CN106986886B - A kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4- - Google Patents
A kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4- Download PDFInfo
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- CN106986886B CN106986886B CN201710220608.9A CN201710220608A CN106986886B CN 106986886 B CN106986886 B CN 106986886B CN 201710220608 A CN201710220608 A CN 201710220608A CN 106986886 B CN106986886 B CN 106986886B
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- trifluomethoxybenzene
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- trifluoromethoxyphen
- pinacol borate
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- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000011737 fluorine Substances 0.000 claims abstract description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 7
- 238000006722 reduction reaction Methods 0.000 claims abstract description 6
- 238000006396 nitration reaction Methods 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 26
- 239000012043 crude product Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 4
- 238000010499 C–H functionalization reaction Methods 0.000 abstract description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- -1 aryl boric acid Chemical compound 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000003682 fluorination reaction Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 239000010813 municipal solid waste Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000010726 Glycine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010063380 Glycine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation methods of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-, and this method comprises the following steps: using adjacent fluorine trifluomethoxybenzene as starting material, the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- is made by nitration reaction；Then, the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- passes through reduction reaction, and the fluoro- 4- amido -2- trifluomethoxybenzene of 1- is made；Finally, the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of the 4- is made in the fluoro- 4- amido -2- trifluomethoxybenzene diazotising of 1-.The method of the present invention technical process route is short, easy to operate, reaction condition is mild and easy to control, and cost is relatively low, it is easy to accomplish industrialization, avoid the generation that existing technique is directly catalyzed C-H activation isomers and by-product, it also avoids using expensive catalyst, product is easy to purify, and yield is higher.
Description
Technical field
It with adjacent fluorine trifluomethoxybenzene is original more particularly, to one kind the present invention relates to the preparation method of medicine intermediate
Material, the method for preparing the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4- by nitrification, reduction, diazo process.
Background technique
Fluorine atom is introduced in organic compound, since fluorine atom is close with the atomic radius of hydrogen atom, is had to have and be compared
Big electronegativity, it is formed by C-F bond energy can be much bigger than c h bond, can obviously increase the stability of compound；In addition,
The general with higher fat-soluble and hydrophobicity of fluorinated organic compound, can promote the absorption and transmitting of drug in vivo
Speed；Simultaneously because fluorine atom has mimic effect, electronic effect, steric effect and osmotic effect, its introducing may make drug
Bioactivity multiplication, and the universal environmental pollution of fluorochemical is smaller, so the development of Drugs Containing Fluorine and intermediate is non-
Often rapidly and widely paid close attention to.
In prior art introduce fluorine method there are mainly two types of: one is directly with various fluorination reagents molecule some
Fluorine or by halogen-fluorine exchange reaction on position, but directly fluorination generally requires and uses special reagent and equipment, Huo Zhexu
Higher reaction temperature is wanted, and expensive, yield is not high, and by-product is more, purification difficult.Another kind is by modes such as couplings
It is introduced directly into fluorine-containing segment, does not need to use special fluorination reagent, often reaction condition is mild, is suitble to industrialization.
Aryl-boric acid ester be it is a kind of it is more stable in air, insensitive to moisture, can be with long-term preservation and reactivity
Higher organic synthesis and medicine, chemical intermediate.The position of the Suzuki coupling reaction of aryl boric acid and halogenated aryl hydrocarbon selects
Property and stereoselectivity it is good, various chemical functional groups do not change in the reaction, and reaction condition is mild, and yield is high, are shapes
At the important channel of C-C key.Fluorine-containing borate has very in terms of organic synthesis, biomedicine, pesticide and materialogy in recent years
Important role.
The preparation side of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4- is reported in existing literature WO2011038293
Method, but selectivity is bad, there is isomers, yield is low and is difficult to separate, and it has used expensive iridium catalyst, cost compared with
Height is unfavorable for amplification production.
Preparation of N-(hetero)arylmethyl-1H-imidazole-4-carboxamides and-
1H-1,2,4-triazole-3-carboxamide derivatives as glycine transporter
Inhibitors, By Moriya, Minoru et al, From PCT Int.Appl., 2012036278,22Mar 2012,
It is middle to use bromide for reaction raw materials, the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4- is prepared, this method raw material is not easy to obtain
, and used catalyst is somewhat expensive Pd, higher cost, in addition purifying needs column to chromatograph, and relative difficulty is also not suitable for amplifying
Production.
