A kind of preparation method of bearing taxanes and its intermediate
Technical field
The invention belongs to medical compounds and its intermediate synthesis technical field, be related to a kind of bearing taxanes and its
The preparation method of the preparation method of intermediate more particularly to a kind of TPI-287 and its intermediate.
Background technique
Bearing taxanes are a major class natural products obtained in the plant, and taxol is as this kind of compound
Star molecule is initially also to purify to obtain after being extracted from plants.With increasing for bearing taxanes, to what is had found
Compound carries out structure of modification, and to improve bioactivity, reduce toxic side effect, searching curative effect, tolerance are more preferable, absorption is easier
Analog become new research hotspot.
TPI-287, molecular formula C46H63NO15, there is structure shown in formula A.TPI-287 is after taxol
(Paclitaxel), the third generation taxanes anticancer after docetaxel (Docetaxel), Cabazitaxel (Cabazitaxel)
Medicine can be used for the treatment of the refractory solid tumors to a variety of drug resistants, be currently under clinical investigation phase.
In the late three decades, for world's cancer morbidity with average annual 3%~5% speed increase, cancer has become the mankind first
How the position cause of the death, be effectively prevented and treated the key issues that cancer is always medical research.With the Japanese yews such as taxol, docetaxel
Alkanes anticarcinogen is the same, and TPI-287, which has, promotes tubulin polymerization, stablizes micro-pipe and inhibits the characteristic of its depolymerization.It is external thin
Born of the same parents experimental studies have found that, TPI-287 can to the cell lines such as breast cancer, uterine cancer and non-small cell lung cancer generate inhibiting effect,
Play the curative effect similar with other taxanes and macrolides anticancer drug.TPI-287 is transplanted in specific animal tumor
The characteristic of inhibition tumour growth is shown in model, it is advantageous that, TPI-287 has the ability to avoid common resistant mechanism, tool
There is better drug resistance, also can penetrate through blood brain barrier, permeates central nervous system.TPI-287 is as the multiple reality for the treatment of
The drug resistant regeneration product of body tumor, wide market.
Currently, about TPI-287 synthetic method report it is less, be usually all 10- deacetylation baccatin III (also known as
It 10-DAB) is used as starting material, subsequent synthesis is carried out, obtains target compound TPI-287, but often there are intermediate receipts
Rate is low and purification difficult, and the utilization rate for ultimately causing female ring 10-DAB is low, at high cost, is not suitable for industrialized production;Or its
His reaction materil structure is complicated, and side reaction is more, influences yield, the problems such as causing side chain usage amount big, be unfavorable for save the cost etc..
Therefore, it is studied by the synthetic method to TPI-287 and its midbody compound, is the synthesis of TPI-287
A possibility that different, is provided, obtains the synthetic method of the TPI-287 for being more suitable for industrialized production and its intermediate with important
Meaning and field in forward-looking manufacturing enterprise and line researcher's urgent problem to be solved.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing the preparation side of a kind of TPI-287 and its intermediate
Method, preparation method reaction step provided by the invention is relatively simple, and reaction condition is controllable, and reaction raw materials are cheap and easy to get, and has
There is higher yield, is suitble to scale mass production.
The present invention provides a kind of preparation methods of TPI-287 intermediate A, comprising the following steps:
1) under the action of organic base, 10- deacetylation baccatin III and hydroxy-protecting agent is subjected to condensation reaction, obtained
To the compound of structure shown in formula (II);
The 10- deacetylation baccatin III has structure shown in formula (I);
Wherein, R is hydroxyl protection base;
2) under the action of oxidant, the compound of structure shown in formula (II) that above-mentioned steps obtain aoxidize anti-
It answers, obtains TPI-287 intermediate A;
The TPI-287 intermediate A has structure shown in formula (III);
Wherein, R is hydroxyl protection base.
Preferably, the organic base includes in pyridine, triethylamine, n,N-diisopropylethylamine, morpholine and N-methylmorpholine
It is one or more;
The hydroxy-protecting agent includes trichloroethyl chloroformate and/or silicon ethers protective agent;
The molar ratio of the 10- deacetylation baccatin III and the hydroxy-protecting agent is 1:(1~2);
The molar ratio of the 10- deacetylation baccatin III and the organic base is 1:(3~8);
The temperature of the condensation reaction is 20~40 DEG C;
The time of the condensation reaction is 20~30h.
Preferably, the oxidation reaction includes Dess-Martin oxidation, TPAP-NMO oxidation, TEMPO oxidation, Swern oxygen
Change, Oppenauer oxidation, Moffatt-Pfitzner oxidation, Sarett is aoxidized or Corey-Kim oxidation;
The oxidant includes Dess-Martin oxidant, TPAP/NMO oxidant, TEMPO, DMSO, (CH3)2CO、PCC
One of oxidant, anhydrous cupric chloride and copper acetate are a variety of;
The compound of structure shown in the formula (II) and the molar ratio of the oxidant are 1:(1.2~5);
The temperature of the oxidation reaction is 0~30 DEG C;
The time of the oxidation reaction is 0.5~10h.
The present invention provides a kind of preparation methods of TPI-287 intermediate B, comprising the following steps:
A) TPI-287 intermediate A described in above-mentioned technical proposal any one and reducing agent are carried out in organic solvent
Chemoselective reduction obtains the compound of structure shown in formula (IV);
Wherein, R is hydroxyl protection base;
B) under the action of organic base, the compound and acetylation reagent of structure shown in formula (IV) that above-mentioned steps are obtained
After acetylization reaction, the compound of structure shown in formula (V) is obtained;
Wherein, R is hydroxyl protection base;
C) in acid condition, after the compound of structure shown in formula (V) being deprotected, TPI-287 intermediate B is obtained;
The TPI-287 intermediate B has structure shown in formula (VI);
Preferably, the reducing agent includes NaBH4、LiBH4And LiAlH4One of or it is a variety of;
The TPI-287 intermediate A and the molar ratio of the reducing agent are 1:(2~3);
The organic solvent includes one of methanol, ethyl alcohol and tetrahydrofuran or a variety of;
The temperature of the reduction reaction is -10~30 DEG C;
The time of the reduction reaction is 0.5~5h.
