The preparation method of bazedoxifene acetate intermediate
Technical field
The present invention relates to the preparation method of bazedoxifene acetate intermediate.
Background technology
The Bazedoxifene (bazedoxifene) developed by Wyeth company is a new generation SERM, and it can be competing
Suppress to striving property 17 beta estradiols and ER α and the combination of ER β, be used alone to human breast cancer cell system without
Agonist activity.Preclinical test shows, in like product, it compares thunder in terms of improving uterus characteristic
Lip river former times fragrant (second filial generation SERM) and lasofoxifene (third generation SERM) more advantage, it addition, blood
Pipe easypro contracting time-dependent model test display, its central nervous system's side effect is the least, is activating hepatic lipase
Promoter aspect, it is the agonist of a kind of relative efficiency, and raloxifene is the most invalid, when with Lei Luoxi
During fragrant combination, it can suppress the raloxifene stimulation to rodent uterus, it is seen that the two is right
The effect in uterus is different.Preclinical test data show, it is than other SERMs known today
More target activity, is so far " optimal in like product ".This medicine at present the most in 2009 in European Union
(trade name: Conbriza) and Japan (trade name: Viviant) listing.Bazedoxifene acetate
(Bazedoxifene Acetate) is the medicine of the osteoporosis for treating and preventing menopausal women.
Bazedoxifene acetate (Bazedoxifene acetate) chemical entitled 1-{4-[2-(cycloheximide base-1-)
Ethyoxyl] benzyl }-2-(4-hydroxy phenyl)-3-Methyl-1H-indole-5-phenol acetate, its preparation method is as follows:
4-[2-(cycloheximide base-1-) ethyoxyl] benzyl chloride hydrochlorate 1 is the pass of synthesis bazedoxifene acetate
Key intermediate, its synthesis the most reported mainly has following three kinds of methods:
Route one: the synthetic route of United States Patent (USP) US6005102 report:
This route is with hydroxy benzaldehyde 6 and 2-(cycloheximide base) chloride hydrochloride 5 is for initial former
Material, obtains 4-[2-(cycloheximide-1-base) ethyoxyl] benzaldehyde 4 through condensation reaction, and compound 4 is again through boron hydrogen
Changing sodium reduction and obtain 4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3, compound 3 leads to hydrogen chloride gas
Hydrochlorate, thionyl chloride carry out chloro and obtain object 1.In this route compound 4 He is found through experiments
Compound 3 need to process respectively, and product extracts difficulty, complex operation from aqueous phase;Compound 3 hydrochloric acid
Need during salt to be passed through hydrogen chloride gas, it is difficult to control and quantitative, and operational hazards, environmental pollution is serious,
Be not suitable for large-scale production.
The synthetic method of route two United States Patent (USP) US6005102 report:
This route is with p-Hydroxybenzylalcohol and 2-(cycloheximide base) chloride hydrochloride 5 as initiation material,
Through being condensed to obtain 4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3, compound 3 is again through thionyl chloride chloro
Obtain object 1.This route starting compound salicylic alcohol is expensive compared with the starting compound 6 of route one;
It is condensed a step yield and only has 61.2%, and starting compound 5 is expensive, causes the huge waste of raw material;
When preparing compound 1, due to not first hydrochloric acid salt, it is easily caused into salt incomplete, poor repeatability, atom
Utilization rate is low, is not suitable for industrialized production.
The route of route three United States Patent (USP) US7375251 report:
This route, with chloracetyl chloride VII and cycloheximide VIII as initiation material, obtains chloracetyl ring after condensation
Own imines IX, compound IX are condensed to obtain 4-[2-(cycloheximide-1-base)-2-oxygen again with starting compound III
For ethyoxyl] benzaldehyde X, compounds X obtains compound V through red aluminium reducing again, and compound V is again through chlorine
In generation, obtains object 1.This route is cumbersome, and starting compound VIII is the toxic articles that domestic use is limited,
It is difficult to buy, is unfavorable for industrialized production.
