CN108484653B - Preparation method of thiophene borate - Google Patents
Preparation method of thiophene borate Download PDFInfo
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- CN108484653B CN108484653B CN201810465013.4A CN201810465013A CN108484653B CN 108484653 B CN108484653 B CN 108484653B CN 201810465013 A CN201810465013 A CN 201810465013A CN 108484653 B CN108484653 B CN 108484653B
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- dioxolane
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- thienyl
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- ODDBHAGNNBEBEY-UHFFFAOYSA-N boric acid;thiophene Chemical compound OB(O)O.C=1C=CSC=1 ODDBHAGNNBEBEY-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims abstract description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 51
- VOJKCZSSUHBMKS-UHFFFAOYSA-N 2-thiophen-3-yl-1,3-dioxolane Chemical compound O1CCOC1C1=CSC=C1 VOJKCZSSUHBMKS-UHFFFAOYSA-N 0.000 claims abstract description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 34
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000003208 petroleum Substances 0.000 claims abstract description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 24
- RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 claims abstract description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 22
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 8
- MRWWWZLJWNIEEJ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane Chemical compound CC(C)OB1OC(C)(C)C(C)(C)O1 MRWWWZLJWNIEEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000007710 freezing Methods 0.000 claims abstract description 6
- 230000008014 freezing Effects 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 238000010791 quenching Methods 0.000 claims abstract description 6
- 230000000171 quenching effect Effects 0.000 claims abstract description 6
- 238000000967 suction filtration Methods 0.000 claims abstract description 6
- 239000012074 organic phase Substances 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000012043 crude product Substances 0.000 claims description 23
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000002274 desiccant Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000009987 spinning Methods 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 3
- WULZFOSYFJWKOH-UHFFFAOYSA-N B(O)(O)O.C(C)(C)OCC(O)(C)C(C)(C)O Chemical compound B(O)(O)O.C(C)(C)OCC(O)(C)C(C)(C)O WULZFOSYFJWKOH-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 11
- 239000004327 boric acid Substances 0.000 abstract description 10
- 239000000463 material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract 2
- 238000010828 elution Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WHQHIIFNBWIJSG-UHFFFAOYSA-N C(C)(C)OOB(O)O.OC(C)(C)C(C)(C)O Chemical compound C(C)(C)OOB(O)O.OC(C)(C)C(C)(C)O WHQHIIFNBWIJSG-UHFFFAOYSA-N 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- FEAXPTKBBNVSSI-UHFFFAOYSA-N OBO.C=1C=CSC=1.CC(C)(O)C(C)(C)O Chemical compound OBO.C=1C=CSC=1.CC(C)(O)C(C)(C)O FEAXPTKBBNVSSI-UHFFFAOYSA-N 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- -1 boric acid ester Chemical class 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001638 boron Chemical class 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- OKCBEPHXQAIBDY-UHFFFAOYSA-N lithium;thiophene Chemical compound [Li].C=1C=CSC=1 OKCBEPHXQAIBDY-UHFFFAOYSA-N 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- QDLYEPXRLHYMJV-UHFFFAOYSA-N propan-2-yloxyboronic acid Chemical compound CC(C)OB(O)O QDLYEPXRLHYMJV-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical class OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method of thiophene borate, which comprises the following steps: the preparation method comprises the steps of mixing 3-thiophenecarboxaldehyde, p-toluenesulfonic acid monohydrate, ethylene glycol and toluene, carrying out reflux dehydration reaction, and then sequentially carrying out extraction, drying, filtering, spin-drying and elution to obtain 2- (3-thienyl) -1, 3-dioxolane; the method comprises the following steps of (1) replacing 2- (3-thienyl) -1, 3-dioxolane with nitrogen, injecting anhydrous tetrahydrofuran, dropwise adding n-butyllithium and isopropoxyboronic acid pinacol ester for reaction, performing quenching reaction, extraction, drying, spin-drying, adding dichloromethane to completely dissolve the materials, and adding petroleum ether until no solid is separated out; and finally, after dichloromethane and residual petroleum ether are evaporated in a rotary mode, when 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene solid begins to be separated out, freezing and performing suction filtration to obtain white solid 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene. The method is simple, high in yield and easy for industrial production.