Preferably, the organic base includes in pyridine, triethylamine, n,N-diisopropylethylamine, morpholine and N-methylmorpholine
It is one or more;
The compound of structure shown in the formula (IV) and the molar ratio of the organic base are 1:(2~5);
The acetylation reagent includes one of chloroacetic chloride, acetic anhydride and glacial acetic acid or a variety of;
The compound of structure shown in the formula (IV) and the molar ratio of acetylation reagent are 1:(2~3);
The temperature of the acetylization reaction is -20~25 DEG C;
The time of the acetylization reaction is 10~30h.
Preferably, the acid condition is by HF-TEA, HF-Pyr, CF3One of COOH, PTSA and CSA or a variety of are mentioned
For;
The acid condition is that pH value is less than or equal to 4;
The time of the deprotection is 3~20h;
The temperature of the deprotection is 20~60 DEG C.
The present invention provides the preparation methods of TPI-287 intermediate C a kind of, comprising the following steps:
By the compound of structure shown in TPI-287 intermediate B described in above-mentioned technical proposal any one, formula (VII) and
After organic acid is reacted, TPI-287 intermediate C is obtained;
The TPI-287 intermediate C has structure shown in formula (VIII);
9, preparation method according to claim 1, which is characterized in that the organic acid includes CSA, PTSA and TFA
One of or it is a variety of;
The compound of structure shown in the TPI-287 intermediate B, the formula (VII) and the molar ratio of organic acid are 1:(5
~10): (0.05~0.1);
The time of the reaction is 2~8h;
The temperature of the reaction is -20~30 DEG C.
The present invention also provides the preparation methods of TPI-287 a kind of, comprising the following steps:
TPI-287 intermediate C described in above-mentioned technical proposal any one is obtained into TPI- after coupling and deprotection
287。
The present invention provides a kind of preparation methods of TPI-287 intermediate A, include the following steps, first in organic base
Under effect, 10- deacetylation baccatin III and hydroxy-protecting agent are subjected to condensation reaction, obtain the change of structure shown in formula (II)
Close object;The 10- deacetylation baccatin III has structure shown in formula (I);Wherein, R is hydroxyl protection base;Then in oxygen
Under the action of agent, the compound of structure shown in formula (II) that above-mentioned steps are obtained carries out oxidation reaction, obtains in TPI-287
Mesosome A;The TPI-287 intermediate A has structure shown in formula (III);Wherein, R is hydroxyl protection base.With prior art phase
Than, the present invention in the synthesis process of existing TPI-287, and purification difficult low there are intermediate yield and other are anti-
The problems such as answering object, structure is complicated, and side reaction is more, influences yield, the present invention is from raw material 10- deacetylation baccatin III (also known as 10-
DAB initial step) is started with, and is protected the position the C-7 hydroxyl of 10-DAB first, is then selectively oxidized reaction, obtains
TPI-287 intermediate A provides good basis for subsequent step, solves the problems such as low intermediate yield and purification difficult,
Preparation method reaction step provided by the invention is relatively simple, and reaction condition is controllable, and reaction raw materials are cheap and easy to get, and have compared with
High yield is suitble to scale mass production.TPI-287 intermediate A prepared by the present invention is intermediate as the key of synthesis TPI-287
Body can be further used for the potential anticancer drug TPI-287 that preparation has anticancer activity.
The experimental results showed that preparation method reaction provided by the invention, prepares each from 10- deacetylation baccatin III
For intermediate to TPI-287, step is simple, and reaction condition is controllable, and reaction raw materials are cheap and easy to get, is suitble to scale mass production, and
Yield with higher and purity.
Detailed description of the invention
Fig. 1 is the HPLC spectrogram for the compound that the embodiment of the present invention 1 is prepared;
Fig. 2 is the HPLC spectrogram for the compound that the embodiment of the present invention 4 is prepared;
Fig. 3 is the HPLC spectrogram for the compound that the embodiment of the present invention 7 is prepared;
Fig. 4 is the HPLC spectrogram for the compound that the embodiment of the present invention 9 is prepared;
Fig. 5 is the HPLC spectrogram for the compound that the embodiment of the present invention 11 is prepared;
Fig. 6 is the HPLC spectrogram for the compound that the embodiment of the present invention 13 is prepared;
Fig. 7 is the mass spectrogram for the compound that the embodiment of the present invention 4 is prepared.
Specific embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described below with reference to embodiment, still
It should be appreciated that these descriptions are intended merely to further illustrate the features and advantages of the present invention, rather than to invention claim
Limitation.
All raw materials and reagents of the present invention, are not particularly limited its source, buying on the market or according to this field
The preparation of conventional method known to technical staff.
All raw materials of the present invention, are not particularly limited its purity, and present invention preferably employs medical pure or taxanes
Close the conventional purity of object preparation field.
The representation method of all structural formulas is not particularly limited in the present invention, with conventional table well known to those skilled in the art
On the basis of showing method, meet the basic common sense in field, those skilled in the art can correctly understand its meaning.
The present invention provides a kind of preparation methods of TPI-287 intermediate A, comprising the following steps:
1) under the action of organic base, 10- deacetylation baccatin III and hydroxy-protecting agent is subjected to condensation reaction, obtained
To the compound of structure shown in formula (II);
The 10- deacetylation baccatin III has structure shown in formula (I);
Wherein, R is hydroxyl protection base;
2) under the action of oxidant, the compound of structure shown in formula (II) that above-mentioned steps obtain aoxidize anti-
It answers, obtains TPI-287 intermediate A;
The TPI-287 intermediate A has structure shown in formula (III);
Wherein, R is hydroxyl protection base.
Under the action of organic base, 10- deacetylation baccatin III is condensed with hydroxy-protecting agent first by the present invention
Reaction, obtains the compound of structure shown in formula (II);
The 10- deacetylation baccatin III has structure shown in formula (I);
Wherein, R is hydroxyl protection base;
R in the compound of structure shown in formula (II) of the present invention is hydroxyl protection base, and the present invention, which is specifically chosen it, not to be had
Especially limitation, with conventional hydroxy protecting group well known to those skilled in the art, those skilled in the art can be according to reality
The condition of production, quality control and product requirement are selected and are adjusted, and R of the present invention derives from hydroxy-protecting agent, the choosing of R
The selection depending on hydroxy-protecting agent is selected, the two is preferably corresponding relationship.
The structure of the 10- deacetylation baccatin III is not particularly limited in the present invention, ripe with those skilled in the art
The structure for the 10- deacetylation baccatin III known, those skilled in the art can be according to practical conditions, quality control
System and product requirement are selected and are adjusted, and 10- deacetylation baccatin III of the present invention preferably has shown in formula (I)
Structure.
