A kind of preparation method of 2- methyl -5- fluobenzoic acid
Technical field
The present invention relates to field of medicine and chemical technology more particularly to a kind of preparation methods of 2- methyl -5- fluobenzoic acid.
Background technique
Oophoroma is common one of the malignant tumour of female sex organ, and the death rate but accounts for the first place of all kinds of gynecological tumors,
Women's life is caused to seriously threaten.Clovis Oncology company obtains in the treatment of ovarian cancer drug Rucaparib ground
The breakthrough therapeutic agent qualification of FDA, this drug is by inhibiting Poly adenosine diphosphate-ribose polymerase-1 class (PARPs) to play
Effect, it can hinder the generation for certain gene mutations that cancer can be made to spread in whole body.It is breakthrough that FDA authorizes Rucaparib
Therapeutic agent label covers it and is used to treat the BRCA mutation Patients with Advanced Ovarian Carcinoma for previously receiving the failure of second line treatment drug.2-
Methyl-3-nitro -5- fluorophenyl carbamate is the important intermediate of Rucaparib anticancer drug, usual 2- methyl -5- fluorobenzene first
Acid can be used as the starting material for preparing it.
Therefore, there is an urgent need in the art to provide a kind of method for obtaining 2- methyl -5- fluobenzoic acid.
Summary of the invention
The present invention is intended to provide a kind of preparation method of 2- methyl -5- fluobenzoic acid, then obtains 2- methyl-3-nitro -
5- fluorophenyl carbamate.
In the first aspect of the present invention, a kind of preparation method of 2- methyl -5- fluobenzoic acid is provided, the method includes
2-X-4- toluene fluoride is reacted with magnesium chips and generates Grignard Reagent, and the Grignard Reagent made converts to obtain 2- methyl -5- fluorobenzene
Formic acid;Wherein X selects chlorine, bromine or iodine;The conversion is mixed after the Grignard Reagent that will be obtained and carbon dioxide reaction with acid solution
Conjunction obtains 2- methyl -5- fluobenzoic acid.
In another preferred example, with organic molten after the conversion is the Grignard Reagent that will be obtained and acid solution mixing, is layered
Organic phase is obtained by extraction in agent 1, directly removes solvent and obtains 2- methyl -5- fluobenzoic acid.
In another preferred example, the conversion includes step:
(a) organic phase is obtained by extraction with organic solvent 1 after obtained Grignard Reagent and acid solution being mixed, be layered;
(b) organic phase, organic solvent 2 and aqueous slkali are mixed, layering, obtains water phase;With
(c) 2- methyl -5- fluobenzoic acid is obtained after mixing water phase and acid solution.
In another preferred example, the acid solution is the aqueous solution of inorganic acid, therein inorganic with the total volume meter of solution
The content of acid is 10-15v/v%;The aqueous slkali is the aqueous solution of inorganic base, therein inorganic with the total volume meter of solution
The content of alkali is 5-15v/v%;The inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid;The inorganic base is selected from sodium hydroxide, hydrogen-oxygen
Change potassium, sodium carbonate or potassium carbonate.
In another preferred example, organic solvent 1 is selected from ethyl acetate, isopropyl acetate or n-butyl acetate;It is described organic
Solvent 2 is selected from toluene, methylene chloride, dimethylbenzene or methyl tertiary butyl ether(MTBE).
In another preferred example, step (a) and (c) in mixed with acid solution and make pH 1-2.
In another preferred example, the method includes the steps:
(i) 2-X-4- toluene fluoride is reacted with magnesium chips and generates Grignard Reagent;
(ii) by Grignard Reagent and carbon dioxide reaction, carboxylate is obtained;With
(iii) organic phase is obtained by extraction with organic solvent 1 after obtained carboxylate and acid solution being mixed, be layered, removes
Solvent obtains 2- methyl -5- fluobenzoic acid;
Or including step:
(1) 2-X-4- toluene fluoride is reacted with magnesium chips and generates Grignard Reagent;
(2) by Grignard Reagent and carbon dioxide reaction, carboxylate is obtained;
(3) organic phase is obtained by extraction with organic solvent 1 after obtained carboxylate and acid solution being mixed, be layered;
(4) organic phase, organic solvent 2 and aqueous slkali are mixed, layering, obtains water phase;With
(5) 2- methyl -5- fluobenzoic acid is obtained after mixing water phase and acid solution.