Summary of the invention
The technical problem to be solved is to overcome existing 4-[2-(cycloheximide base-1-) ethoxy
Base] the preparation method route of benzyl chloride hydrochlorate is longer, and cost of material is more expensive, preparation method reaction condition
Harshness, toxicity is big, and environmental pollution is serious, and Atom economy is poor, and reaction yield is low, product purity difference etc.
Defect, and provide the preparation method of bazedoxifene acetate intermediate.The preparation method route of the present invention is relatively
Short, reaction condition is gentle, operates safety, and last handling process is simple, and reaction conversion ratio is high, product yield
Height, purity is good, environmental friendliness, is suitable for industrialized production.
The invention provides the preparation method of the midbody compound 3 of a kind of bazedoxifene acetate, it includes
Following steps:
Step is (1): in polar non-solute, under conditions of alkali exists, by hydroxy benzaldehyde 6 with
Compound 5 carries out condensation reaction, obtains midbody compound 4;
Step is (2): by step (1) in the reactant liquor that obtains is the most post-treated directly mixes with proton solvent, then
Carry out reduction reaction with reducing agent and obtain the midbody compound 3 of bazedoxifene acetate;
Prepare the step of midbody compound 3 of bazedoxifene acetate (1) in, described aprotic, polar
Solvent is the conventional polar aprotic solvent occurring such to react in this area, in the present invention particularly preferably
DMF (DMF), N,N-dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO)
With one or more in 1,3-dimethyl-2-imidazolinone (DMI);Further preferably N, N-diformazan
Base Methanamide (DMF).
Prepare the step of midbody compound 3 of bazedoxifene acetate (1) in, described aprotic, polar
The volume mass of solvent and described hydroxy benzaldehyde 6 is than preferred 1g/mL~5g/mL, the most excellent
Select 1g/mL~3g/mL.
Prepare the step of midbody compound 3 of bazedoxifene acetate (1) in, described compound 5 with
Preferred 1:1~1:1.5 of mol ratio, further preferred 1:1~1 of described hydroxy benzaldehyde 6:
1.1。
Prepare the step of midbody compound 3 of bazedoxifene acetate (1) in, described alkali is the most organic
Alkali and/or inorganic base, the preferred sodium hydride of described organic base, Sodamide., Lithamide., potassium tert-butoxide and uncle
One or more in sodium butoxide, further preferred sodium hydride;The preferred potassium carbonate of described inorganic base, carbon
One or more in acid sodium and sodium hydroxide.
Prepare the step of midbody compound 3 of bazedoxifene acetate (1) in, described alkali with described
The molar ratio of hydroxy benzaldehyde 6 preferably 1~5, further preferred 1~2.5.
Prepare the step of midbody compound 3 of bazedoxifene acetate (1) in, described condensation reaction
Temperature is to carry out the ordinary temperature of such reaction in this area, in the present invention particularly preferred 0 DEG C~50 DEG C,
Further preferred 0 DEG C~30 DEG C.
Prepare the step of midbody compound 3 of bazedoxifene acetate (1) in, described condensation reaction
Process can use the traditional test methods (such as HPLC or TLC) of this area to determine, with compound 5
It is reaction end, preferably 1h~6h during disappearance, further preferred 2h~4h.
Prepare the step of midbody compound 3 of bazedoxifene acetate (2) in, described proton solvent is
This area carries out the conventional protic solvent of such reduction reaction, particularly preferred methanol, ethanol in the present invention
With one or more in isopropanol;Further preferably methanol.
Prepare the step of midbody compound 3 of bazedoxifene acetate (2) in, described proton solvent with
The volume mass of described hydroxy benzaldehyde 6 is than preferred 1g/mL~20g/mL, further preferably
1g/mL~10g/mL.
Prepare the step of midbody compound 3 of bazedoxifene acetate (2) in, described reducing agent is this
Field carries out the conventional reduction agent of such reduction reaction, particularly preferred lithium aluminium hydride reduction, boron hydrogen in the present invention
Change one or more in sodium and potassium borohydride;Further preferably sodium borohydride.
Prepare the step of midbody compound 3 of bazedoxifene acetate (2) in, described reducing agent and institute
The molar ratio preferably 0.5~2 of the hydroxy benzaldehyde 6 stated, further preferred 0.5~1.