The organic base is not particularly limited in the present invention, has with the common of such reaction well known to those skilled in the art
Machine alkali, those skilled in the art can select and adjust according to practical condition, quality control and product requirement
Whole, organic base of the present invention preferably includes in pyridine, triethylamine, n,N-diisopropylethylamine, morpholine and N-methylmorpholine
It is one or more, more preferably pyridine, triethylamine, n,N-diisopropylethylamine, morpholine or N-methylmorpholine.
The dosage of the organic base is not particularly limited in the present invention, with such reaction well known to those skilled in the art
Conventional amount used, those skilled in the art can select according to practical condition, quality control and product requirement
And adjustment, the molar ratio of 10- deacetylation baccatin III of the present invention and the organic base is preferably 1:(3~8), it is more excellent
It is selected as 1:(4~7), most preferably 1:(5~6).
The hydroxy-protecting agent is not particularly limited in the present invention, with the normal of such reaction well known to those skilled in the art
With hydroxy-protecting agent, those skilled in the art can carry out according to practical condition, quality control and product requirement
Selection and adjustment, hydroxy-protecting agent of the present invention are preferably capable the hydroxyl protection of deprotection group in acid condition
Agent, more preferably includes trichloroethyl chloroformate and/or silicon ethers protective agent, and most preferably trichloroethyl chloroformate or silicon ethers is protected
Protect agent.The silicon ethers protective agent is not particularly limited in the present invention, with the normal of such reaction well known to those skilled in the art
With silicon ethers protective agent, those skilled in the art can according to practical condition, quality control and product requirement into
Row selection and adjustment, silicon ethers protective agent of the present invention preferably include chlorotriethyl silane, trim,ethylchlorosilane, trifluoro methylsulphur
One of sour trimethylsilyl group, tert-butyl diphenyl chlorosilane, tert-butyl chloro-silicane and tri isopropyl chlorosilane or
It is a variety of;More preferably chlorotriethyl silane, trim,ethylchlorosilane, Trimethylsilyl trifluoromethanesulfonate, tert-butyl diphenyl chlorine silicon
Alkane, tert-butyl chloro-silicane or tri isopropyl chlorosilane, most preferably chlorotriethyl silane.
The dosage of the hydroxy-protecting agent is not particularly limited in the present invention, with well known to those skilled in the art such anti-
The conventional amount used answered, those skilled in the art can carry out according to practical condition, quality control and product requirement
Selection and adjustment, the molar ratio of 10- deacetylation baccatin III of the present invention and the hydroxy-protecting agent be preferably 1:(1~
2), more preferably 1:(1.2~1.8), more preferably 1:(1.3~1.7), most preferably 1:(1.4~1.6).
The reaction temperature of the condensation reaction is not particularly limited in the present invention, with well known to those skilled in the art such
The reaction temperature of reaction, those skilled in the art can according to practical condition, quality control and product requirement into
Row selection and adjustment, the temperature of condensation reaction of the present invention is preferably 20~40 DEG C, and more preferably 24~36 DEG C, most preferably
28~32 DEG C.The reaction time of the condensation reaction is not particularly limited in the present invention, with it is well known to those skilled in the art this
The reaction time of class reaction, those skilled in the art can be according to practical condition, quality control and product requirements
It is selected and is adjusted, the time of condensation reaction of the present invention is preferably 20~30h, more preferably 22~28h, most preferably
24~26h.
Other reaction conditions of the condensation reaction are not particularly limited in the present invention, with well known to those skilled in the art
The reaction condition of such reaction, those skilled in the art can want according to practical condition, quality control and product
It asks and is selected and adjusted, condensation reaction of the present invention can carry out under protective gas atmosphere or normality, wherein described
Protective gas atmosphere preferably includes nitrogen and/or inert gas, more preferably nitrogen or argon gas;The normality is preferably normal pressure
Non- isolation air condition.
Then under the action of oxidant, the compound of structure shown in formula (II) that above-mentioned steps are obtained carries out the present invention
Oxidation reaction obtains TPI-287 intermediate A.
R in the compound of structure shown in formula (III) of the present invention is hydroxyl protection base, and the present invention, which is specifically chosen it, not to be had
Especially limitation, with conventional hydroxy protecting group well known to those skilled in the art, those skilled in the art can be according to reality
The condition of production, quality control and product requirement are selected and are adjusted, and R of the present invention derives from hydroxy-protecting agent, the choosing of R
The selection depending on hydroxy-protecting agent is selected, the two is preferably corresponding relationship.
TPI-287 intermediate A of the present invention with structure shown in formula (III) is not particularly limited, with this field skill
Some intermediate of TPI-287 process is prepared known to art personnel, those skilled in the art can be according to actual production feelings
Condition, quality control and product requirement are selected and are adjusted.
The type of the oxidation reaction is not particularly limited in the present invention, with regular oxidation well known to those skilled in the art
Type, those skilled in the art can select and adjust according to practical condition, quality control and product requirement
Whole, the type of oxidation reaction of the present invention is preferably the common oxidized reaction type in TPI-287 preparation process, more preferably
Secondary alcohol can be oxidized to the oxidation reaction of ketone, more preferably aoxidized including Dess-Martin oxidation, TPAP-NMO oxidation, TEMPO,
Swern oxidation, Oppenauer oxidation, Moffatt-Pfitzner oxidation, Sarett oxidation or Corey-Kim oxidation, most preferably
For Dess-Martin oxidation reaction, TPAP-NMO oxidation reaction or TEMPO oxidation reaction.
The oxidant is not particularly limited in the present invention, with the common oxygen of such reaction well known to those skilled in the art
Agent, those skilled in the art can select and adjust according to practical condition, quality control and product requirement
Whole, oxidant of the present invention is preferably the common oxidant of above-mentioned oxidation reaction type, more preferably includes Dess-Martin oxygen
Agent, TPAP/NMO oxidant, TEMPO, DMSO, (CH3)2One of CO, PCC oxidant, anhydrous cupric chloride and copper acetate or
It is a variety of, more preferably Dess-Martin oxidant, TPAP/NMO oxidant, TEMPO, DMSO, (CH3)2CO, PCC oxidant, nothing
Water copper chloride or copper acetate, most preferably Dess-Martin oxidant, TPAP/NMO (TPAP-NMO) oxidant or TEMPO.
