CN104876956B - The technique of one pot process boron aminated compounds - Google Patents
The technique of one pot process boron aminated compounds Download PDFInfo
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- CN104876956B CN104876956B CN201510321171.9A CN201510321171A CN104876956B CN 104876956 B CN104876956 B CN 104876956B CN 201510321171 A CN201510321171 A CN 201510321171A CN 104876956 B CN104876956 B CN 104876956B
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- 229910052796 boron Inorganic materials 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 17
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 12
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 claims abstract description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 6
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- -1 boron amide Chemical class 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 239000010410 layer Substances 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 5
- 229950002366 nafoxidine Drugs 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical class NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 150000002009 diols Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 9
- 238000000926 separation method Methods 0.000 abstract description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract 1
- 150000001502 aryl halides Chemical class 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- 230000031709 bromination Effects 0.000 description 5
- 238000005893 bromination reaction Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 229910003002 lithium salt Inorganic materials 0.000 description 5
- 159000000002 lithium salts Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical class BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- SMKMXVCNNASZEB-UHFFFAOYSA-N 2-(3-methylphenyl)thiophene Chemical class CC1=CC=CC(C=2SC=CC=2)=C1 SMKMXVCNNASZEB-UHFFFAOYSA-N 0.000 description 2
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical compound BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- PAVZHTXVORCEHP-UHFFFAOYSA-N ethylboronic acid Chemical compound CCB(O)O PAVZHTXVORCEHP-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- XGBMQBPLWXTEPM-UHFFFAOYSA-N 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1CC1 XGBMQBPLWXTEPM-UHFFFAOYSA-N 0.000 description 1
- 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
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- TZHYBRCGYCPGBQ-UHFFFAOYSA-N [B].[N] Chemical compound [B].[N] TZHYBRCGYCPGBQ-UHFFFAOYSA-N 0.000 description 1
- IFHFJXMGNOFCNW-UHFFFAOYSA-N acetyl acetate;potassium Chemical compound [K].CC(=O)OC(C)=O IFHFJXMGNOFCNW-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QARVLSVVCXYDNA-IDEBNGHGSA-N bromobenzene Chemical group Br[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 QARVLSVVCXYDNA-IDEBNGHGSA-N 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- RDHPKYGYEGBMSE-VQEHIDDOSA-N bromoethane Chemical group C[13CH2]Br RDHPKYGYEGBMSE-VQEHIDDOSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- UQXKXGWGFRWILX-UHFFFAOYSA-N ethylene glycol dinitrate Chemical compound O=N(=O)OCCON(=O)=O UQXKXGWGFRWILX-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical class ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 238000010792 warming 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
-
- 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 the techniques of one pot process boron aminated compounds：By anhydrous solvent, bromo-derivative RBr and XBY2It after three's mixing, is slowly dropped into the anhydrous solvent containing lithium metal, maintains temperature at 20~20 DEG C during being added dropwise, after reaction causes, all addition finishes by remaining, then maintains 20~40 DEG C of 3 8h of reaction, RBY is obtained after separation2.The intermediate can be reacted with glycol with acid hydrolysis at organic boronic and generate borate, or directly carry out coupling reaction with aryl halides.The technological operation is simple, avoids the dependence of ultralow temperature reaction and lithiumation object stability to solvent, and by-product is few, and reaction yield is high, is suitble to industrialization amplification, is conducive to the core competitiveness for improving product.
Description
Technical field
The present invention relates to the techniques of one pot process boron aminated compounds, belong to fine-chemical intermediate synthesis field.
Background technology
In recent years, as people are to the pay attention to day by day of health degree, increasingly along with corresponding new drug development paces
Soon, various organic chemical reactions also emerge one after another.As most directly effective, mild condition structure carbon-carbon bond mode, Suzuki
Coupling reaction has successfully applied to naturally by the extensive favor of industrial quarters in many new drug synthesis listed.
As the important source material of Suzuki couplings, the synthesis of boric acid/ester mainly has following two modes at present：Magnesium metal is joined
With the lithium reagent that participates in of Grignard Reagent or lithium metal/lithium alkylide reacted with trimethylborate, corresponding boron is obtained after sour water solution
Acid；Corresponding borate is obtained after carrying out coupling reaction with connection borate as catalyst halides using Metal Palladium/nickel copper.