Prepare the step of midbody compound 3 of bazedoxifene acetate (2) in, described reduction reaction
Temperature is to carry out the ordinary temperature of such reaction in this area, in the present invention particularly preferred 0 DEG C~35 DEG C,
Further preferred 10 DEG C~25 DEG C.
Prepare the step of midbody compound 3 of bazedoxifene acetate (2) in, described reduction reaction
Process can use the traditional test methods (such as HPLC or TLC) of this area to determine, with intermediate
It is reaction end, preferably response time 0.5h~4h when compound 4 disappears, further preferred 0.5h~2h.
Present invention also offers the preparation method of the midbody compound 2 of a kind of bazedoxifene acetate, its bag
Include following steps: prepare described by the preparation method of described bazedoxifene acetate midbody compound 3
After the midbody compound 3 of bazedoxifene acetate, further comprising the steps of: in aprotic solvent, will
The ester solution of hydrogen chloride reacts with the midbody compound 3 of described bazedoxifene acetate, obtains vinegar
The midbody compound 2 of acid Bazedoxifene;
In the method for midbody compound 2 preparing bazedoxifene acetate, the ester of described hydrogen chloride is molten
Liquid is preferably carried out reaction by acyl chlorides and alcohol and obtains;Described acyl chlorides be this area is carried out such reaction normal
Rule acyl chlorides, preferably C1~C6Straight or branched alkyl acyl chloride, described C1~C6Straight or branched
Alkyl acyl chloride can be that single acyl chlorides can also be for diacid chloride, and described single acyl chlorides is that intramolecular contains an acyl
The acyl chlorides of base, described diacid chloride is the acyl chlorides that intramolecular contains two acyl groups;Described C1~C6's
The straight or branched alkyl preferred chloroacetic chloride of list acyl chlorides and/or propionyl chloride;Described C1~C6Straight chain or
The preferred oxalyl chloride of alkyl group diacid chloride;Described alcohol is the conventional alcohol carrying out such reaction in this area, excellent
Select C1~C6Straight or branched alkylol, described C1~C6Straight or branched alkylol can be
Monohydric alcohol, dihydroxylic alcohols or trihydroxylic alcohol, described monohydric alcohol is the alcohol that intramolecular contains a hydroxyl, described
Dihydroxylic alcohols be the alcohol that intramolecular contains two hydroxyls, described trihydroxylic alcohol is that intramolecular contains three hydroxyls
Alcohol;Described C1~C6The preferred methanol of straight or branched alkyl monocarbon alcohol, ethanol and isopropanol in
One or more;Described ester is to be reacted, by described acyl chlorides, the corresponding ester obtained with described alcohol,
Generally C3~C20Ester, described ester can be monoesters, diester or three esters;Preferably C3~C12
Ester, further preferred methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate,
Isopropyl propionate, oxalic acid methyl monoester, dimethyl oxalate., oxalic acid mono ethyl ester, ethyl oxalate, oxalic acid list
One or more in isopropyl ester and oxalic acid diisopropyl ester.Described acyl chlorides rubs with described compound 3
That ratio preferably 1~1.5, further preferred 1~1.1.Described alcohol and described compound 3 mole
Ratio preferably 1~1.5, further preferred 1~1.1.
In the method for midbody compound 2 preparing bazedoxifene acetate, described aprotic solvent is
This area there is the conventional aprotic solvent that such reacts, particularly preferred oxolane in the present invention
(THF), one or more in ethyl acetate, dioxane, diisopropyl ether, ether and toluene;Enter
The preferred oxolane of one step (THF).
In the method for midbody compound 2 preparing bazedoxifene acetate, described aprotic solvent with
The volume mass of described compound 3 than preferred 1g/mL~10g/mL, further preferred 1g/mL~
3g/mL。
In the method for midbody compound 2 preparing bazedoxifene acetate, the ester of described hydrogen chloride is molten
Hydrogen chloride in liquid and the molar ratio preferably 1~1.5 of described compound 3, further preferred 1~1.1.