The dosage of the oxidant is not particularly limited in the present invention, with such reaction well known to those skilled in the art
Conventional amount used, those skilled in the art can select according to practical condition, quality control and product requirement
And adjustment, the compound of structure shown in formula (II) of the present invention and the molar ratio of the oxidant are preferably 1:(1.2~5),
More preferably 1:(1.7~4.5), more preferably 1:(2.2~4), most preferably 1:(2.7~3.5).
The reaction temperature of the oxidation reaction is not particularly limited in the present invention, with well known to those skilled in the art such
The reaction temperature of reaction, those skilled in the art can according to practical condition, quality control and product requirement into
Row selection and adjustment, the temperature of oxidation reaction of the present invention is preferably 0~30 DEG C, more preferably 5~25 DEG C, most preferably 10
~25 DEG C.The reaction time of the oxidation reaction is not particularly limited in the present invention, with well known to those skilled in the art such
The reaction time of reaction, those skilled in the art can according to practical condition, quality control and product requirement into
Row selection and adjustment, the time of oxidation reaction of the present invention is preferably 0.5~10h, more preferably 2.5~8h, most preferably
4.5~6h.
The present invention provides a kind of preparation methods of TPI-287 intermediate B, comprising the following steps:
A) TPI-287 intermediate A described in above-mentioned technical proposal any one and reducing agent are carried out in organic solvent
Chemoselective reduction obtains the compound of structure shown in formula (IV);
Wherein, R is hydroxyl protection base;
B) under the action of organic base, the compound and acetylation reagent of structure shown in formula (IV) that above-mentioned steps are obtained
After acetylization reaction, the compound of structure shown in formula (V) is obtained;
Wherein, R is hydroxyl protection base;
C) in acid condition, after the compound of structure shown in formula (V) being deprotected, TPI-287 intermediate B is obtained;
The TPI-287 intermediate B has structure shown in formula (VI);
The present invention is first by TPI-287 intermediate A described in above-mentioned technical proposal any one and reducing agent organic molten
Chemoselective reduction is carried out in agent, obtains the compound of structure shown in formula (IV).
R in the compound of structure shown in formula (IV) of the present invention is hydroxyl protection base, and the present invention, which is specifically chosen it, not to be had
Especially limitation, with conventional hydroxy protecting group well known to those skilled in the art, those skilled in the art can be according to reality
The condition of production, quality control and product requirement are selected and are adjusted, and R of the present invention derives from hydroxy-protecting agent, the choosing of R
The selection depending on hydroxy-protecting agent is selected, the two is preferably corresponding relationship.
The reducing agent is not particularly limited in the present invention, and common with such reaction well known to those skilled in the art is gone back
Former agent, those skilled in the art can select and adjust according to practical condition, quality control and product requirement
Whole, reducing agent of the present invention preferably includes NaBH4、LiBH4And LiAlH4One of or a variety of, more preferably NaBH4、
LiBH4Or LiAlH4。
The dosage of the reducing agent is not particularly limited in the present invention, with such reaction well known to those skilled in the art
Conventional amount used, those skilled in the art can select according to practical condition, quality control and product requirement
And adjustment, the molar ratio of TPI-287 intermediate A of the present invention and the reducing agent are 1:(2~3), more preferably 1:(2.2
~2.8), most preferably 1:(2.4~2.6).
The organic solvent is not particularly limited in the present invention, with the common of such reaction well known to those skilled in the art
Organic solvent, those skilled in the art can select according to practical condition, quality control and product requirement
And adjustment, organic solvent of the present invention preferably include one of methanol, ethyl alcohol and tetrahydrofuran or a variety of, more preferably first
Alcohol, ethyl alcohol or tetrahydrofuran.
The dosage of the organic solvent is not particularly limited in the present invention, with such reaction well known to those skilled in the art
Conventional amount used, those skilled in the art can according to practical condition, quality control and product requirement select
It selects and adjusts.
The reaction temperature of the Chemoselective reduction is not particularly limited in the present invention, known to those skilled in the art
Such reaction reaction temperature, those skilled in the art can according to practical condition, quality control and product
It is required that selected and adjusted, preferably -10~30 DEG C of the temperature of Chemoselective reduction of the present invention, more preferably -5~
25 DEG C, more preferably 0~20 DEG C, most preferably 5~15 DEG C.The present invention does not have the reaction time of the Chemoselective reduction
Especially limitation, with the reaction time of such reaction well known to those skilled in the art, those skilled in the art can basis
Practical condition, quality control and product requirement selected and adjusted, Chemoselective reduction of the present invention when
Between preferably 0.5~5h, more preferably 1.5~4h, most preferably 2.5~3h.
Other reaction conditions of the Chemoselective reduction are not particularly limited in the present invention, with those skilled in the art
The reaction condition of well known such reaction, those skilled in the art can according to practical condition, quality control and
Product requirement is selected and is adjusted, Chemoselective reduction of the present invention can under protective gas atmosphere or normality into
Row, wherein the protective gas atmosphere preferably includes nitrogen and/or inert gas, more preferably nitrogen or argon gas;It is described normal
State is preferably the non-isolation air condition of normal pressure.
The present invention is then under the action of organic base, the compound and second of structure shown in formula (IV) that above-mentioned steps are obtained
Acylating reagent obtains the compound of structure shown in formula (V) after acetylization reaction.
R in the compound of structure shown in formula (V) of the present invention is hydroxyl protection base, and the present invention is specifically chosen it without spy
It does not limit, with conventional hydroxy protecting group well known to those skilled in the art, those skilled in the art can be according to practical life
It produces situation, quality control and product requirement to be selected and adjusted, R of the present invention derives from hydroxy-protecting agent, the selection of R
Depending on the selection of hydroxy-protecting agent, the two is preferably corresponding relationship.
The organic base is not particularly limited in the present invention, has with the common of such reaction well known to those skilled in the art
Machine alkali, those skilled in the art can select and adjust according to practical condition, quality control and product requirement
Whole, organic base of the present invention preferably includes in pyridine, triethylamine, n,N-diisopropylethylamine, morpholine and N-methylmorpholine
It is one or more, more preferably pyridine, triethylamine, n,N-diisopropylethylamine, morpholine or N-methylmorpholine.