Summary of the invention
In view of the above-mentioned problems existing in the prior art, the applicant provides a kind of fluoro- 3- trifluomethoxybenzenes of 4-
The preparation method of ylboronic acid pinacol ester.The method of the present invention technical process route is short, easy to operate, reaction condition is mild and easily-controllable
System, cost is relatively low, it is easy to accomplish and industrialization avoids the generation that existing technique is directly catalyzed C-H activation isomers and by-product,
It also avoids using expensive catalyst, product is easy to purify, and yield is higher.
Technical scheme is as follows:
A kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-, includes the following steps: with adjacent fluorine three
Fluorine methoxyl group benzene is starting material, and the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- is made by nitration reaction；Then, the fluoro- 4- of 1-
Nitro -2- trifluomethoxybenzene passes through reduction reaction, and the fluoro- 4- amido -2- trifluomethoxybenzene of 1- is made；Finally, by the fluoro- 4- of 1-
The fluoro- 3- Trifluoromethoxyphen-l pinacol borate of the 4- is made in amido -2- trifluomethoxybenzene diazotising.
The detailed process of the nitration reaction are as follows: using adjacent fluorine trifluomethoxybenzene as raw material, be first dissolved in 3~10 equivalents
The concentrated sulfuric acid in, the concentrated nitric acid of 1~5 equivalent is added dropwise after being cooled to -5 DEG C, then is warming up to 30~80 DEG C of 1~12h of reaction, pours into ice
Water quenching is gone out, and solid obtains the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- by filtering, drying.
The detailed process of the reduction reaction are as follows: the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- is dissolved in solvent, is added 1
The reducing agent of~5 equivalents is heated to 30~100 DEG C of reaction 2h, and cooling concentration falls ethyl alcohol, and ethyl acetate extraction is added, and crude product is used
Methylene chloride/petroleum ether is recrystallized to give the fluoro- 4- amido -2- trifluomethoxybenzene of 1-.
The reducing agent is Na2O3S2、Fe、Zn、SnCl2, one of Pd/C, Ni or a variety of.
The solvent is NH4One of Cl aqueous solution, acetic acid, methanol, ethyl alcohol, tetrahydrofuran, ethyl acetate, water are more
Kind；The methylene chloride/petroleum ether volume ratio is 10:1.
The diazotizing concrete operations are as follows: at room temperature, by the fluoro- 4- amido -2- trifluomethoxybenzene of 1- be dissolved in methanol,
In HCl and water mixed solvent, after ice-water bath is cooling, the NaNO of 1~5 equivalent is added dropwise2Aqueous solution, addition 1~5 is worked as after stirring 0.5h
The duplex pinacol borate of amount, being stirred for 1.5h reaction terminates, and adopts to be extracted with dichloromethane and is concentrated to get crude product, crude product passes through
The fluoro- 3- Trifluoromethoxyphen-l pinacol borate of the 4- is made in soda acid extraction.
The volume ratio of the in the mixed solvent methanol, HCl and water is 2:1:1.The NaNO2The mass concentration of aqueous solution is
10~80%.
The present invention is beneficial to be had the technical effect that
Raw material of the present invention is cheap and easily-available, and good reaction selectivity, by-product is few, and reaction condition is mildly easily operated, cost compared with
It is low, it is easy to carry out industrialization, resulting product purity is high, stability is good, and complies fully with and want as the use of pharmaceutical intermediate
It asks.The generation that existing technique is directly catalyzed C-H activation isomers and by-product is avoided, is also avoided using expensive catalysis
Agent, product are easy to purify, and yield is higher.
Detailed description of the invention
Fig. 1 is schematic diagram of the present invention.
Specific embodiment
With reference to the accompanying drawings and examples, the present invention is specifically described.
