CN103896975B - A kind of synthetic method of 3-cyclic ethers methyl trifluoro potassium borate - Google Patents
A kind of synthetic method of 3-cyclic ethers methyl trifluoro potassium borate Download PDFInfo
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- cyclic ethers
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- tetramethyl ethylene
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- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- -1 tetramethyl ethylene ketone Chemical class 0.000 claims abstract description 32
- 239000004327 boric acid Substances 0.000 claims abstract description 26
- WGLLSSPDPJPLOR-UHFFFAOYSA-N tetramethylethylene Natural products CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910000085 borane Inorganic materials 0.000 claims abstract description 10
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- ASZZHBXPMOVHCU-UHFFFAOYSA-N 3,9-diazaspiro[5.5]undecane-2,4-dione Chemical compound C1C(=O)NC(=O)CC11CCNCC1 ASZZHBXPMOVHCU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000005595 deprotonation Effects 0.000 claims abstract description 4
- 238000010537 deprotonation reaction Methods 0.000 claims abstract description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 150000003384 small molecules Chemical class 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000002547 new drug Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 150000004292 cyclic ethers Chemical class 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- ZIZHEHXAMPQGEK-UHFFFAOYSA-N dirhenium decacarbonyl Chemical group [Re].[Re].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] ZIZHEHXAMPQGEK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- OWQUYBAASOSGNO-CDNKMLFNSA-N 2-[[(Z)-N-(2-hydroxy-5-sulfoanilino)-C-phenylcarbonimidoyl]diazenyl]benzoic acid Chemical compound C1=CC=C(C=C1)/C(=N/NC2=C(C=CC(=C2)S(=O)(=O)O)O)/N=NC3=CC=CC=C3C(=O)O OWQUYBAASOSGNO-CDNKMLFNSA-N 0.000 description 1
- NPAXPTHCUCUHPT-UHFFFAOYSA-N 3,4,7,8-tetramethyl-1,10-phenanthroline Chemical class CC1=CN=C2C3=NC=C(C)C(C)=C3C=CC2=C1C NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 1
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- YULMNMJFAZWLLN-UHFFFAOYSA-N methylenecyclohexane Chemical compound C=C1CCCCC1 YULMNMJFAZWLLN-UHFFFAOYSA-N 0.000 description 1
- WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FWZMWMSAGOVWEZ-UHFFFAOYSA-N potassium;hydrofluoride Chemical class F.[K] FWZMWMSAGOVWEZ-UHFFFAOYSA-N 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229940043798 zincon Drugs 0.000 description 1
Abstract
The present invention relates to 3-cyclic ethers methyl trifluoro potassium borate, particularly relate to the synthetic method of 3-cyclic ethers methyl trifluoro potassium borate, mainly solve expensive catalyst that existing preparation method exists, the technical problem such as reaction conditions is violent, synthetic route is long.Technical solution of the present invention: a kind of synthetic method of synthesizing 3-cyclic ethers methyl trifluoro potassium borate: with 2-cyclic ethers alkene for after raw material and borine addition, tetramethyl ethylene ketone cancellation obtains 3-cyclic ethers base tetramethyl ethylene ketone boric acid ester; Then highly basic deprotonation, is obtained by reacting 3-cyclic ethers methyl tetramethyl ethylene ketone boric acid ester with methyl chlorobromide; Last and potassium hydrogen fluoride is obtained by reacting 3-cyclic ethers methyl trifluoro potassium borate.This compounds is important medical compounds structural modification small molecules in new drug research field.
Description
Technical field
The present invention relates to 3-cyclic ethers methyl trifluoro potassium borate, particularly relate to the synthetic method of 3-cyclic ethers methyl trifluoro potassium borate, this compounds is important medical compounds structural modification small molecules in new drug research field.