The dosage of the organic base is not particularly limited in the present invention, with such reaction well known to those skilled in the art
Conventional amount used, those skilled in the art can select according to practical condition, quality control and product requirement
And adjustment, the compound of structure shown in formula (IV) of the present invention and the molar ratio of the organic base are preferably 1:(2~5), more
Preferably 1:(2.5~4.5), most preferably 1:(3~4).
The acetylation reagent is not particularly limited in the present invention, with the normal of such reaction well known to those skilled in the art
With acetylation reagent, those skilled in the art can carry out according to practical condition, quality control and product requirement
Selection and adjustment, acetylation reagent of the present invention preferably include one of chloroacetic chloride, acetic anhydride and glacial acetic acid or a variety of, more
Preferably chloroacetic chloride, acetic anhydride or glacial acetic acid.
The dosage of the acetylation reagent is not particularly limited in the present invention, with well known to those skilled in the art such anti-
The conventional amount used answered, those skilled in the art can carry out according to practical condition, quality control and product requirement
Selection and adjustment, the compound of structure shown in formula (IV) of the present invention and the molar ratio of acetylation reagent be preferably 1:(2~
3), more preferably 1:(2.2~2.8), most preferably 1:(2.4~2.6).
The reaction temperature of the acetylization reaction is not particularly limited in the present invention, with it is well known to those skilled in the art this
The reaction temperature of class reaction, those skilled in the art can be according to practical condition, quality control and product requirements
It is selected and is adjusted, preferably -20~25 DEG C of the temperature of acetylization reaction of the present invention, more preferably -10~15 DEG C, most
Preferably 0~5 DEG C.The reaction time of the acetylization reaction is not particularly limited in the present invention, ripe with those skilled in the art
The reaction time for the such reaction known, those skilled in the art can control and produce according to practical condition, quality
Product require to be selected and adjusted, and the time of acetylization reaction of the present invention is preferably 10~30h, more preferably 14~26h,
Most preferably 18~22h.
Other reaction conditions of the reaction are not particularly limited in the present invention, with well known to those skilled in the art such
The reaction condition of reaction, those skilled in the art can according to practical condition, quality control and product requirement into
Row selection and adjustment, acetylization reaction of the present invention can carry out under protective gas atmosphere or normality, wherein the guarantor
Shield property atmosphere preferably includes nitrogen and/or inert gas, more preferably nitrogen or argon gas;The normality is preferably that normal pressure is non-
Completely cut off air condition.
The present invention finally in acid condition, after the compound of structure shown in formula (V) is deprotected, obtains in TPI-287
Mesosome B.
TPI-287 intermediate B of the present invention with structure shown in formula (VI) is not particularly limited, with art technology
Prepare some intermediate of TPI-287 process known to personnel, those skilled in the art can according to practical condition,
Quality control and product requirement are selected and are adjusted.
The raw material for generating the acid condition is not particularly limited in the present invention, with well known to those skilled in the art such
The raw material of the common generation acid condition of reaction, those skilled in the art can control according to practical condition, quality
And product requirement is selected and is adjusted, acid condition of the present invention is preferably by HF-TEA, HF-Pyr, CF3COOH、PTSA
With one of CSA or a variety of offers, more preferably by HF-TEA (hydrofluoric acid triethylamine), HF-Pyr (hydrofluoric acid pyridine),
CF3COOH, PTSA (p-methyl benzenesulfonic acid) or CSA (camphorsulfonic acid) are provided.
The dosage of the raw material for generating the acid condition is not particularly limited in the present invention, with those skilled in the art
The conventional amount used of well known such reaction, those skilled in the art can according to practical condition, quality control and
Product requirement is selected and is adjusted, and acid condition of the present invention is preferably that pH value is less than or equal to 4, is more preferably less than equal to
3.5, most preferably less than it is equal to 3.
The reaction temperature of the deprotection reaction is not particularly limited in the present invention, with it is well known to those skilled in the art this
The reaction temperature of class reaction, those skilled in the art can be according to practical condition, quality control and product requirements
It is selected and is adjusted, the temperature of deprotection reaction of the present invention is preferably 20~60 DEG C, more preferably 30~50 DEG C, optimal
It is selected as 35~45 DEG C.The time of the deprotection reaction is not particularly limited in the present invention, with well known to those skilled in the art
The reaction time of such reaction, those skilled in the art can want according to practical condition, quality control and product
It asks and is selected and adjusted, the time of deprotection reaction of the present invention is preferably 3~20h, more preferably 5~18h, most preferably
For 8~15h.
Other reaction conditions of the deprotection are not particularly limited in the present invention, with it is well known to those skilled in the art this
The reaction condition of class reaction, those skilled in the art can be according to practical condition, quality control and product requirements
It is selected and is adjusted, deprotection of the present invention can carry out under protective gas atmosphere or normality, wherein the protection
Property atmosphere preferably includes nitrogen and/or inert gas, more preferably nitrogen or argon gas;The normality be preferably normal pressure it is non-every
Exhausted air condition.
The present invention provides the preparation methods of TPI-287 intermediate C a kind of, comprising the following steps:
By the compound of structure shown in TPI-287 intermediate B described in above-mentioned technical proposal any one, formula (VII) and
After organic acid is reacted, TPI-287 intermediate C is obtained;
The TPI-287 intermediate C has structure shown in formula (VIII);
TPI-287 intermediate C of the present invention with structure shown in formula (VIII) is not particularly limited, with this field skill
Some intermediate of TPI-287 process is prepared known to art personnel, those skilled in the art can be according to actual production feelings
Condition, quality control and product requirement are selected and are adjusted.
The compound of structure shown in formula (VII) is not particularly limited in the present invention, with tool well known to those skilled in the art
Have a compound of structure shown in formula (VII), those skilled in the art can according to practical condition, quality control and
Product requirement is selected and is adjusted, and the compound of structure shown in formula (VII) of the present invention is preferably 3,3- dimethoxy -1-
Propylene, the two have equivalent concept in the present invention.
The present invention is to the compound of structure shown in the formula (VII), i.e. the dosage of 3,3- dimethoxy -1- propylene is without spy
It does not limit, with the conventional amount used of such reaction well known to those skilled in the art, those skilled in the art can be according to reality
The border condition of production, quality control and product requirement selected and adjusted, TPI-287 intermediate B of the present invention with it is described
The molar ratio of the compound of structure shown in formula (VII) is 1:(5~10), more preferably 1:(6~9), most preferably 1:(7~8).