In another preferred example, in step (i) or (1) magnesium chips in 1-3 times of mole;Reaction temperature in step (i) or (1)
In 20 DEG C of -85 DEG C of reactions;Solvent for use is selected from following one or more in step (i) or (1):The tertiary ether of toluene, first, second
Ether, isopropyl ether, tetrahydrofuran and methyltetrahydrofuran.
In another preferred example, step (ii) or the temperature of (2) are at -20 DEG C -50 DEG C;More preferably at 0-20 DEG C.
In another preferred example, the temperature of step (5) is at -10 DEG C -40 DEG C;More preferably at 0-10 DEG C.
In the second aspect of the present invention, a kind of preparation method of 2- methyl-3-nitro -5- fluorophenyl carbamate is provided,
The method includes the steps:
(A) by the 2- methyl -5- fluobenzoic acid being prepared present invention as described above and dust technology, concentrated nitric acid or smoke
Nitric acid reaction obtains 2- methyl-3-nitro -5- fluobenzoic acid;With
(B) 2- methyl-3-nitro -5- fluobenzoic acid is reacted to obtain 2- methyl-3-nitro -5- fluobenzoic acid first with methanol
Ester.
In another preferred example, the reaction dissolvent of step (A) is selected from following one or more:Sulfuric acid, the concentrated sulfuric acid,
Oleum, acetic acid and methylene chloride.
In another preferred example, the catalyst in step (B) is selected from following one or more:Sulfuric acid, chloroacetic chloride,
Thionyl chloride and oxalyl chloride;Catalyst amount is 0.1-2 times of mole;In step (B) solvent for use be selected from following one kind or
It is two or more:Toluene, methylene chloride and methanol;The reaction temperature of step (B) is at 0 DEG C -110 DEG C.
Accordingly, the present invention provides a kind of methods for obtaining 2- methyl -5- fluobenzoic acid.
Specific embodiment
After extensive and in-depth study, discovery can be reacted inventor under mild conditions by cheap raw material
Obtain 2- methyl -5- fluobenzoic acid.On this basis, the present invention is completed.
Prepare 2- methyl -5- fluobenzoic acid
2- methyl -5- fluobenzoic acid preparation method provided by the invention includes the following steps:
The first step obtains Grignard Reagent by 2-X-4- toluene fluoride (X=Cl, Br, I) and magnesium chips;
Second step, by carboxyl in Grignard Reagent;
Third step, it is acidified to obtain 2- methyl -5- fluobenzoic acid.
In the above-mentioned first step, it will mix, do not surpassing in 2-X-4- toluene fluoride (X=Cl, Br, I) and the reaction dissolvent of magnesium chips
It is reacted to obtain Grignard Reagent in the case where crossing 85 DEG C;The reaction dissolvent is toluene, the tertiary ether of first, ether, isopropyl ether, tetrahydro
One of furans and methyltetrahydrofuran are several.
In the above-mentioned first step, reaction temperature is at 25-85 DEG C, preferably at 25-55 DEG C, more preferably at 25-35 DEG C.To solvent
Dosage does not have particular/special requirement, as long as not influencing stable reaction progress.Preferred solvent dosage is 1-5 times of 2-X-4- toluene fluoride
Volume.
The above-mentioned first step can be used conventional method (such as gas-chromatography) and carry out tracking and monitoring to the performance level of reaction.Instead
Reaction temperature, solvent and specific reactant are depended between seasonable, under the above-described reaction conditions, generally 2-24h or so can be complete
At reaction.
In one embodiment of the invention, above-mentioned second step is logical at -20 DEG C -50 DEG C after first step fully reacting
Enter carbon dioxide gas until intermediate disappears substantially;It is preferred that at 0-20 DEG C;More preferably at 0-10 DEG C.
In one embodiment of the invention, after above-mentioned second step disappears substantially to intermediate, pH is made by acid solution
For 1-2, layering, water phase organic solvent 1 merges organic phase after extracting, and organic phase, organic solvent 2 and aqueous slkali are mixed splitting or integrating
Water phase is extracted with organic solvent 2 after layer, and resulting water phase makes pH 1-2 by acid solution again at -10 DEG C -40 DEG C after extraction, obtains
To 2- methyl -5- fluobenzoic acid;It is preferred that at 0-10 DEG C.