Description
Technical Field
The invention relates to an organic intermediate synthesis technology applied in the fields of medicines and materials, in particular to a preparation method of thiophene borate.
Background
Thiophene boronic acid pinacol ester is used as an important reaction intermediate and widely applied to the fields of medicines, chemical industry and materials. The method expands the synthesis of novel thiophene borate and has great practical significance in the synthesis and screening of medicines and organic materials. However, few thiophene-2 boronic acid derivatives of aldehyde group 3 and aldehyde group precursors are reported at present because the reaction precursors are difficult to prepare, and boron esters prepared by bromination recoupling of 3-thiophenecarboxaldehyde or direct butyl lithium hydrogen abstraction cannot efficiently obtain the target product of the invention. This is not conducive to subsequent drug preparation or modular combinatorial screening of materials. In addition, the thiophene boric acid derivative has high additional value, and the research on the efficient preparation and synthesis of thiophene boronic acid pinacol ester has great practical significance from the perspective of potential development and generation.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of thiophene borate, which is simple, high in yield and easy for industrial production.
In order to solve the problems, the preparation method of the thiophene borate provided by the invention comprises the following steps:
mixing 3-thiophenecarboxaldehyde, p-toluenesulfonic acid monohydrate, ethylene glycol and toluene, performing reflux dehydration reaction, cooling to room temperature, and extracting for 1 time by using a saturated sodium bicarbonate aqueous solution with the volume of 0.5-2.0 times of that of the mixture to obtain an organic phase A and a water phase respectively; extracting the water phase for 2 times by using ethyl acetate with the same volume to obtain an organic phase B; after the organic phase A and the organic phase B are combined, the mixture is dried by anhydrous sodium sulfate with the mass of 5-15 percent, filtered to remove the drying agent and dried in a spinning way to obtain a crude product of 2- (3-thienyl) -1, 3-dioxolane; eluting the crude 2- (3-thienyl) -1, 3-dioxolane product by using petroleum ether-dichloromethane mixed solution with the mass of 1000-3000 times that of the crude product to obtain 2- (3-thienyl) -1, 3-dioxolane; the molar ratio of the 3-thiophenecarboxaldehyde to the p-toluenesulfonic acid monohydrate is 95: 1-105: 1; the molar ratio of the 3-thiophenecarboxaldehyde to the ethylene glycol is 1: 6-1: 8; the ratio of the 3-thiophenecarboxaldehyde to the toluene is 1 mol: 1.0L-1 mol: 10L;
after the 2- (3-thienyl) -1, 3-dioxolane is replaced by nitrogen for three times, anhydrous tetrahydrofuran is injected, the temperature is reduced to minus 70 ℃ to minus 50 ℃, and n-butyllithium is dripped within 10min at minus 65 ℃ to minus 50 ℃; after dripping is finished, preserving heat for 10-30 min, then dripping isopropoxy pinacol borate for reaction, naturally heating to room temperature after 30min, then adding an ammonium chloride aqueous solution for quenching reaction to obtain a crude product of 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene, extracting the crude product of 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene for three times by using ethyl acetate with the same volume, and merging an organic phase C; drying the organic phase C by using anhydrous sodium sulfate with the mass of 5-15% of that of the organic phase C, then spin-drying, adding dichloromethane to completely dissolve the organic phase C, and adding petroleum ether until no solid is precipitated; finally, rotationally evaporating dichloromethane and residual petroleum ether at 25-35 ℃, and then beginning to precipitate 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene solid, placing a rotationally evaporated single-mouth bottle at-5 ℃ for freezing for 5 hours, and then performing suction filtration to obtain white solid 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene; the ratio of the 2- (3-thienyl) -1, 3-dioxolane to the anhydrous tetrahydrofuran is 1 mol: 0.5L-1 mol: 2.5L; the molar ratio of the n-butyllithium to the 2- (3-thienyl) -1, 3-dioxolane is 1: 1-1.5: 1; the molar ratio of the isopropoxyboronic acid pinacol ester to the 2- (3-thienyl) -1, 3-dioxolane is 1: 1-1: 1.125.
the structural formula of the 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene is as follows:
the reflux dehydration reaction condition in the step I is that the temperature is 100-140 ℃ and the time is 6-10 h.