Organic acid is not particularly limited in the present invention, with the common organic acid of such reaction well known to those skilled in the art
, those skilled in the art can be controlled according to practical condition, quality and product requirement be selected and be adjusted, this
It invents the organic acid and preferably includes one of CSA, PTSA and TFA or a variety of, more preferably CSA, PTSA or TFA (trifluoro
Acetic acid).
The dosage of the organic acid is not particularly limited in the present invention, with such reaction well known to those skilled in the art
Conventional amount used, those skilled in the art can select according to practical condition, quality control and product requirement
And adjustment, the molar ratio of TPI-287 intermediate B of the present invention and organic acid is preferably 1:(0.05~0.1), more preferably 1:
(0.1~0.9), more preferably 1:(0.3~0.7), most preferably 1:(0.4~0.6).
The temperature of the reaction is not particularly limited in the present invention, with the anti-of such reaction well known to those skilled in the art
Answer temperature, those skilled in the art can be selected according to practical condition, quality control and product requirement and
Adjustment, the temperature of reaction of the present invention are preferably -20~30 DEG C, more preferably -10~20 DEG C, most preferably 0~10 DEG C.This
The time of the reaction is not particularly limited in invention, and the reaction time with such reaction well known to those skilled in the art is
Can, those skilled in the art can select and adjust, this hair according to practical condition, quality control and product requirement
The time of the bright reaction is preferably 2~8h, more preferably 3~7h, most preferably 4~6h.
The present invention also provides the preparation methods of TPI-287 a kind of, comprising the following steps:
TPI-287 intermediate C described in above-mentioned technical proposal any one is obtained into TPI- after coupling and deprotection
287。
The process of TPI-287 is prepared to the TPI-287 intermediate C by the present invention and parameter is not particularly limited, with
Conventional process well known to those skilled in the art and parameter, those skilled in the art can be according to practical conditions, matter
Amount control and product requirement are selected and are adjusted, and TPI-287 intermediate C of the present invention after treatment, obtains TPI-
287.Processing of the present invention is preferably included to be coupled and is deprotected, but is not limited to above-mentioned steps.
The TPI-287 and its structure is not particularly limited in the present invention, with TPI-287 well known to those skilled in the art
And its structure, those skilled in the art can select according to practical condition, quality control and product requirement
And adjustment.
The present invention provides a kind of TPI-287 intermediate A, the preparation method of B, C and TPI-287, the present invention is for existing
TPI-287 synthesis process in, and purification difficult low there are intermediate yield and other reaction materil structures are complicated, secondary anti-
Ying Duo, the problems such as influencing yield, the present invention enters from the initial step of raw material 10- deacetylation baccatin III (also known as 10-DAB)
Hand protects the position the C-7 hydroxyl of 10-DAB first, is then selectively oxidized, reduction reaction, then C-10 hydroxyls of acetylation
Base, deprotection, finally carries out acetalation, solves that intermediate yield present in existing preparation process is low and purification difficult etc. is asked
Topic, preparation method good reaction selectivity provided by the invention, high income is easy to operate, and reaction condition is controllable, and reaction raw materials are cheap
It is easy to get, and yield with higher, is suitble to scale mass production.TPI-287 intermediate A prepared by the present invention, B and C conduct
The key intermediate for synthesizing TPI-287 can be further used for the potential anticancer drug TPI-287 that preparation has anticancer activity.
The experimental results showed that preparation method reaction provided by the invention, prepares each from 10- deacetylation baccatin III
For intermediate to TPI-287, step is simple, and reaction condition is controllable, and reaction raw materials are cheap and easy to get, is suitble to scale mass production, and
Yield with higher and purity.
For a further understanding of the present invention, below with reference to embodiment to a kind of bearing taxanes provided by the invention and
Wherein the preparation method of mesosome is illustrated, but it is to be understood that these embodiments are based on the technical solution of the present invention
Under implemented, the detailed implementation method and specific operation process are given, only to further illustrate feature of the invention
And advantage, rather than limiting to the claimed invention, protection scope of the present invention are also not necessarily limited to following embodiments.
In the preparation method of TPI-287 intermediate provided in the present invention, raw materials used or reagent is available on the market.
Embodiment 1
The preparation of compound shown in formula (II-a)
By the deacetylated baccatin III female ring of 10.0g 10-, 250mL circle is added in methylene chloride 25mL and anhydrous pyridine 40mL
It is completely dissolved in the flask of bottom.Nitrogen protection, is slowly added dropwise chlorotriethyl silane 6.0mL at room temperature, and drop finishes, is stirred at room temperature.HPLC
Monitoring, until the reaction is complete.
After about 20h is stirred at room temperature, water, which is added, stops reaction;Then it is extracted with ethyl acetate 3 times, merges organic phase, use
500mL saturated common salt water washing, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated into no distillate.N-hexane mashing is added to stir
1h is mixed, is filtered, reduced vacuum is dry to protect female ring 11.2g, white to get compound 7- triethyl silyl shown in formula (II-a)
Solid.
Product prepared by the embodiment of the present invention 1 is detected through HPLC, is production prepared by the embodiment of the present invention 1 referring to Fig. 1, Fig. 1
The HPLC of object schemes.As shown in Figure 1, purity 94.7%, yield 92.2%.
Embodiment 2
The preparation of compound shown in formula (II-b)
By the deacetylated baccatin III female ring of 10.0g 10-, 250mL round bottom is added in methylene chloride 30mL and triethylamine 40mL
It is completely dissolved in flask.Tri isopropyl chlorosilane 7.5mL is slowly added dropwise at 20 DEG C, drop finishes, 20 DEG C of stirrings.HPLC monitoring, until
Reaction is completed.
After 20 DEG C of stir about 23h, water, which is added, stops reaction;Then it is extracted with ethyl acetate 3 times, merges organic phase, use
Saturated common salt water washing, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated into no distillate.Add n-hexane mashing stirring 1h,
Filtering, reduced vacuum is dry to protect female ring 11.7g to get compound 7- tri isopropyl silane base shown in formula (II-b), and white is solid
Body.
Product prepared by the embodiment of the present invention 2 is detected through HPLC, purity 95.2%, yield 90.8%.
Embodiment 3
The preparation of compound shown in formula (II-c)
By the deacetylated baccatin III female ring of 10.0g 10-, pyridine 70mL is added in 250mL round-bottomed flask and is completely dissolved.