In the method for midbody compound 2 preparing bazedoxifene acetate, the ester of described hydrogen chloride is molten
Hydrogen chloride in liquid and the molar ratio preferably 0.5~2 of described ester, further preferred 1~1.1.
In the method for midbody compound 2 preparing bazedoxifene acetate, the temperature of described reaction is
This area carries out the ordinary temperature of such reaction, in the present invention particularly preferably-15 DEG C~15 DEG C, enters one
Walk preferably 0 DEG C~10 DEG C.
In the method for midbody compound 2 preparing bazedoxifene acetate, the process of described reaction can
To use the traditional test methods (such as HPLC or TLC) of this area to determine, when disappearing with compound 3
For reaction end, preferably 0.5h~5h, further preferred 0.5h~3h.
Present invention also offers the midbody compound 4-[2-(cycloheximide base-1-) of a kind of bazedoxifene acetate
Ethyoxyl] preparation method of benzyl chloride hydrochlorate 1, it comprises the following steps: by described acetic acid Abbado
The preparation method of former times sweet smell midbody compound 3 prepares the midbody compound of described bazedoxifene acetate
3, then prepare described acetic acid bar by the preparation method of described bazedoxifene acetate midbody compound 2
After the midbody compound 2 that many former times are fragrant, further comprising the steps of:
The midbody compound 2 of described bazedoxifene acetate is reacted with chlorination reagent, obtains
4-[2-(cycloheximide base-1-) ethyoxyl] benzyl chloride hydrochlorate 1;
Prepare midbody compound 4-[2-(cycloheximide base-1-) ethyoxyl] benzyl chloride of bazedoxifene acetate
The method of hydrochlorate 1 preferably employs following steps, and described prepares bazedoxifene acetate midbody compound
The reaction of 2 is the most post-treated after terminating, and is directly prepared the intermediate 4-[2-(ring of bazedoxifene acetate
Own imido grpup-1-) ethyoxyl] reaction of benzyl chloride hydrochlorate 1.
Preparing intermediate 4-[2-(cycloheximide base-1-) ethyoxyl] the benzyl chloride hydrochloric acid of bazedoxifene acetate
In the method for salt 1, the preferred thionyl chloride of described chlorination reagent.
Preparing intermediate 4-[2-(cycloheximide base-1-) ethyoxyl] the benzyl chloride hydrochloric acid of bazedoxifene acetate
In the method for salt 1, described chlorination reagent and the molar ratio preferably 1~3 of described compound 2, enter
One step preferably 1~1.5.
Preparing intermediate 4-[2-(cycloheximide base-1-) ethyoxyl] the benzyl chloride hydrochloric acid of bazedoxifene acetate
In the method for salt 1, the temperature of described reaction is to carry out the ordinary temperature of such reaction in this area, this
In invention particularly preferred 25 DEG C~65 DEG C, further preferred 40 DEG C~50 DEG C.
Preparing intermediate 4-[2-(cycloheximide base-1-) ethyoxyl] the benzyl chloride hydrochloric acid of bazedoxifene acetate
In the method for salt 1, the time of described reaction can use the traditional test methods of this area (such as HPLC
Or TLC) determine, with midbody compound 2 disappear time as reaction end, preferably the response time be 0.5h~
5h, further preferred 0.5h~2h.
In the present invention, described 4-[2-(cycloheximide base-1-) ethyoxyl] benzyl chloride hydrochlorate 1 be for
Prepare bazedoxifene acetate (Bazedoxifene Acetate) (1-{4-[2-(cycloheximide base-1-) ethyoxyl]
Benzyl }-2-(4-hydroxy phenyl)-3-Methyl-1H-indole-5-phenol acetate) key intermediate.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain this
Invent each preferred embodiments.
Agents useful for same of the present invention and raw material are the most commercially.
Heretofore described room temperature refers to ambient temperature, is 10 DEG C~35 DEG C.
The most progressive effect of the present invention is: the present invention uses " one pot " method to shorten reactions steps, letter
Change the last handling process of reaction, reduced cost, be suitable for large-scale production.The present invention uses in situ
Generating hydrogen chloride gas, safe and reliable, it is easy to quantitatively, easy to operate and safe, Atom economy is high, instead
Answer yield high, environmental friendliness, it is easy to amplify and produce.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention to
Among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to often
Rule method and condition, or select according to catalogue.