Embodiment 1
A kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-, includes the following steps:
(1) preparation of the fluoro- 4- nitro -2- trifluomethoxybenzene of 1-
The concentrated sulfuric acid (20mL, 0.35mol, 3.5eq) is added into the three-necked flask of 500mL, raw material is added portionwise under stirring
Adjacent fluorine trifluomethoxybenzene (18g, 0.1mol, 1eq), solution is clarified after stirring half an hour, is cooled to -5 DEG C with ice salt bath, slowly
It being added dropwise concentrated nitric acid (6.6mL, 0.1mol, 1eq), exothermic heat of reaction, rate of addition keeps interior temperature to be no more than 0 DEG C, after being added dropwise,
After 0 DEG C of 1 hour of stirring, 40 DEG C of stirring 12h are warming up to, after reaction solution is cooled to room temperature, are slowly poured into trash ice, and constantly stir
It mixes, a large amount of yellow solids are precipitated, and filter, and filter cake is washed with water three times, drains, and are dried in vacuo to obtain yellow solid 18g, yield
80%, HPLC purity 95%.
(2) preparation of the fluoro- 4- amido -2- trifluomethoxybenzene of 1-
The fluoro- 4- nitro -2- trifluomethoxybenzene (22.5g, 0.1mol) of 1- is successively added into the three-necked flask of 500mL,
Sodium thiosulfate (47.4g, 0.3mol, 1eq), ethyl alcohol (250mL) and water (100mL), reaction solution are heated to 80 DEG C and stir 2h
After be cooled to room temperature, be removed under reduced pressure after most of ethyl alcohol and ethyl acetate (100mL) is added extracts 3 times, liquid separation, organic phase merges,
With saturated common salt water washing, sodium sulphate is dried, filtered, and is concentrated to get crude product, and crude product is tied again with methylene chloride/petroleum ether (10:1)
Crystalline substance obtains white solid 16.7g, yield 86%, and content is up to 93%.
1H NMR(400MHz,CDCl3): δ 6.99 (dd, J=9.7,9.0Hz, 1H), 6.66-6.59 (m, 1H), 6.59-
6.52(m,1H).
(3) preparation of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-
The fluoro- 4- amido -2- trifluomethoxybenzene (5g, 0.025mol, 1eq) of 1- is successively added into the there-necked flask of 250mL,
MeOH (50mL), HCl (3M, 25mL, 3eq) and water (25mL), reaction solution are cooled to 5 DEG C after stirring 30 minutes, are slowly added dropwise
NaNO2Aqueous solution (the NaNO of 1.73g2(1eq) is dissolved in 12.5mL water) continue stirring 30 minutes, duplex pinacol borate is added
(19g, 0.075mol, 3eq) is stirred at room temperature 1.5 hours, is diluted with water, and methylene chloride extracts 3 times, merges organic phase, saturation food
Salt water washing, sodium sulphate, which dries, filters, is concentrated to get crude product, and crude product is dissolved in the NaOH (100mL) of 1M, and methylene chloride extraction is added
Three times, water phase pH is transferred to 6 with 1M HCl, then is extracted with dichloromethane three times, merges organic phase, and sodium sulphate dries, filters concentration
Obtain white solid 7g, yield 90%, content 95%.
1H NMR(400MHz,CDCl3): δ 7.72-7.68 (m, 1H), 7.67-7.60 (m, 1H), 7.10 (dd, J=10,
8.8Hz,1H),1.31(s,12H)。
Embodiment 2
A kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-, includes the following steps:
(1) preparation of the fluoro- 4- nitro -2- trifluomethoxybenzene of 1-
The concentrated sulfuric acid (28.5mL, 0.5mol, 5eq) is added into the three-necked flask of 500mL, raw material neighbour is added portionwise under stirring
Fluorine trifluomethoxybenzene (18g, 0.1mol, 1eq), solution is clarified after stirring half an hour, is cooled to -5 DEG C with ice salt bath, is slowly dripped
Enriching nitric acid (13.2mL, 0.2mol, 2eq), exothermic heat of reaction, rate of addition keeps interior temperature to be no more than 0 DEG C, after being added dropwise, 0
DEG C stirring 1 hour after, be warming up to 50 DEG C stir 12 hours, after reaction solution is cooled to room temperature, slowly pour into trash ice, and constantly
Stirring, a large amount of yellow solids are precipitated, and filter, and filter cake is washed with water three times, drains, and are dried in vacuo to obtain yellow solid 16g, yield
71%, HPLC purity 92%.