Trichloroethyl chloroformate 4.0mL is slowly added dropwise at 35 DEG C, drop finishes, 35 DEG C of stirrings.HPLC monitoring, until the reaction is complete.
After 35 DEG C of stir about 27h, water, which is added, stops reaction;Then it is extracted with ethyl acetate 3 times, merges organic phase, use
Saturated common salt water washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration.Add n-hexane mashing stirring 1h, filters, decompression
Vacuum drying protects female ring 11.1g, white solid to get compound 7- trichloroethyl shown in formula (II-c).
Product prepared by the embodiment of the present invention 3 is detected through HPLC, purity 94.2%, yield 89.7%.
Embodiment 4
The preparation of compound shown in formula (III-a)
By compound 10.0g, methylene chloride 150ml shown in the formula (II-a) prepared according to embodiment 1,500ml tri- is added
In mouth bottle, it is placed in 0 DEG C of freezing tank, the dichloromethane solution of Dai Si-Martin (Dess-Martin) oxidant (0.03mol) is added dropwise
10ml is added dropwise, and reaction, HPLC monitoring reaction is stirred at room temperature.After reaction about 1h is stirred at room temperature, reaction solution is gone into liquid separation leakage
Bucket, successively with saturation NaHCO3Solution is saturated NaHSO3Solution, saturation NaCl solution washing, collects organic phase.Use anhydrous slufuric acid
Sodium dries, filters, and filtrate decompression concentration, vacuum oven is dried under reduced pressure, and obtains compound 9.6g shown in formula (III-a).
Product prepared by the embodiment of the present invention 4 is detected through HPLC, and referring to fig. 2, Fig. 2 is production prepared by the embodiment of the present invention 4
The HPLC of object schemes.It as shown in Figure 2, is 95.5% through HPLC detection purity, yield 96.3%.
Referring to Fig. 7, Fig. 7 is the mass spectrogram for the compound that the embodiment of the present invention 4 is prepared.As shown in Figure 7, system of the present invention
It is standby to have obtained the compound with formula (III-a) structure.
Embodiment 5
The preparation of compound shown in formula (III-b)
By compound 10.0g, methanol 300ml shown in the formula (II-b) prepared according to embodiment 2,500ml round bottom is added and burns
In bottle, it being sufficiently stirred dissolution, under the conditions of 30 DEG C, copper acetate 12.5g is added, is stirred to react 10h, filtering, filtrate is depressurized and spin-dried,
Merge filter cake and 250ml water is added;Then it is extracted with ethyl acetate 3 times, combined ethyl acetate layer is concentrated to dryness, and will be evaporated product silica gel
Column chromatography, obtains compound 6.5g shown in formula (III-b).
Product prepared by the embodiment of the present invention 5 is detected through HPLC, is 97.5% through HPLC detection purity, yield 66.3%.
Embodiment 6
The preparation of compound shown in formula (III-c)
By compound 30.0g shown in the formula (II-c) prepared according to embodiment 3, a small amount of potassium bromide, methylene chloride 120ml,
Purified water 30ml, TEMPO oxidant 0.07g is added in 500ml reaction flask, is placed in 0 DEG C of freezing tank, 7%NaHCO is slowly added dropwise3
Aqueous solution 120g, 12.5%NaClO aqueous solution 33g, is vigorously stirred about 30min, goes to separatory funnel extraction.Organic layer is successively used
10%NaHSO comprising 0.76gNaI4Solution, 10%Na2S2O3Solution and 108.5g saturated common salt water washing, anhydrous sodium sulfate
It dries, filters, is concentrated into no distillate, compound 22.5g shown in formula (III-c) is obtained after column chromatographs.
Product prepared by the embodiment of the present invention 6 is detected through HPLC, purity 97.2%, yield 75.2%.
Embodiment 7
The preparation of compound shown in formula (IV-a)
By compound 4.0g, tetrahydrofuran 20ml, methanol 4ml shown in the formula (III-a) prepared according to embodiment 4, it is added
It in 250ml single port bottle, is completely dissolved, places it in -10 DEG C of freezing tanks.Under nitrogen protection, it is slowly added to 2.0M LiBH4's
THF solution 7.2ml.It after being added dropwise, is stirred at room temperature and reacts 1h, under condition of ice bath, the ethyl alcohol that 10% ammonium acetate is slowly added dropwise is molten
Liquid 15ml.Then 0.1ml glacial acetic acid is added and terminates reaction, pure water 50ml is added dropwise into reaction solution, gained precipitates, through filtering, water
It washes, is dried in vacuo, obtains compound 3.6g shown in formula (IV-a).
Product prepared by the embodiment of the present invention 7 is detected through HPLC, is production prepared by the embodiment of the present invention 7 referring to Fig. 3, Fig. 3
The HPLC of object schemes.From the figure 3, it may be seen that be 95.4% through HPLC detection purity, yield 91.1%.
Embodiment 8
The preparation of compound shown in formula (IV-c)
By compound 10.0g, ethyl alcohol 100ml shown in the formula (III-c) prepared according to embodiment 6,250ml single port bottle is added
In, it is completely dissolved, places it in 0 DEG C of freezing tank.Under nitrogen protection, it is slowly added to 2.0M LiAlH4THF solution
20.0ml.After being added dropwise, 0~10 DEG C is stirred to react 4h, and under condition of ice bath, the ethanol solution of 10% ammonium acetate is slowly added dropwise
40ml.Then glacial acetic acid is added and terminates reaction, pure water is added dropwise into reaction solution, gained precipitating is filtered, is washed, vacuum drying,
Obtain compound 8.9g shown in formula (IV-c).
Product prepared by the embodiment of the present invention 8 is detected through HPLC, purity 95.8%, yield 89.2%.
Embodiment 9
The preparation of compound shown in formula (V-a)
By compound 3.6g, anhydrous pyridine 25ml shown in the formula (IV-a) prepared according to embodiment 7,250ml single port is added
In bottle, it is completely dissolved, is placed in -20 DEG C of freezing tanks.Under nitrogen protection, DMF solution (the 1.0ml chloroacetic chloride of chloroacetic chloride is slowly added dropwise
It is dissolved in 10mlDMF), it is added dropwise, -20 DEG C are stirred to react, HPLC monitoring, about 20h end of reaction.Reaction solution is poured into about 5
Again in the ice water of amount, stirring, gained precipitating is filtered, washing, and vacuum drying obtains compound 3.34g shown in formula (V-a).
