane chemically bonded silica, mobile phase for 40vol% methyl alcohol, respectively
The mass ratio of reactive component is, taxol crude product：Organic solvent=1：2.
Embodiment one
Semi-synthetic taxol impurity raw material is weighed, the organic solvent stirring and dissolving of constant weight is added, certain weight is added
The hydrazine hydrate of amount, stirring reaction 4 hours at 10 DEG C, the solution after being hydrolyzed adds certain weight in the solution after hydrolysis
The acidulant of amount, the reaction at 10 DEG C obtains mixture in 6 hours, adds weak base to adjust pH to 5 in mixture, uses constant weight
Extractant extracted after, concentrate, be dried to obtain the crude products of 10-DAB III, the crude products of 10-DAB III are through conventional silica gel column chromatography point
The products of 10-DAB III are obtained from rear.Organic solvent is methyl alcohol；The organic solvent of the constant weight is semi-synthetic taxol
Impurity：Organic solvent=1:4；The hydrazine hydrate of the constant weight is semi-synthetic taxol impurity：Hydrazine hydrate=1:1；The acid
Agent is formic acid；The acidulant of the constant weight is semi-synthetic taxol impurity：Acidulant=1:3；The weak base is carbonic acid
Hydrogen sodium；The extractant is dichloromethane；The extractant of the constant weight is semi-synthetic taxol impurity：Extractant=1:
20；The high incomes of products obtained therefrom 10-DAB III are up to 98.2%% up to the contents of 25.6%, 10-DAB III.
Embodiment two
Semi-synthetic taxol impurity raw material is weighed, the organic solvent stirring and dissolving of constant weight is added, certain weight is added
The hydrazine hydrate of amount, stirring reaction 48 hours at 60 DEG C, the solution after being hydrolyzed adds certain weight in the solution after hydrolysis
The acidulant of amount, the reaction at 40 DEG C obtains mixture in 24 hours, adds weak base to adjust pH to 7 in mixture, with certain weight
After the extractant of amount is extracted, concentrate, be dried to obtain the crude products of 10-DAB III, the crude products of 10-DAB III are through conventional silica gel column chromatography
The products of 10-DAB III are obtained after separation.The organic solvent is ethyl acetate；The organic solvent of the constant weight is half
Taxol biosynthesis impurity：Organic solvent=1:10；The hydrazine hydrate of the constant weight is semi-synthetic taxol impurity：Hydrazine hydrate=
1:3；The acidulant is trifluoroacetic acid；The acidulant of the constant weight is semi-synthetic taxol impurity：Acidulant=1:8；
The weak base is ammoniacal liquor；The extractant is ethyl acetate；The extractant of the constant weight is semi-synthetic taxol impurity：Extraction
Take agent=1:50；The high incomes of products obtained therefrom 10-DAB III are up to 99.1% up to the contents of 36.8%, 10-DAB III.
Embodiment three
Semi-synthetic taxol impurity raw material is weighed, the organic solvent stirring and dissolving of constant weight is added, certain weight is added
The hydrazine hydrate of amount, stirring reaction 24 hours at 30 DEG C, the solution after being hydrolyzed adds certain weight in the solution after hydrolysis
The acidulant of amount, the reaction at 25 DEG C obtains mixture in 12 hours, adds weak base to adjust pH to 6 in mixture, with certain weight
After the extractant of amount is extracted, concentrate, be dried to obtain the crude products of 10-DAB III, the crude products of 10-DAB III are through conventional silica gel column chromatography
The products of 10-DAB III are obtained after separation.The organic solvent is tetrahydrofuran；The organic solvent of the constant weight is half
Taxol biosynthesis impurity：Organic solvent=1:7；The hydrazine hydrate of the constant weight is semi-synthetic taxol impurity：Hydrazine hydrate=
1:2；The acidulant is acetic acid；The acidulant of the constant weight is semi-synthetic taxol impurity：Acidulant=1:5；It is described
Weak base is saleratus；The extractant is chloroform；The extractant of the constant weight is semi-synthetic taxol impurity：Extraction
Take agent=1:35；The high incomes of products obtained therefrom 10-DAB III are up to 98.5% up to the contents of 30.7%, 10-DAB III.