The preparation of embodiment 14-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3
Under nitrogen protection, sodium tert-butoxide (24.2g, 253mmol) adds to (150mL) in DMF, stirring
30min, the DMF(80mL of 0 DEG C of dropping hydroxy benzaldehyde (16.6g, 136mmol)) solution,
Drip and finish, insulation (0 DEG C) stirring 30min.0 DEG C adds 2-(cycloheximide base) chloride hydrochloride (25
G, 124mmol), finish, temperature rises to 25 DEG C of reaction 4h.TLC tracing display 2-(cycloheximide
Base) chloride hydrochloride reaction complete, methanol (110mL) adds in reactant liquor, and temperature is down to 0 DEG C,
Being dividedly in some parts sodium borohydride (2.7g, 69.6mmol), finish, 25 DEG C are reacted 2 hours.Reactant liquor is poured into
In frozen water (200mL), ethyl acetate (100mL × 3) is extracted, and saturated nacl aqueous solution is washed, anhydrous slufuric acid
Sodium is dried, and concentrating under reduced pressure obtains 26.3g yellow dense fluids 4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol
3, yield 92%, HPLC purity: 96%.MS(m/z)[M+H]+:250。
The preparation of embodiment 24-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3
Under nitrogen protection, sodium hydride (10.1g, 253mmol) adds to (80mL) in DMF, stirs 10
Min, the DMF(80mL of 0 DEG C of dropping hydroxy benzaldehyde (16.6g, 136mmol)) solution, drip and finish,
Insulation (0 DEG C) stirring 30min.0 DEG C adds 2-(cycloheximide base) and chloride hydrochloride (25g, 124
Mmol), finishing, temperature rises to 25 DEG C of reaction 2h.TLC tracing display 2-(cycloheximide base) second
The reaction of base villaumite hydrochlorate is complete, and ethanol (100mL) adds in reactant liquor, and temperature is down to 0 DEG C, adds in batches
Entering sodium borohydride (2.7g, 69.6mmol), finish, room temperature 25 DEG C is reacted 2 hours.Reactant liquor pours ice into
In water (200mL), ethyl acetate (100mL × 3) is extracted, and saturated nacl aqueous solution is washed, anhydrous sodium sulfate
Being dried, concentrating under reduced pressure obtains 28.2g yellow dense fluids 4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3,
Yield 98%.HPLC purity: 97%.
The preparation of embodiment 34-[2-(cycloheximide base-1-) ethyoxyl] benzyl chloride hydrochlorate 1
Under nitrogen protection, adding absolute methanol (0.7mL, 17mmol) in there-necked flask, temperature is down to
0 DEG C, being slowly added dropwise chloroacetic chloride (1.2mL, 17mmol), insulation (0 DEG C) stirring 30min, by 4-[2-(ring
Own imines-1-base) ethyoxyl] THF(10mL of benzyl alcohol (4.3g, 17mmol)) solution slowly drips
It is added in above-mentioned solution, has white solid to generate.Treat that solid no longer increases, equality of temperature dropping thionyl chloride (1.8
ML, 25mmol), drip and finish, be warming up to 50 degree, solid is the most molten clearly, TLC tracing display 4-[2-(ring
Own imines-1-base) ethyoxyl] benzyl alcohol hydrochloride total overall reaction is complete, is evaporated to the one of liquor capacity
Half, 0 degree of freeze overnight, sucking filtration, it is dried, obtains 4.5g faint yellow solid 4-[2-(cycloheximide base-1-)
Ethyoxyl] benzyl chloride hydrochlorate 1, yield 87%, HPLC purity: 95.4%.MS(m/z)[M-HCl]+:268,1H-NMR(400MHz,d6-DMSO)δ(ppm):10.472(s,1H,HCl),7.405(d,2H,
J=8.8Hz,Ar-H),7.007(d,2H,J=8.8Hz,Ar-H),4.740(s,2H,-CH2Cl),4.402(t,
2H,J=5.2Hz,-OCH2-),3.185-3.529(m,6H,N(CH2)3-),1.623-1.857(m,8H,
-N(CH2)4-).