Product prepared by the embodiment of the present invention 9 is detected through HPLC, and referring to fig. 4, Fig. 4 is production prepared by the embodiment of the present invention 9
The HPLC of object schemes.As shown in Figure 4, it is detected through HPLC, purity 92.5%, yield 87.4%.
Embodiment 10
The preparation of compound shown in formula (V-c)
By compound 5.0g, morpholine 10ml, methylene chloride 50ml shown in the formula (IV-c) prepared according to embodiment 8, it is added
It in 250ml single port bottle, is completely dissolved, is placed in 0 DEG C of freezing tank.Under nitrogen protection, the DMF solution (2.0ml of acetic anhydride is slowly added dropwise
Acetic anhydride is dissolved in 10mlDMF), it is added dropwise, 0~20 DEG C is stirred to react, HPLC monitoring, about 25h end of reaction.By reaction solution
In ice water, methylene chloride is extracted 2 times, and organic phase is washed with water, anhydrous Na SO4It is dry, it is concentrated under reduced pressure, vacuum drying obtains formula
(V-c) compound 4.4g shown in.
Product prepared by the embodiment of the present invention 10 is detected through HPLC, purity 94.1%, yield 83.3%.
Embodiment 11
The preparation of compound shown in formula (VI)
250ml single port is added in compound 10.0g, 80ml tetrahydrofuran shown in the formula (V-a) prepared according to embodiment 9 to burn
In bottle, stirring and dissolving instills hydrofluoric acid triethylamine 15ml at room temperature, is warming up to 50 DEG C and continues to be stirred to react, HPLC monitoring, about 3h
Fully reacting.Appropriate ice water is added into reaction solution, saturation NaOH solution is added dropwise and slowly adjusts pH to 7 or so, is then added solid
Body NaHCO3To reaction solution in alkalinity;Ethyl acetate is added and extracts liquid separation, collects organic phase.Then it is washed with saturation NaCl solution
3 times, anhydrous sodium sulfate dries, filters, filtrate concentration, and vacuum drying obtains being deprotected compound 8.1g shown in formula (VI).
Product prepared by the embodiment of the present invention 11 is detected through HPLC, is prepared by the embodiment of the present invention 11 referring to Fig. 5, Fig. 5
The HPLC of product schemes.As shown in Figure 5, it is detected through HPLC, purity 98.7%, yield 96.8%.
Embodiment 12
The preparation of compound shown in formula (VI)
By compound 10.0g, methanol 100ml shown in the formula (V-c) prepared according to embodiment 10,250ml single port is added and burns
In bottle, 20~30 DEG C of stirring and dissolvings are added p-methyl benzenesulfonic acid (PTSA), and drop adds water in reaction solution, guarantee reaction solution without solid
It is precipitated.Drop finishes, and HPLC monitoring reaction after reacting 15~20h, adds 50mL ethyl acetate and 50mL water to extract, water layer acetic acid second
Ester washing, merges organic phase.Organic phase saturated common salt water washing, collected organic layer decompression are spin-dried for, after silica gel column chromatography, obtain
To compound 7.8g shown in formula (VI).
Product prepared by the embodiment of the present invention 12 is detected through HPLC, purity 98.5%, yield 94.1%.
Embodiment 13
The preparation of TPI-287 intermediate shown in formula (VIII)
By compound 10.0g, 50ml methylene chloride shown in formula (VI), it is added in 250ml single port bottle, dissolved clarification is stirred at room temperature,
The compound 3 shown in addition formula (VII) into reaction solution, 3- dimethoxy -1- propylene 12.1g, camphorsulfonic acid (CSA) 0.175g,
HPLC is monitored, and stops reaction after 3.5h.125ml methylene chloride dilute reaction solution is added, is transferred to and fills 250ml 5%NaHCO3
In the separatory funnel of solution, organic phase is collected in extraction, and water phase washed once with methylene chloride, merges organic layer, with saturation chlorination
Sodium washing, anhydrous Na2SO4It is dry, it filters, filtrate decompression concentration through silica gel column chromatography, obtains compound shown in formula (VIII)
9.1g。
Product prepared by the embodiment of the present invention 13 is detected through HPLC, is prepared by the embodiment of the present invention 13 referring to Fig. 6, Fig. 6
The HPLC of product schemes.It will be appreciated from fig. 6 that being detected through HPLC, purity 98.1%, yield 85.1%.
The intermediate as shown in above-mentioned formula (VIII) obtains TPI-287 after coupling and deprotection.
Embodiment 14
The preparation of TPI-287 intermediate shown in formula (VIII)
By compound 10.0g, 70ml methylene chloride shown in formula (VI), it is added in 250ml single port bottle, -20 DEG C of stirring dissolved clarifications,
The compound 3 shown in addition formula (VII) into reaction solution, 3- dimethoxy -1- propylene 15.6g, p-methyl benzenesulfonic acid (PTSA) 0.3g,
HPLC is monitored, and stops reaction after 7h.100ml methylene chloride dilute reaction solution is added, is transferred to and fills 5%NaHCO3Point of solution
In liquid funnel, organic phase is collected in extraction, and water phase washed once with methylene chloride, is merged organic layer, is washed with saturated sodium-chloride,
Anhydrous Na2SO4It is dry, it filters, filtrate decompression concentration through silica gel column chromatography, obtains compound 8.4g shown in formula (VIII).
Product prepared by the embodiment of the present invention 14 is detected through HPLC, purity 98.4%, yield 78.8%.
The intermediate as shown in above-mentioned formula (VIII) obtains TPI-287 after coupling and deprotection.
The preparation method of TPI-287 provided by the invention and its intermediate are described in detail above, herein
Apply that a specific example illustrates the principle and implementation of the invention, the explanation of above example is only intended to help
Understand method and its core concept of the invention, including best mode, and but also any person skilled in the art can
Enough practice present invention, including any device or system of manufacture and use, and implement the method for any combination.It should be pointed out that for
For those skilled in the art, without departing from the principle of the present invention, if can also be carried out to the present invention
Dry improvement and modification, these improvements and modifications also fall within the scope of protection of the claims of the present invention.The invention patent protection
Range is defined by the claims, and may include those skilled in the art it is conceivable that other embodiments.If these its
He has the structural element for being not different from claim character express at embodiment, or if they include and claim
Equivalent structural elements of the character express without essence difference, then these other embodiments should also be included in the scope of the claims
It is interior.