The method comprises the steps of firstly, drying the steel plate in a rotary manner at a temperature of 35-45 ℃.
The petroleum ether-dichloromethane mixed liquid in the step is prepared by mixing petroleum ether and dichloromethane according to the ratio of 2: 1-5: 1 by volume ratio.
Compared with the prior art, the invention has the following advantages:
1. the invention adopts a method that thiophene lithium salt attacks isopropanol borate to prepare 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene, and the 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene is purified by a convenient method.
2. The method adopts a crystallization method to purify the boric acid ester, improves the purification efficiency of the boric acid ester, and is beneficial to industrial large-scale production.
3. The thiophene borate containing the aldehyde group precursor is novel and unique in structure, and can conveniently remove the ethylene glycol protecting group after SUZUKI coupling; various reactions or functional group transformations can also be carried out on the basis of aldehydes, providing an effective method for broadening the construction of thiophene functional units.
Detailed Description
Embodiment 1 a method for preparing thiophene borate, comprising the steps of:
mixing 3-thiophenecarboxaldehyde, p-toluenesulfonic acid monohydrate, ethylene glycol and toluene, carrying out reflux dehydration reaction at 100 ℃ for 10 hours, cooling to room temperature, and extracting for 1 time by using a saturated sodium bicarbonate aqueous solution with the volume of 0.5 times that of the mixture to obtain an organic phase A and a water phase respectively; extracting the water phase for 2 times by using ethyl acetate with the same volume to obtain an organic phase B;
after the organic phase A and the organic phase B are combined, the mixture is dried by anhydrous sodium sulfate with the mass of 5 percent, filtered to remove the drying agent and dried by spinning at the temperature of 35 ℃ in sequence to obtain a crude product of 2- (3-thienyl) -1, 3-dioxolane; eluting the crude product of the 2- (3-thienyl) -1, 3-dioxolane by petroleum ether-dichloromethane mixed solution with the mass of 1000 times of that of the crude product to obtain the 2- (3-thienyl) -1, 3-dioxolane. The yield thereof was found to be 70.5%.
1H NMR (400 MHz, CDCl3) δ 7.41(d, 1H), 7.31(m, 1H), 7.15(d, 1H), 5.91(s, 1H), 4.11(m, 2H), 4.01(m, 2H).
Wherein: the molar ratio of 3-thiophenecarboxaldehyde to p-toluenesulfonic acid monohydrate was 95: 1; the molar ratio of 3-thiophenecarboxaldehyde to ethylene glycol is 1: 6; the ratio of 3-thiophenecarboxaldehyde to toluene was 1 mol: 1.0L; the petroleum ether-dichloromethane mixed solution is prepared by mixing petroleum ether and dichloromethane according to the weight ratio of 2: 1 by volume ratio.
The reaction formula is as follows:
。
after the 2- (3-thienyl) -1, 3-dioxolane is replaced by nitrogen for three times, anhydrous tetrahydrofuran is injected, the temperature is reduced to-70 ℃, and n-butyllithium is dripped within 10min at-65 ℃; after dripping, preserving the temperature for 10min, then dripping isopropoxy boric acid pinacol ester for reaction, naturally heating to room temperature after 30min, then adding an ammonium chloride aqueous solution for quenching reaction to obtain a 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene crude product;
extracting the crude product of the 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene by using equal volume of ethyl acetate for three times, and combining organic phases C; drying the organic phase C by using anhydrous sodium sulfate with the mass of 5% of that of the organic phase C, then carrying out spin drying at 35 ℃, adding dichloromethane to completely dissolve the organic phase C, and adding petroleum ether until no solid is separated out;
and finally, rotationally evaporating dichloromethane and residual petroleum ether at 25 ℃, and then beginning to precipitate 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene solid, placing a rotationally evaporated single-neck bottle at-5 ℃ for freezing for 5 hours, and then carrying out suction filtration to obtain the white solid 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene. The yield thereof was found to be 75%.