The acid solution is the aqueous solution of inorganic acid, and with the total volume meter of solution, the content of inorganic acid therein is 10-
15v/v%;The inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
The aqueous slkali is the aqueous solution of inorganic base, and with the total volume meter of solution, the content of inorganic base therein is 5-
15v/v%;The inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
The organic solvent 1 is selected from ethyl acetate, isopropyl acetate or n-butyl acetate;The organic solvent 2 is selected from first
Benzene, dimethylbenzene, methylene chloride or methyl tertiary butyl ether(MTBE).
In one embodiment of the invention, in above-mentioned third step, merge after being extracted by organic solvent 1 organic
Crude product is obtained after being mutually concentrated, carries out subsequent operation after crude product, organic solvent 2 and aqueous slkali are mixed.
Prepare 2- methyl-3-nitro -5- fluorophenyl carbamate
2- methyl-3-nitro -5- fluorophenyl carbamate provided by the invention is the 2- that will be obtained by means of the present invention
Methyl -5- fluobenzoic acid is nitrified to obtain 2- methyl-3-nitro -5- fluobenzoic acid, by 2- methyl-3-nitro -5- fluorobenzene first
Acid is esterified to obtain 2- methyl-3-nitro -5- fluorophenyl carbamate.
The mode of nitrification is to use 2- methyl -5- fluobenzoic acid and nitric acid reaction, to obtain 2- methyl-3-nitro -5- fluorine
Benzoic acid.Its nitric acid can use dust technology, concentrated nitric acid, fuming nitric aicd;It is preferred that fuming nitric aicd.Its dosage is equivalent to 2- methyl -3- nitre
1.2-2.5 times of mole of base -5- fluobenzoic acid.
Nitration reaction carries out in a solvent, and any solvent having no adverse effects to reaction, such as dilute sulfuric acid, dense sulphur can be used
Acid, oleum, acetic acid, one of methylene chloride or several.The dosage of solvent does not have particular/special requirement, as long as not influencing anti-
The stability answered, preferred solvent dosage are 4.0-8.0 times of volume of 2- methyl -5- fluobenzoic acid.
Reaction temperature does not have particular/special requirement, preferably 0 DEG C -50 DEG C, at preferred temperature, available good reaction effect
Rate, nitration reaction yield can be to 60% or more.
Conventional method (such as thin-layer chromatography, liquid chromatogram etc.) can be used, tracking and monitoring is carried out to the performance level of reaction.Instead
Reaction temperature, solvent and specific reactant are depended between seasonable, under the conditions of above-mentioned preferred, generally i.e. at 1-5 hours or so
Achievable reaction.
The mode of esterification is 2- methyl-3-nitro -5- fluobenzoic acid and methanol reaction, to obtain 2- methyl -3-
Nitro -5- fluorophenyl carbamate.Methanol usage is 1.5-30 times of mole of 2- methyl-3-nitro -5- fluobenzoic acid.
Reaction carries out in a solvent, can be used to any solvent for having no adverse effects of reaction, such as toluene, methylene chloride,
One of methanol is several.The dosage of solvent does not have particular/special requirement, preferably molten as long as not influencing the stability of reaction
Agent dosage is 2.0-8.0 times of volume of 2- methyl -3- nitro -5- fluobenzoic acid.
Reaction temperature does not have particular/special requirement, preferably 0 DEG C -110 DEG C, at preferred temperature, available good reaction
Efficiency, esterification yield can be to 80% or more.
Conventional method (such as thin-layer chromatography, liquid chromatogram etc.) can be used, tracking and monitoring is carried out to the performance level of reaction.Instead
Reaction temperature, solvent and specific reactant are depended between seasonable, under the conditions of above-mentioned preferred, generally i.e. at 2-8 hours or so
Achievable reaction.
Target product 2- methyl-3-nitro -5- fluorophenyl carbamate can use fusing point test, and liquid phase is simple, and nuclear-magnetism is total
The methods of vibration testing identity.