(2) preparation of the fluoro- 4- amido -2- trifluomethoxybenzene of 1-
The fluoro- 4- nitro -2- trifluomethoxybenzene (22.5g, 0.1mol) of 1- is successively added into the three-necked flask of 500mL,
Sodium thiosulfate (16g, 0.1mol, 1eq), ethyl alcohol (250mL) and water (100mL), reaction solution is heated to 100 DEG C and stirring 2 is small
When after be cooled to room temperature, be removed under reduced pressure after most of ethyl alcohol and ethyl acetate (100mL) is added extracts 3 times, liquid separation is organic to be harmonious
And with saturated common salt water washing, sodium sulphate is dried, filtered, and is concentrated to get crude product, and crude product is with methylene chloride/petroleum ether (10:1)
It is recrystallized to give white solid 14g, yield 72%.
(3) preparation of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-
The fluoro- 4- amido -2- trifluomethoxybenzene (5g, 0.025mol, 1eq) of 1- is successively added into the there-necked flask of 250mL,
MeOH (50mL), HCl (3M, 8mL, 1eq) and water (25mL), reaction solution are cooled to 0 DEG C after stirring 30 minutes, are slowly added dropwise
NaNO2Aqueous solution (the NaNO of 5.19g2(3eq) is dissolved in 12.5mL water) continue stirring 30 minutes, duplex pinacol borate is added
(18.9g, 0.075mol, 3eq) is stirred at room temperature 1.5 hours, is diluted with water, and methylene chloride extracts 3 times, merges organic phase, saturation
Brine It, sodium sulphate, which dries, filters, is concentrated to get crude product, and crude product is dissolved in the NaOH (100mL) of 1M, and methylene chloride extraction is added
It takes three times, water phase pH is transferred to 6 with 1M HCl, then is extracted with dichloromethane three times, merges organic phase, sodium sulphate dries, filters dense
Contract to obtain white solid 5g, yield 64%.
Embodiment 3
A kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-, includes the following steps:
(1) preparation of the fluoro- 4- nitro -2- trifluomethoxybenzene of 1-
The concentrated sulfuric acid (57mL, 1mol, 10eq) is added into the three-necked flask of 500mL, raw material neighbour's fluorine is added portionwise under stirring
Trifluomethoxybenzene (18g, 0.1mol, 1eq), solution is clarified after stirring half an hour, is cooled to -5 DEG C with ice salt bath, is slowly added dropwise
Concentrated nitric acid (19.8mL, 0.3mol, 3eq), exothermic heat of reaction, rate of addition keeps interior temperature to be no more than 0 DEG C, after being added dropwise, at 0 DEG C
After stirring 1 hour, it is warming up to 80 DEG C and stirs 12 hours, after reaction solution is cooled to room temperature, slowly pour into trash ice, and constantly stir
It mixes, a large amount of yellow solids are precipitated, and filter, and filter cake is washed with water three times, drains, and are dried in vacuo to obtain yellow solid 15g, yield
67%.
(2) preparation of the fluoro- 4- amido -2- trifluomethoxybenzene of 1-
Successively into the three-necked flask of 500mL be added the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- (22.5g, 0.1mol,
1eq) with acetic acid (200mL), it is slowly added into iron powder (28g, 0.5mol, 5eq) reaction solution at room temperature and is heated to 80℃And it is small to stir 2
When after be cooled to room temperature, filter and remove iron powder, filter cake washed three times with ethyl acetate, and second is added after reduced pressure in merging filtrate
Acetoacetic ester (500mL), organic phase use water and saturated common salt water washing respectively, and organic phase is dried, filtered with sodium sulphate, are concentrated to get
Crude product, crude product are recrystallized to give white solid 16g with methylene chloride/petroleum ether (10:1), yield 82%, and content is up to 95%.
(3) preparation of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-
The fluoro- 4- amido -2- trifluomethoxybenzene (5g, 0.025mol, 1eq) of 1- is successively added into the there-necked flask of 250mL,
MeOH (50mL), HCl (3M, 25mL, 1eq) and water (25mL), reaction solution are cooled to 0~5 after stirring 30 minutes℃, it is slowly added dropwise
NaNO2Aqueous solution (the NaNO of 8.65g2(5eq) is dissolved in 12.5mL water) continue stirring 30 minutes, duplex pinacol borate is added
(31.7g, 0.125mol, 5eq) is stirred at room temperature 1.5 hours, is diluted with water, and methylene chloride extracts 3 times, merges organic phase, saturation
Brine It, sodium sulphate, which dries, filters, is concentrated to get crude product, and crude product is dissolved in the NaOH (100mL) of 1M, and methylene chloride extraction is added
It takes three times, water phase pH is transferred to 6 with 1M HCl, then is extracted with dichloromethane three times, merges organic phase, sodium sulphate dries, filters dense
Contract to obtain white solid 6g, yield 77%.