1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H), 7.30 (d, 1H), 6.33 (s, 1H), 4.16 (m, 2H), 4.04 (m, 2H), 1.34(s, 12H).
The structural formula of the 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene is shown as follows:
wherein: the ratio of 2- (3-thienyl) -1, 3-dioxolane to anhydrous tetrahydrofuran is 1 mol: 0.5L; the molar ratio of n-butyllithium to 2- (3-thienyl) -1, 3-dioxolane is 1: 1; the molar ratio of the isopropoxyboronic acid pinacol ester to the 2- (3-thienyl) -1, 3-dioxolane is 1: 1.
the reaction formula is as follows:
。
embodiment 2 a method for preparing thiophene borate, comprising the steps of:
mixing 3-thiophenecarboxaldehyde, p-toluenesulfonic acid monohydrate, ethylene glycol and toluene, carrying out reflux dehydration reaction at 140 ℃ for 6 hours, cooling to room temperature, and extracting for 1 time by using saturated sodium bicarbonate aqueous solution with the volume 2.0 times of that of the mixture to obtain an organic phase A and a water phase respectively; extracting the water phase for 2 times by using ethyl acetate with the same volume to obtain an organic phase B;
after the organic phase A and the organic phase B are combined, the mixture is dried by anhydrous sodium sulfate with the mass of 15 percent, filtered to remove a drying agent and dried by spinning at the temperature of 45 ℃ in sequence to obtain a crude product of 2- (3-thienyl) -1, 3-dioxolane; and eluting the crude product of the 2- (3-thienyl) -1, 3-dioxolane by using petroleum ether-dichloromethane mixed solution with the mass being 3000 times that of the crude product to obtain the 2- (3-thienyl) -1, 3-dioxolane. The yield thereof was found to be 70%.
1H NMR (400 MHz, CDCl3) δ 7.41(d, 1H), 7.31(m, 1H), 7.15(d, 1H), 5.91(s, 1H), 4.11(m, 2H), 4.01(m, 2H).
Wherein: the molar ratio of 3-thiophenecarboxaldehyde to p-toluenesulfonic acid monohydrate was 105: 1; the molar ratio of 3-thiophenecarboxaldehyde to ethylene glycol is 1: 8; the ratio of 3-thiophenecarboxaldehyde to toluene was 1 mol: 10L; the petroleum ether-dichloromethane mixed solution is prepared by mixing petroleum ether and dichloromethane according to the weight ratio of 5: 1 by volume ratio.
The reaction formula is the same as that of example 1.
After the 2- (3-thienyl) -1, 3-dioxolane is replaced by nitrogen for three times, anhydrous tetrahydrofuran is injected, the temperature is reduced to minus 50 ℃, and n-butyllithium is dripped within 10min at minus 50 ℃; after dripping, preserving the temperature for 30min, then dripping isopropoxy boric acid pinacol ester for reaction, naturally heating to room temperature after 30min, then adding an ammonium chloride aqueous solution for quenching reaction to obtain a 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene crude product;
extracting the crude product of the 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene by using equal volume of ethyl acetate for three times, and combining organic phases C; drying the organic phase C by anhydrous sodium sulfate with the mass of 15% of that of the organic phase C, then carrying out spin drying at 45 ℃, adding dichloromethane to completely dissolve the organic phase C, and adding petroleum ether until no solid is separated out;
and finally, rotationally evaporating dichloromethane and residual petroleum ether at 35 ℃ to separate out 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene solid, placing a rotationally evaporated single-neck bottle at-5 ℃ for freezing for 5 hours, and performing suction filtration to obtain the white solid 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene. The yield thereof was found to be 65%.
1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H), 7.30 (d, 1H), 6.33 (s, 1H), 4.16 (m, 2H), 4.04 (m, 2H), 1.34(s, 12H).
The structural formula of 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene is the same as in example 1.