Background technology
Boric acid compound and derivative thereof are a class in organic synthesis field by the compound of extensive concern, and it has, and stable in properties, reactive behavior are high, the feature of environmental protection.This compounds is used for the intermediate of transition-metal catalysis usually used as electrophilic center, thus builds C-C key, and compare the linked reaction of grignard reagent, zincon, lithium reagent participation, this kind of reaction has better functional group tolerance.In recent years along with the catalyzer for boric acid ester compound and multiple halohydrocarbon coupled reaction is developed in succession, the application of this compounds in C-C key, C-O key, C-N key, the formation of C-S key is also more and more extensive.In biological medicine research field, organoboron compound has more application in synthesis cancer therapy drug, antitumor drug, anti-deterioration medicine etc.3-cyclic ethers methyl trifluoro potassium borate is a wherein compounds structural modification small molecules, and be widely used in medicament research and development and synthesis aspect, as compound 1, compound 2, compound 3 and compound 4 are the molecule of pharmaceutical activity.
US2012/0226041A1 discloses a kind of synthetic method of synthesizing cyclic ethers base tetramethyl ethylene ketone boric acid ester, take cyclic ethers as raw material, (η
6-sym-trimethylbenzene) iridium three (tetramethyl ethylene ketone borine) is catalyzer, 3,4,7,8-tetramethyl--1,10-phenanthrolines are part, react with duplex tetramethyl ethylene ketone borine, prepare cyclic ethers base tetramethyl ethylene ketone boric acid ester (formula 1).
Formula 1:
。
The synthetic method of 3-cyclic ethers methyl trifluoro potassium borate has no report, and the synthetic method of similar cycloalkanes methyl-boron-dihydroxide ester has three kinds, for hexanaphthene: 1. " German applied chemistry " discloses methylcyclohexane and duplex tetramethyl ethylene ketone borine at catalyzer: cyclopentadiene three rhenium carbonyl [C
5h
5re (CO)
3] catalysis under prepare (formula 2, Angew.Chem.Int.Ed. 1999,38 (22), 3391);
Formula 2:
。
2. after " German applied chemistry " discloses hexahydrobenzaldehyde and tosic acid hydrazine reaction, be obtained by reacting with tetramethyl ethylene ketone borine in the basic conditions (formula 3, Angew.Chem.Int.Ed. 2012,51 (12), 2943);
Formula 3:
。
3. methylenecyclohexane and 9-boron dicyclo (3,3,1)-nonane are obtained by reacting (formula 4, WO2007/67612A1):
Formula 4:
。
And for the synthesis of 3-cyclic ethers methyl tetramethyl ethylene ketone boric acid ester, if use similar approach, corresponding raw material is not easy to obtain, expensive or need multistep synthesize just can obtain, as tetrahydropyrans-3-formaldehyde sigma offers 25mg 86 dollars, 3-methyl tetrahydropyrans and 3-methylene radical tetrahydropyrans all need two steps to synthesize to obtain (formula 5); For needing the reaction of using catalyzer, not only can cause heavy metal contamination to environment, and production cost can be made to increase.
Formula 5:
。
Summary of the invention
The method of existing synthesis 3-cycloalkanes methyl trifluoro potassium borate compounds has many unfavorable factors, needs to use costliness and the catalyzer be not easy to obtain, as (η
6-sym-trimethylbenzene) iridium (tetramethyl ethylene ketone borine)
3with ring penta triolefin three carbon monoxide rhenium etc., and the use of precious metal can bring environmental pollution, and environment is unfriendly; Reaction conditions is violent, narrates reaction pressure 1520 Torr(2 normal atmosphere described in temperature of reaction 120 DEG C, formula two such as formula 1); And route is long, raw material is not easy to obtain, and such as formula the raw material that unconventional class in 3 and formula 4 can commercially buy, needs multistep to synthesize and obtains, add preparation cost.The invention provides a kind of method and can obtain 3-cyclic ethers methyl trifluoro potassium borate compounds efficiently, use the method technique is simple, yield is high, cost is low, raw material is easy to get, operate and purifying is convenient, purifying products is simple, be suitable for suitability for industrialized production, is also the synthesis supplying method reference of similar structures small molecules boric acid ester compound.