Next step reaction can directly be carried out after the reaction was completed by respectively walking involved in preparation method provided by the invention, but be adopted
The intermediate product that each step is reacted is isolated and purified with post processing modes such as extraction, suction filtration, washing, drying, concentrations to be conducive to mention
The efficiency of relative superiority or inferiority single step reaction.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Disclosed in this case specification
All features can be used in combination with any composition form, each feature disclosed in specification, any can provide it is identical,
The alternative characteristics of impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar spy
The general example of sign.
Main advantages of the present invention are:
1, the raw material that method provided by the invention uses is cheap, is easy to get.
2, method side reaction provided by the invention is few, and production capacity is big, and reaction condition is milder, at low cost, easily industrializes
Production.
3, purity after the 2- methyl-3-nitro -5- fluorophenyl carbamate that preparation method provided by the invention obtains is purified
It can reach 99% or more, total recovery can reach 40% or more.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number is pressed
Poidometer.The unit in percent weight in volume in the present invention is well-known to those skilled in the art, such as is referred to 100
The weight of solute in the solution of milliliter.Unless otherwise defined, all professional and scientific terms as used herein and this field are ripe
It is identical to practice meaning known to personnel.In addition, any method similar to or equal to what is recorded and material all can be applied to
In the method for the present invention.The preferred methods and materials described herein are for illustrative purposes only.
Embodiment 1
2- methyl -5- fluobenzoic acid is prepared with the chloro- 4- toluene fluoride of 2-
By magnesium chips 20g (0.83mol), methyltetrahydrofuran 100ml is added into the four-hole bottle of 1L, under nitrogen protection, is added
Enter the chloro- 4- toluene fluoride of 10g (0.07mol) 2-, stirring is warming up to reaction and causes, 55 DEG C, cause successfully, and highly exothermic, stops
Stirring, after stablizing, stirring is warming up to reflux, and the chloro- 4- toluene fluoride 90g (0.62mol) of remaining 2- is dissolved in the methyl of 300ml
In tetrahydrofuran, slowly instill in above-mentioned reaction solution, and at reflux by temperature.9h is dripped, and reacts 2h, gas phase inspection
It surveys, fully reacting.It is cooled to 0-10 DEG C, is passed through clean carbon dioxide gas, until intermediate disappears substantially.It is added dropwise 12%
Hydrochloric acid solution is up to pH 1-2.Layering, water phase use ethyl acetate 200ml to extract 1 time again, merge organic phase, and concentration is dry, obtains slightly
Product.Toluene 200ml is added.10% sodium hydrate aqueous solution 320g, stirring to dissolved clarification, stratification, water phase toluene 200ml
Extraction 1 time.Organic phase is discarded, water phase is at 0-10 DEG C, with 12% hydrochloric acid tune pH to 1-2.There is a large amount of white solid to be precipitated.It crosses
Filter, filter cake are rinsed with water, are drained, 50 DEG C of filter cake drying.Obtain crude product 80.4g, HPLC 90%.Pure yield 67.9%.This is thick
Product can directly react in next step.
1H-NMR CDCl32.50 (S, 3H), 7.26-7.34 (m, 2H), 7.51-7.54 (d, 1H), 13.09 (S, 1H).
LC-MS(MH-):153.1
Embodiment 2
2- methyl -5- fluobenzoic acid is prepared with the bromo- 4- toluene fluoride of 2-
By magnesium chips 20g (0.83mol), tetrahydrofuran 100ml is added into the four-hole bottle of 1L, and under nitrogen protection, 6g is added
The bromo- 4- toluene fluoride of (0.032mol) 2-, stirring is warming up to reaction and causes, 25 DEG C, causes successfully, and heat release extremely flows back, ice-water bath
25 DEG C are cooled to, the bromo- 4- toluene fluoride 124g (0.66mol) of remaining 2- is dissolved in the tetrahydrofuran of 300ml, is slowly instilled
It states in reaction solution, and 25-35 DEG C.2h is dripped, and reacts 2h, vapor detection, fully reacting.It is cooled to 0-10 DEG C, is passed through clean
Carbon dioxide gas, until intermediate disappears substantially.The hydrochloric acid solution of dropwise addition 12% is up to pH 1-2.Layering, water phase is again
It is extracted 1 time with ethyl acetate 200ml, merges organic phase, concentration is dry, obtains crude product.Toluene 200ml is added.10% sodium hydroxide
Aqueous solution 320g, stirring to dissolved clarification, stratification, water phase are extracted 1 time with toluene 200ml.Organic phase is discarded, water phase is in 0-10
DEG C, with 12% hydrochloric acid tune pH to 1-2.There is a large amount of white solid to be precipitated.Filtering, filter cake are rinsed with water, are drained, and 50 DEG C of filter cake
Drying.Obtain crude product 85g, HPLC 95%.Pure yield 75.8%.This crude product can directly react in next step.