Wherein: the ratio of 2- (3-thienyl) -1, 3-dioxolane to anhydrous tetrahydrofuran is 1 mol: 2.5L; the molar ratio of n-butyllithium to 2- (3-thienyl) -1, 3-dioxolane is 1.5: 1; the molar ratio of the isopropoxyboronic acid pinacol ester to the 2- (3-thienyl) -1, 3-dioxolane is 1: 1.125.
the reaction formula is the same as that of example 1.
Embodiment 3 a method for preparing thiophene borate, comprising the steps of:
mixing 3-thiophenecarboxaldehyde, p-toluenesulfonic acid monohydrate, ethylene glycol and toluene, carrying out reflux dehydration reaction at 120 ℃ for 8 hours, cooling to room temperature, and extracting for 1 time by using saturated sodium bicarbonate aqueous solution with the volume of 1.5 times of that of the mixture to obtain an organic phase A and a water phase respectively; extracting the water phase for 2 times by using ethyl acetate with the same volume to obtain an organic phase B;
after the organic phase A and the organic phase B are combined, the mixture is dried by anhydrous sodium sulfate with the mass of 10 percent, filtered to remove the drying agent and dried by spinning at 40 ℃ in sequence to obtain a crude product of 2- (3-thienyl) -1, 3-dioxolane; eluting the crude product of the 2- (3-thienyl) -1, 3-dioxolane by using petroleum ether-dichloromethane mixed solution with the mass of 2000 times that of the crude product to obtain the 2- (3-thienyl) -1, 3-dioxolane. The yield thereof was found to be 72%.
1H NMR (400 MHz, CDCl3) δ 7.41(d, 1H), 7.31(m, 1H), 7.15(d, 1H), 5.91(s, 1H), 4.11(m, 2H), 4.01(m, 2H).
Wherein: the molar ratio of 3-thiophenecarboxaldehyde to p-toluenesulfonic acid monohydrate is 100: 1; the molar ratio of 3-thiophenecarboxaldehyde to ethylene glycol is 1: 7; the ratio of 3-thiophenecarboxaldehyde to toluene was 1 mol: 5L; the petroleum ether-dichloromethane mixed solution is prepared by mixing petroleum ether and dichloromethane according to the weight ratio of 3.5: 1 by volume ratio.
The reaction formula is the same as that of example 1.
After the 2- (3-thienyl) -1, 3-dioxolane is replaced by nitrogen for three times, anhydrous tetrahydrofuran is injected, the temperature is reduced to-60 ℃, and n-butyllithium is dripped within 10min at-55 ℃; after dripping, preserving the temperature for 20min, then dripping isopropoxy boric acid pinacol ester for reaction, naturally heating to room temperature after 30min, then adding an ammonium chloride aqueous solution for quenching reaction to obtain a 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene crude product;
extracting the crude product of the 2-boric acid pinacol diester-3- (1, 3-dioxolane) thiophene by using equal volume of ethyl acetate for three times, and combining organic phases C; drying the organic phase C by 10% of anhydrous sodium sulfate by mass, then spin-drying at 40 ℃, adding dichloromethane to completely dissolve the organic phase C, and adding petroleum ether until no solid is separated out;
and finally, rotationally evaporating dichloromethane and residual petroleum ether at 30 ℃, and then beginning to precipitate 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene solid, placing a rotationally evaporated single-neck bottle at-5 ℃ for freezing for 5 hours, and then carrying out suction filtration to obtain the white solid 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene. The yield thereof was found to be 68%.
1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H), 7.30 (d, 1H), 6.33 (s, 1H), 4.16 (m, 2H), 4.04 (m, 2H), 1.34(s, 12H).
The structural formula of 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene is the same as in example 1.
Wherein: the ratio of 2- (3-thienyl) -1, 3-dioxolane to anhydrous tetrahydrofuran is 1 mol: 1.5L; the molar ratio of n-butyllithium to 2- (3-thienyl) -1, 3-dioxolane is 1.3: 1; the molar ratio of the isopropoxyboronic acid pinacol ester to the 2- (3-thienyl) -1, 3-dioxolane is 1: 1.105.
the reaction formula is the same as that of example 1.