Above-mentioned technical proposal only embodies the preferred embodiment of technical solution of the present invention, and those skilled in the art are to it
In some variations that may make of certain parts embody the principle of the present invention, belong within the scope of protection of the invention.
Claims (1)
1. a kind of preparation method of the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of 4-, it is characterised in that include the following steps:
Using adjacent fluorine trifluomethoxybenzene as starting material, the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- is made by nitration reaction；Then,
The fluoro- 4- nitro -2- trifluomethoxybenzene of 1- passes through reduction reaction, and the fluoro- 4- amido -2- trifluomethoxybenzene of 1- is made；Finally, will
The fluoro- 4- amido -2- trifluomethoxybenzene diazotising of 1-, is made the fluoro- 3- Trifluoromethoxyphen-l pinacol borate of the 4-；
The detailed process of the nitration reaction are as follows: using adjacent fluorine trifluomethoxybenzene as raw material, be first dissolved in the dense of 3~10 equivalents
In sulfuric acid, the concentrated nitric acid of 1~5 equivalent is added dropwise after being cooled to -5 DEG C, then is warming up to 30~80 DEG C of 1~12h of reaction, pours into ice water and quenches
It goes out, solid obtains the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- by filtering, drying；
The detailed process of the reduction reaction are as follows: the fluoro- 4- nitro -2- trifluomethoxybenzene of 1- is dissolved in solvent, is added 1~5
The reducing agent of equivalent is heated to 30~100 DEG C of reaction 2h, and cooling concentration falls ethyl alcohol, and ethyl acetate extraction, crude product dichloro is added
Methane/petroleum ether is recrystallized to give the fluoro- 4- amido -2- trifluomethoxybenzene of 1-；
The diazotizing concrete operations are as follows: at room temperature, by the fluoro- 4- amido -2- trifluomethoxybenzene of 1- be dissolved in methanol, HCl with
In water mixed solvent, after ice-water bath is cooling, the NaNO of 1~5 equivalent is added dropwise21~5 equivalent is added after stirring 0.5h in aqueous solution
Duplex pinacol borate, being stirred for 1.5h reaction terminates, and adopts to be extracted with dichloromethane and is concentrated to get crude product, crude product passes through soda acid
The fluoro- 3- Trifluoromethoxyphen-l pinacol borate of the 4- is made in extraction；
The reducing agent is Na2O3S2、Fe、Zn、SnCl2, one of Pd/C, Ni or a variety of；
The solvent is NH4One of Cl aqueous solution, acetic acid, methanol, ethyl alcohol, tetrahydrofuran, ethyl acetate, water are a variety of；Institute
Stating methylene chloride/petroleum ether volume ratio is 10:1；
The volume ratio of the in the mixed solvent methanol, HCl and water is 2:1:1；
The NaNO2The mass concentration of aqueous solution is 10~80%.
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| DE4221152C1 (en) * | 1992-06-27 | 1993-11-18 | Merck Patent Gmbh | 4-Bromo-2,6-di:fluoro-tri:fluoro-methoxy-benzene prodn. - by nitration of 2,6-di:fluoro-tri:fluoro:methoxy:benzene, redn., bromination and diazotisation and redn. |
| CN104045661A (en) * | 2014-05-07 | 2014-09-17 | 陕西师范大学 | Method for preparation of aryl boronic acid and aryl borate by alcohol-promoted boronation reaction of aromatic amine |
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| DE4221152C1 (en) * | 1992-06-27 | 1993-11-18 | Merck Patent Gmbh | 4-Bromo-2,6-di:fluoro-tri:fluoro-methoxy-benzene prodn. - by nitration of 2,6-di:fluoro-tri:fluoro:methoxy:benzene, redn., bromination and diazotisation and redn. |
| CN104045661A (en) * | 2014-05-07 | 2014-09-17 | 陕西师范大学 | Method for preparation of aryl boronic acid and aryl borate by alcohol-promoted boronation reaction of aromatic amine |
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