The preparation of embodiment 44-[2-(cycloheximide base-1-) ethyoxyl] benzyl chloride hydrochlorate 1
Under nitrogen protection, adding dehydrated alcohol (2.4mL, 40mmol) in there-necked flask, temperature is down to 0 DEG C,
Being slowly added dropwise chloroacetic chloride (2.8mL, 40mmol), insulation (0 DEG C) stirring 30min, by 4-[2-(ring
Own imines-1-base) ethyoxyl] ethyl acetate (20mL) solution of benzyl alcohol (10g, 40mmol) is slow
It is added drop-wise in above-mentioned solution, has white solid to generate.Treat that solid no longer increases, equality of temperature dropping thionyl chloride
(4.3mL, 60mmol), drips and finishes, be warming up to 50 degree, and solid is the most molten clearly, TLC tracing display
4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol hydrochloride total overall reaction is complete, is evaporated to liquor capacity
Half, 0 degree of freeze overnight, sucking filtration, be dried, obtain 11.1g white solid 4-[2-(cycloheximide base-1-)
Ethyoxyl] benzyl chloride hydrochlorate 1, yield 91%, HPLC purity: 96.2%.
The synthetic method synthesis compound 1 that comparative example 1 reports according to United States Patent (USP) US6005102
The preparation of 4-[2-(cycloheximide-1-base) ethyoxyl] benzaldehyde 4
Under nitrogen protection, sodium hydride (6.5g, 163mmol) adds to DMF(50mL) in, stir 10min,
The DMF(80mL of 0 DEG C of dropping hydroxy benzaldehyde (9g, 74mmol)) solution, drips and finishes, be incubated (0 DEG C)
Stirring 30min.0 DEG C adds 2-(cycloheximide base) chloride hydrochloride (15.3g, 77mmol), add
Finishing, temperature rises to 25 DEG C of reaction 1h.Reactant liquor adds water and each 100mL of ethyl acetate, is layered,
Aqueous phase ethyl acetate (50mL × 2) is extracted, and merges organic layer, and saturated nacl aqueous solution is washed, anhydrous
Sodium sulfate is dried, and concentrating under reduced pressure obtains 21.1g yellow liquid compound 4, yield 89.7%, HPLC purity:
78%。
The preparation of 4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3
Being added to by compound 4 in methanol (40mL), temperature is down to 0 DEG C, be dividedly in some parts sodium borohydride (1.5g,
39mmol), finishing, room temperature 25 DEG C is reacted 0.5 hour.Reactant liquor is poured in frozen water (50mL), acetic acid
Ethyl ester (40mL × 2) extracts, and saturated nacl aqueous solution is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure obtains 15.6g
Yellow dense fluids 4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3, yield 70%, HPLC purity:
75%。
The preparation of 4-[2-(cycloheximide base-1-) ethyoxyl] benzyl chloride hydrochlorate 1
At 0 DEG C to 10 DEG C, toward the THF solution of 4-[2-(cycloheximide-1-base) ethyoxyl] benzyl alcohol 3
(30mL) HCl(g it is passed through in)/THF (1mol/L, 47mL, 1.0eq), drip and finish, insulated and stirred 3
Hour, there is white solid to generate.Dropping thionyl chloride (5.1mL, 64mmol, 1.5eq), drips and finishes,
Being warming up to 50 DEG C, system gradual change is clarified.Reactant liquor is concentrated into 20mL, is placed in refrigerator freezing (0 DEG C)
Overnight, sucking filtration, solid, with cold THF solution (8mL) washing, is evaporated, obtains 8.6g pale yellow colored solid
Body 1, yield 61%.HPLC purity: 85%.
During the synthetic route repeating United States Patent (USP) US6005102, the present inventor sends out
During preparing now compound 3, if first separated by compound 4, then carry out reduction reaction
When preparing compound 3, TLC monitoring finds to generate a bigger impurity in course of reaction.And use
When the one kettle way of the present invention prepares compound 3, described bigger impurity substantially tails off.