Technical solution of the present invention: a kind of synthetic method (formula 6) of synthesizing 3-cyclic ethers methyl trifluoro potassium borate: with 2-cyclic ethers alkene for after raw material and borine addition, tetramethyl ethylene ketone cancellation obtains 3-cyclic ethers base tetramethyl ethylene ketone boric acid ester; Then highly basic deprotonation, is obtained by reacting 3-cyclic ethers methyl tetramethyl ethylene ketone boric acid ester with methyl chlorobromide; Last and potassium hydrogen fluoride is obtained by reacting 3-cyclic ethers methyl trifluoro potassium borate.
Formula 6:
n=1,2。
Described 2-cyclic ethers alkene is the one in 2,3 dihydro furan or 3,4-dihydropyrane.
Described highly basic is n-Butyl Lithium.
Described 3-cyclic ethers methyl trifluoro potassium borate is the one in 3-tetrahydrofuran methyl three potassium fluoborate or 3-tetrahydropyrans methyl trifluoro potassium borate.
Advantageous Effects of the present invention: the raw material 2 used in the present invention, 3-dihydrofuran (280 yuan/500g) and 3,4-dihydro-2H-pyrans (180 yuan/500g) low price, to be easy to get, other reagent used also are conventional reagent, preparation cost is very cheap, avoids using highly toxic organotin reagent or and the rare heavy metal catalyst of costliness.By three steps, wherein only the first step needs to use simple column chromatography purification, and operation is conventional, and aftertreatment is simple, and product is easy to get, and avoids high-temperature high-voltage reaction condition or heavy metal catalyst, reaction can be handling and repeatability is all fine.
Embodiment
embodiment 1
1) 3-tetrahydrofuran base tetramethyl ethylene ketone boric acid ester
In a dry 1000mL there-necked flask, add 25 g 2,3 dihydro furans and 120 mL anhydrous tetrahydro furans, reaction solution is cooled to 0 DEG C, 360 mL 1M borine/tetrahydrofuran solutions are slowly added drop-wise in reaction solution.44 g tetramethyl ethylene ketones are dissolved in 100 mL tetrahydrofuran (THF)s, are slowly added drop-wise in reaction solution.Reaction solution stirred overnight at room temperature.Be added drop-wise to slowly in reaction solution by water, be extracted with ethyl acetate, flash column chromatography after organic phase is concentrated, obtains 3-tetrahydrofuran base tetramethyl ethylene ketone boric acid ester 29g, yield 41%.
1H-NMR (300 MHz, CDCl
3): δ3.93-3.96 (m, 1H), 3.75-3.81 (m, 1H), 3.56-3.71 (m, 2H), 1.97-2.02 (m, 1H), 1.76-1.87 (m, 1H), 1.54-1.60 (m, 1H), 1.25 (s, 12H)。
) 3-tetrahydrofuran methyl tetramethyl ethylene ketone boric acid ester
In a dry 500mL there-necked flask, add 29g 3-tetrahydrofuran base tetramethyl ethylene ketone boric acid ester and 250mL anhydrous tetrahydro furan, reaction solution is cooled to-78 DEG C.N-Butyl Lithium/the tetrahydrofuran solution of 58mL 2.5M is added drop-wise in reaction solution slowly, and then 20g methyl chlorobromide is added drop-wise in reaction solution slowly.Reaction solution is slowly warming up to room temperature, then stirred overnight at room temperature.Poured into by reaction solution in ammonium chloride saturated aqueous solution, be extracted with ethyl acetate, organic phase is dry, concentrated, obtains 3-tetrahydrofuran methyl tetramethyl ethylene ketone boric acid ester crude product 30g.