1H-NMR CDCl32.50 (S, 3H), 7.26-7.34 (m, 2H), 7.51-7.54 (d, 1H), 13.09 (S, 1H).
LC-MS(MH-):153.1
Embodiment 3
2- methyl -5- fluobenzoic acid is prepared with the iodo- 4- toluene fluoride of 2-
By magnesium chips 20g (0.83mol), the tertiary ether 100ml of first is added into the four-hole bottle of 1L, and under nitrogen protection, 6g is added
The iodo- 4- toluene fluoride of (0.025mol) 2-, be stirred at room temperature it is lower cause successfully, and heat release, to 50 DEG C or so, ice-water bath is cooled to 25 DEG C,
The iodo- 4- toluene fluoride 157g (0.665mol) of remaining 2- is dissolved in the tertiary ether of first of 300ml, is slowly instilled in above-mentioned reaction solution,
And 25-35 DEG C.2h is dripped, and reacts 2h, vapor detection, fully reacting.It is cooled to 0-10 DEG C, is passed through clean carbon dioxide gas
Body, until intermediate disappears substantially.The hydrochloric acid solution of dropwise addition 12% is up to pH 1-2.Layering, water phase use ethyl acetate again
200ml is extracted 1 time, merges organic phase, and concentration is dry, obtains crude product.Toluene 200ml is added.10% sodium hydrate aqueous solution 320g,
Stirring to dissolved clarification, stratification, water phase is extracted 1 time with toluene 200ml.Organic phase is discarded, water phase is at 0-10 DEG C, with 12% salt
Acid adjusts pH to 1-2.There is a large amount of white solid to be precipitated.Filtering, filter cake are rinsed with water, are drained, 50 DEG C of filter cake drying.Obtain crude product
90g, HPLC 96%.Pure yield 81%.This crude product can directly react in next step.
1H-NMR CDCl32.50 (S, 3H), 7.26-7.34 (m, 2H), 7.51-7.54 (d, 1H), 13.09 (S, 1H).
LC-MS(MH-):153.1
Embodiment 4
The preparation of 2- methyl-3-nitro -5- fluobenzoic acid
2- methyl -5- the fluobenzoic acid of 30g (0.195mol) is added into the concentrated sulfuric acid of 120ml, under stirring, is warming up to
30℃-40℃.It is added dropwise concentrated nitric acid 24.5g (0.39mol), 30-40 DEG C of temperature control.After dripping off, 2h is reacted, raw material disappears substantially, stops
It only reacts, reaction solution pours into ice water.Filtering, filter cake are rinsed with water, are drained.Wet product is obtained, 50 DEG C, drying obtains 28g,
HPLC 95%.Pure yield 66.5%.
1H-NMR DMSO 2.45 (S, 3H), 7.83-7.85 (d, 1H), 8.02-8.04 (d, 1H), 13.78 (S, 1H).
LC-MS(MH-):198.1
Embodiment 5
The preparation of 2- methyl-3-nitro -5- fluobenzoic acid
2- methyl -5- the fluobenzoic acid of 30g (0.195mol) is added into the acetic acid of 150ml, under stirring, is warming up to 40
℃-50℃.It is added dropwise fuming nitric aicd 24.5g (0.39mol), 40-50 DEG C of temperature control.After dripping off, 3h is reacted, raw material disappears substantially, stops
It only reacts, reaction solution pours into ice water.Filtering, filter cake are rinsed with water, are drained.Wet product is obtained, 50 DEG C, drying obtains 35g,
HPLC 96%.Pure yield 84.