Claims (10)
1. a kind of method for preparing 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity, it is characterised in that：Including step
Suddenly：
A. hydrolyze：Semi-synthetic taxol impurity raw material organic solvent is dissolved, hydrazine hydrate hydrolysis is added；
B. it is acidified：Acidulant is added to be acidified in hydrolysis mixture；
C. neutralize：In acidifying solution weak base obtained in step B and 10- deacetylate Bakating IIIs will be obtained final product.
2. the method for preparing 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity according to claim 1, its
It is characterised by：The technological parameter of hydrolysis is stirring reaction 4～48 hours at 10～60 DEG C in step A.
3. the method for preparing 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity according to claim 1, its
It is characterised by：The technological parameter of acidification reaction is reaction 6～24 hours at 10～40 DEG C in step B.
4. the method for preparing 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity according to claim 1, its
It is characterised by：Weak base is added to adjust pH to 5～7 in mixture in step C.
5. the method for preparing 10- deacetylate Bakating IIIs using semi-synthetic taxol impurity according to claim 1, its
It is characterised by：The step C gained mixed liquor obtains 10- deacetylate bar card booth crude products Jing after extractant extraction, concentrate drying,
10- deacetylate bar card booth crude products are obtained into 10- deacetylate Bakating III products after silica gel column chromatography separation.
6. it is as claimed in any of claims 1 to 5 to prepare 10- deacetylate bar cards using semi-synthetic taxol impurity
The method of booth III, it is characterised in that：The organic solvent is in methyl alcohol, ethanol, tetrahydrofuran, dichloromethane, ethyl acetate
One or more mixing.
7. it is as claimed in any of claims 1 to 5 to prepare 10- deacetylate bar cards using semi-synthetic taxol impurity
The method of booth III, it is characterised in that：The acidulant is one or more in formic acid, acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid
Mixing.
8. it is as claimed in any of claims 1 to 5 to prepare 10- deacetylate bar cards using semi-synthetic taxol impurity
The method of booth III, it is characterised in that：The weak base is the one kind in sodium acid carbonate, sodium carbonate, saleratus, potassium carbonate, ammoniacal liquor
Or various mixing.
9. it is as claimed in any of claims 1 to 5 to prepare 10- deacetylate bar cards using semi-synthetic taxol impurity
The method of booth III, it is characterised in that：The extractant is mixed one or more in dichloromethane, chloroform, ethyl acetate
Close.
10. it is as claimed in any of claims 1 to 5 to prepare 10- deacetylate bars using semi-synthetic taxol impurity
The method of card booth III, it is characterised in that：The organic solvent is 1 with the mass ratio of semi-synthetic taxol impurity：(4～10)；Institute
It is 1 that hydrazine hydrate is stated with the mass ratio of semi-synthetic taxol impurity：(1～3)；The mass ratio of semi-synthetic taxol impurity and acidulant
For 1：(3～8)；The extractant is 1 with the mass ratio of semi-synthetic taxol impurity：(20～50).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115304558A (en) * | 2022-08-17 | 2022-11-08 | 上海卓鼎生物技术有限公司 | Purification method of 1-hydroxy baccatin I |
Citations (3)
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|---|---|---|---|---|
| CN1538963A (en) * | 2001-07-05 | 2004-10-20 | 拿坡罗生物治疗股份有限公司 | Etticient process for production of 10-DAB III by selective hydrazinolysis of various taxanes |
| CA2533414A1 (en) * | 2006-01-23 | 2007-07-23 | Jian Liu | Semi-synthetic route for the preparation of paclitaxel ocetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
| CN103288785A (en) * | 2013-06-27 | 2013-09-11 | 江苏红豆杉药业有限公司 | Treatment method of paclitaxel waste residues |
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2016
- 2016-12-21 CN CN201611186352.6A patent/CN106632159A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1538963A (en) * | 2001-07-05 | 2004-10-20 | 拿坡罗生物治疗股份有限公司 | Etticient process for production of 10-DAB III by selective hydrazinolysis of various taxanes |
| CA2533414A1 (en) * | 2006-01-23 | 2007-07-23 | Jian Liu | Semi-synthetic route for the preparation of paclitaxel ocetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
| CN103288785A (en) * | 2013-06-27 | 2013-09-11 | 江苏红豆杉药业有限公司 | Treatment method of paclitaxel waste residues |
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| CN115304558A (en) * | 2022-08-17 | 2022-11-08 | 上海卓鼎生物技术有限公司 | Purification method of 1-hydroxy baccatin I |
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