1H-NMR (300 MHz, CDCl
3): δ3.82-3.91 (m, 1H), 3.74-3.81 (m, 1H), 3.69-3.72 (m, 1H), 3.17-3.23 (m, 1H), 2.26-2.33 (m, 1H), 1.99-2.06 (m, 1H), 1.40-1.48 (m, 1H), 1.21 (s, 12H), 0.83-0.86 (d, 2H)。
) 3-tetrahydrofuran methyl three potassium fluoborate
In dry 2000 mL there-necked flasks, add 30g 3-tetrahydrofuran methyl tetramethyl ethylene ketone boric acid ester crude product and 600mL acetonitrile, 29 g potassium hydrogen fluorides are dissolved in 500mL water, are added dropwise to reaction solution, stirred overnight at room temperature.Concentrated except desolventizing, 500 mL methanol ethyl acetate mixed solvents (methyl alcohol: ethyl acetate=2ml:1ml) are added in condensate residue, stirs 30 minutes.Filter, filtrate is concentrated.200mL methyl tertiary butyl ether is added in condensate residue, stirs 30 minutes.Filter, solid vacuum-drying.Obtain 3-tetrahydrofuran methyl three potassium fluoborate 26g, yield 92%.
1H-NMR (300 MHz, D
2O): δ3.69-3.80 (m, 2H), 3.57-3.62 (m, 1H), 3.06-3.12 (t, 1H), 1.91-2.05 (m, 2H), 1.33-1.40 (m, 1H), 0.19-0.24 (m, 2H)。
Embodiment 2:
1) 3-THP trtrahydropyranyl tetramethyl ethylene ketone boric acid ester
In a dry 1000mL there-necked flask, add 25 g 3,4-dihydropyrane and 120 mL anhydrous tetrahydro furans, reaction solution is cooled to 0 DEG C, 300 mL 1M borine/tetrahydrofuran solutions are slowly added drop-wise in reaction solution.35 g tetramethyl ethylene ketones are dissolved in 100 mL tetrahydrofuran (THF)s, are slowly added drop-wise in reaction solution.Reaction solution stirred overnight at room temperature.Be added drop-wise to slowly in reaction solution by water, be extracted with ethyl acetate, flash column chromatography after organic phase is concentrated, obtains 3-THP trtrahydropyranyl tetramethyl ethylene ketone boric acid ester 28g, yield 45%.
1H-NMR (300 MHz, CDCl
3): δ3.78-3.89 (m, 2H), 3.40-3.51 (m, 2H), 1.79-1.82 (m, 1H), 1.48-1.57 (m, 3H), 1.29-1.32 (m, 1H), 1.23 (s, 12H)。
) 3-tetrahydropyrans methyl tetramethyl ethylene ketone boric acid ester
Prepare N-Lithiodiisopropylamide (LDA): in a dry 500mL there-necked flask 1, add 150mL tetrahydrofuran (THF) and 14g Diisopropylamine.Reaction solution is cooled to-60 DEG C, and the n-Butyl Lithium/hexane solution of 53mL 2.5M is slowly added drop-wise in reaction solution.Reaction solution is slowly warmed up to 0 DEG C, stirs 30 minutes.
In a dry 1000mL there-necked flask, add 28g 3-THP trtrahydropyranyl tetramethyl ethylene ketone boric acid ester and 250mL anhydrous tetrahydro furan, reaction solution is cooled to-78 DEG C.Be added drop-wise to slowly in reaction solution by the LDA/THF solution prepared, then 17 g methyl chlorobromides are added drop-wise in reaction solution slowly.Reaction solution is slowly warming up to room temperature, then stirred overnight at room temperature.Poured into by reaction solution in ammonium chloride saturated aqueous solution, be extracted with ethyl acetate, organic phase is dry, concentrated, obtains 3-tetrahydropyrans methyl tetramethyl ethylene ketone boric acid ester crude product 32g.