Claims (1)
1. A preparation method of thiophene borate comprises the following steps:
mixing 3-thiophenecarboxaldehyde, p-toluenesulfonic acid monohydrate, ethylene glycol and toluene, performing reflux dehydration reaction, cooling to room temperature, and extracting for 1 time by using a saturated sodium bicarbonate aqueous solution with the volume of 0.5-2.0 times of that of the mixture to obtain an organic phase A and a water phase respectively; extracting the water phase for 2 times by using ethyl acetate with the same volume to obtain an organic phase B; after the organic phase A and the organic phase B are combined, the mixture is dried by anhydrous sodium sulfate with the mass of 5-15 percent, filtered to remove the drying agent and dried in a spinning way to obtain a crude product of 2- (3-thienyl) -1, 3-dioxolane; eluting the crude 2- (3-thienyl) -1, 3-dioxolane product by using petroleum ether-dichloromethane mixed solution with the mass of 1000-3000 times that of the crude product to obtain 2- (3-thienyl) -1, 3-dioxolane; the molar ratio of the 3-thiophenecarboxaldehyde to the p-toluenesulfonic acid monohydrate is 95: 1-105: 1; the molar ratio of the 3-thiophenecarboxaldehyde to the ethylene glycol is 1: 6-1: 8; the ratio of the 3-thiophenecarboxaldehyde to the toluene is 1 mol: 1.0L-1 mol: 10L; the reflux dehydration reaction condition is that the temperature is 100-140 ℃ and the time is 6-10 h; the spin-drying conditions mean that the temperature is 35-45 ℃; the petroleum ether-dichloromethane mixed solution is prepared by mixing petroleum ether and dichloromethane according to the weight ratio of 2: 1-5: 1 by volume ratio;
after the 2- (3-thienyl) -1, 3-dioxolane is replaced by nitrogen for three times, anhydrous tetrahydrofuran is injected, the temperature is reduced to minus 70 ℃ to minus 50 ℃, and n-butyllithium is dripped within 10min at minus 65 ℃ to minus 50 ℃; after dripping is finished, preserving heat for 10-30 min, then dripping isopropoxy pinacol borate for reaction, naturally heating to room temperature after 30min, then adding an ammonium chloride aqueous solution for quenching reaction to obtain a crude product of 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene, extracting the crude product of 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene for three times by using ethyl acetate with the same volume, and merging an organic phase C; drying the organic phase C by using anhydrous sodium sulfate with the mass of 5-15% of that of the organic phase C, then spin-drying, adding dichloromethane to completely dissolve the organic phase C, and adding petroleum ether until no solid is precipitated; finally, rotationally evaporating dichloromethane and residual petroleum ether at 25-35 ℃, and then beginning to precipitate 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene solid, placing a rotationally evaporated single-mouth bottle at-5 ℃ for freezing for 5 hours, and then performing suction filtration to obtain white solid 2-boronic acid pinacol diester-3- (1, 3-dioxolane) thiophene; the ratio of the 2- (3-thienyl) -1, 3-dioxolane to the anhydrous tetrahydrofuran is 1 mol: 0.5L-1 mol: 2.5L; the molar ratio of the n-butyllithium to the 2- (3-thienyl) -1, 3-dioxolane is 1: 1-1.5: 1; the molar ratio of the isopropoxyboronic acid pinacol ester to the 2- (3-thienyl) -1, 3-dioxolane is 1: 1-1: 1.125; the spin drying condition is that the temperature is 35-45 ℃.
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| CN102731542A (en) * | 2012-06-18 | 2012-10-17 | 台州市华南医化有限公司 | Preparation method of p-bromophenyl-boric acid |
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| CN102731542A (en) * | 2012-06-18 | 2012-10-17 | 台州市华南医化有限公司 | Preparation method of p-bromophenyl-boric acid |
| CN103044470A (en) * | 2012-11-30 | 2013-04-17 | 大连联化化学有限公司 | Method for preparing 5-formyl-3-furan/thiophene boronic acid pinacol cyclic ester |
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