1H-NMR DMSO 2.45 (S, 3H), 7.83-7.85 (d, 1H), 8.02-8.04 (d, 1H), 13.78 (S, 1H).
LC-MS(MH-):198.1
Embodiment 6
The preparation of 2- methyl-3-nitro -5- fluobenzoic acid
The methylene chloride to the concentrated sulfuric acid of 30ml and 150ml is added in the 2- methyl -5- fluobenzoic acid of 30g (0.195mol)
Mixed liquor in, under stirring, be warming up to 30 DEG C -40 DEG C.It is added dropwise fuming nitric aicd 24.5g (0.39mol), 30-40 DEG C of temperature control.It drips off
Afterwards, 3h is reacted, raw material disappears substantially, stops reaction, reaction solution pours into ice water.Filtering, filter cake are rinsed with water, are drained.?
To wet product, 50 DEG C, drying obtains 30g, HPLC 94%.Pure yield 70.5%.
1H-NMR DMSO 2.45 (S, 3H), 7.83-7.85 (d, 1H), 8.02-8.04 (d, 1H), 13.78 (S, 1H).
LC-MS(MH-):198.1
Embodiment 7
The preparation of 2- methyl-3-nitro -5- fluorophenyl carbamate
3g (15.1mmol) 2- methyl-3-nitro -5- fluobenzoic acid is added into the methanol of 30ml, under stirring, is added dropwise
The 0.3g concentrated sulfuric acid (98%) is then refluxed for 8h, stops reaction, and sodium bicarbonate aqueous solution tune pH to 7 or so is added.Methanol is concentrated,
After complete, methylene chloride 30ml is added, washes 2 times, saturated common salt is washed 1 time, and organic phase concentration is dry to obtain crude product, recrystallizing methanol
2 * 10ml obtain product 2.4g, 99% or more HPLC.Yield 74.8%.
1H-NMR DMSO 2.43 (S, 3H), 3.88 (S, 3H), 7.85-7.87 (d, 1H), 8.07-8.09 (d, 1H).LC-
MS(MH+):214.1
Embodiment 8
The preparation of 2- methyl-3-nitro -5- fluorophenyl carbamate
58g (0.291mol) 2- methyl-3-nitro -5- fluobenzoic acid is added into 300ml methanol, is stirred, 0-10 DEG C,
It is added dropwise thionyl chloride 41.6g (0.35mol), has obvious heat release, temperature control is at 20 DEG C or less.After dripping off, it is warming up to reflux, is reacted
7h, raw material disappear substantially, stop reaction, 25 DEG C are cooled under stirring, have a large amount of solids to be precipitated, filtering, filter cake 60ml methanol
Rinsing, is drained, filter cake uses 150ml recrystallizing methanol again, obtains wet product, after drying, obtains 45g product.99% or more HPLC.
Yield 72.6%.
1H-NMR DMSO 2.43 (S, 3H), 3.88 (S, 3H), 7.85-7.87 (d, 1H), 8.07-8.09 (d, 1H).LC-
MS(MH+):214.1
Embodiment 9
The preparation of 2- methyl-3-nitro -5- fluorophenyl carbamate
By 30g (0.151mol) 2- methyl-3-nitro -5- fluobenzoic acid, 150ml toluene is added in 10g (0.31mol) methanol
In solution, stirring is warming up to reflux, after reflux, is added dropwise thionyl chloride 18g (0.227mol), there is HCl gas releasing, after dripping off,
Back flow reaction 2h, raw material disappear substantially, and reaction solution has muddy become to clarify.Stop reaction, concentrated solvent obtains crude product, uses methanol
2 * 100ml are recrystallized, product 28g, 99% or more HPLC, yield 87.2% are obtained.
1H-NMR DMSO 2.43 (S, 3H), 3.88 (S, 3H), 7.85-7.87 (d, 1H), 8.07-8.09 (d, 1H).LC-
MS(MH+):214.1
The foregoing is merely illustrative of the preferred embodiments of the present invention, the substantial technological content model being not intended to limit the invention
It encloses, substantial technological content of the invention is broadly defined in the scope of the claims of application, any technology that other people complete
Entity or method also or a kind of equivalent change, will if identical with defined in the scope of the claims of application
It is considered as being covered by among the scope of the claims.