1H-NMR (300MHz, CDCl
3): δ3.78-3.86 (m, 2H), 3.23-3.30 (m, 1H), 2.91-1.2.96 (m, 1H), 1.74-1.85 (m, 1H), 1.47-1.62 (m, 3H), 1.25-1.30 (m, 1H), 1.23 (s, 12H), 0.59-0.61 (d, 2H)。
) 3-tetrahydropyrans methyl trifluoro potassium borate
In dry 2000 mL there-necked flasks, add 32g 3-tetrahydropyrans methyl tetramethyl ethylene ketone boric acid ester crude product and 600mL acetonitrile, 26g potassium hydrogen fluoride is dissolved in 500mL water, is added dropwise to reaction solution, stirred overnight at room temperature.Concentrated except desolventizing, 500 mL methanol ethyl acetate mixed solvents (methyl alcohol: ethyl acetate=2ml:1ml) are added in condensate residue, stirs 30 minutes.Filter, filtrate is concentrated.200mL methyl tertiary butyl ether is added in condensate residue, stirs 30 minutes.Filter, solid vacuum-drying.Obtain 3-tetrahydropyrans methyl trifluoro potassium borate 27.5g, yield 95%.
1H-NMR (300MHz, D
2O): δ3.67-3.70 (d, 2H), 3.08-3.16 (m, 1H), 2.70-2.77 (t, 1H), 1.72-1.77 (d, 1H), 1.34-1.42 (m, 3H), 0.83-0.97 (m, 1H), 0.26-0.17 (m, 2H)。
Embodiment 3:
1) 2-(4-chloro-phenyl-)-4-(3-tetrahydrofuran methyl) thieno-[2,3-d] pyrazine-7-methane amide
In dry 250 mL there-necked flasks; the chloro-2-of 4-(4-c chloro-phenyl-)-thieno-[2 is added under nitrogen protection; 3-d] pyrazine-7-methane amide (10.0g); anhydrous tetrahydro furan (100 mL) and 1; two (diphenylphosphino) ferrocene of 1'-] palladium chloride (1.13g); then add 3-tetrahydrofuran methyl three potassium fluoborate (6.53g), reaction mixture spends the night 60 DEG C of stirrings.After cool to room temperature, add saturated aqueous ammonium chloride, layering, aqueous layer with ethyl acetate extracts.After merging organic layer, saturated common salt is washed, anhydrous sodium sulfate drying, concentrates except desolventizing obtains crude product.Crude product column layer chromatography silicone rubber purifying (petrol ether/ethyl acetate volume ratio=5/1) obtains 2-(4-chloro-phenyl-)-4-(3-tetrahydrofuran methyl) thieno-[2, the 3-d] pyrazine-7-methane amide of 7.04g, yield 61%.
1h-NMR (300MHz, DMSO-d6): δ 7.55-7.45 (d, 2H), 7.38-7.30 (d, 2H), 7.02 (s, 1H), 6.52 (s, 2H), 3.85-3.58 (m, 2H), 3.57-3.62 (m, 1H), 3.06-3.12 (t, 1H), 1.91-2.05 (m, 2H), 1.33-1.40 (m, 1H), 0.19-0.24 (m, 2H).
Claims (2)
1. a synthetic method for 3-cyclic ethers methyl trifluoro potassium borate, is characterized in that: reaction comprises the following steps:
1) with 2-cyclic ethers alkene for raw material, after reacting with borine, obtain 3-cyclic ethers base tetramethyl ethylene ketone boric acid ester with tetramethyl ethylene ketone cancellation,
Wherein n=1,2;
2), after 3-cyclic ethers base tetramethyl ethylene ketone boric acid ester and highly basic deprotonation, react with methyl chlorobromide, obtain 3-cyclic ethers methyl tetramethyl ethylene ketone boric acid ester,
Wherein n=1,2;
3) 3-cyclic ethers methyl tetramethyl ethylene ketone boric acid ester and potassium hydrogen fluoride obtain 3-cyclic ethers methyl trifluoro potassium borate after reacting,
Wherein n=1,2.
2. the synthetic method of a kind of 3-cyclic ethers methyl trifluoro potassium borate according to claim 1, is characterized in that: the highly basic that described deprotonation uses is n-Butyl Lithium.
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| CN102786541A (en) * | 2012-07-24 | 2012-11-21 | 上海瑞博化学有限公司 | Preparation method and application of potassium (iso)quinoline thifluoroborate |
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