Grignard Reagent due to the characteristics of itself reaction dissolvent be often confined to ether or tetrahydrofuran, and concentration is relatively low,
Crystallization is easy when more than a certain concentration to be precipitated.Lithium reagent is strong to solvent dependant, and it is most often that preparation is directly reacted with lithium metal
It can only be prepared in ether, all there is the risk that half-life period degenerates in other solvents.The reaction side that halides are exchanged with butyl lithium
Formula generally requires ultralow temperature progress.Grignard and lithium reagent method, which usually all exist, reacts with trimethylborate under general low temperature and can produce
Raw secondary substituted by-product.Coupling reaction prepares borate there are of high cost, is easy the shortcomings of heavy metal is remaining.
Invention content
In order to overcome drawbacks described above, emphasis of the present invention to study lithium reagent method, selected lithium metal, bromo-derivative with
The halogen borane reagent mode that one kettle way carries out in common industrialization amplifies solvent, has synthesized the intermediate stablized, the intermediate
It can be with acid hydrolysis at boric acid, borate corresponding with glycol reaction generation or directly progress Suzuki coupling reactions.
The present invention relates to the techniques of one pot process boron aminated compounds, it is characterised in that：By anhydrous solvent, bromo-derivative
RBr and XBY2It after three's mixing, is slowly dropped into the anhydrous solvent containing lithium metal, maintains temperature -20 during being added dropwise
~20 DEG C, when temperature increases to over 3 DEG C or more in reaction solution, by remaining, all addition finishes, and then maintains -20~40 DEG C of reactions
3-8h, the reaction was complete for detection, and saturated ammonium chloride tune PH=4-6 is added, separates organic layer, and water layer extracts once again, merges organic
Layer, saturated common salt water washing obtain the boron amide class compound R BY of 98% or more purity after being evaporated under reduced pressure solvent2。
Further, in the above-mentioned technical solutions, the XBY2Middle X is chlorine or bromine, and Y is diisopropylamine, di-iso-butylmanice, two
Cyclopropylamine, nafoxidine, hexahydro piperidines, morpholine.
Further, in the above-mentioned technical solutions, the R is alkyl or aryl.Alkyl includes：Methyl, ethyl, isopropyl
Base, cyclopropyl, normal-butyl, isobutyl group, cyclopenta or cyclohexyl.Aryl includes：Phenyl, neighbour// p-methylphenyl, neighbour// it is right
Anisyl, neighbour// p-fluorophenyl, neighbour// rubigan, neighbour// p-bromophenyl, 2/3- furans, 2/3- thiophene,
N- methyl -4- pyrazoles or N- benzyl -4- pyrazoles.
Further, in the above-mentioned technical solutions, the anhydrous solvent is tetrahydrofuran, 2- methyltetrahydrofurans, methyl
Tertbutyl ether, cyclopentyl-methyl ether, glycol dimethyl ether and diethoxymethane.
Further, in the above-mentioned technical solutions, described RBr, XBY2Molar ratio with lithium metal is 1:1-1.2:2-
2.4。
Further, in the above-mentioned technical solutions, the reaction initiation basis for estimation is:Temperature increases to over 3 in reaction solution
DEG C or more.
Boron amide class compound R BY obtained by the above method2One of application：By RBY2In organic solvent, acid is added in dissolving
Boric acid compound RB (OH) is obtained after hydrolysis2；Acid is hydrochloric acid, sulfuric acid or acetic acid；Hydrolysis temperature is 40~100 DEG C.
Boron amide class compound R BY obtained by the above method2Application it two：Boron amide class compound R BY2Life is reacted with glycol
At borate, glycol is：Pinacol, neopentyl glycol or catechol；Operating condition is：By RBY21-1.1 equivalent weight diols are added,
It is to slowly warm up to back flow reaction 1-3 hours, corresponding borate is obtained after distillation.
Boron amide class compound R BY obtained by the above method2Application it three：Boron amide class compound R BY2With 1-1.05 equivalents
In the presence of 1-3% moles of palladium catalyst and 1.5-3.0 equivalent alkali, 80~120 DEG C of coupling reactions obtain PhR for bromobenzene or iodobenzene；Institute
Stating alkali is：KOAc、K3PO4Or K2CO3；The solvent is：Dioxane, dimethyl sulfoxide (DMSO), tetrahydrofuran or glycol dinitrate
Ether；Catalyst is Pd (OAc)2/Pt-Bu3、Pd(OAc)2/PCy3、PdCl2Dppf or Pd (PPh4)3。
Invention advantageous effect：
The present invention selects the mode of one kettle way charging, and the moment of lithium reagent is generated in bromo-derivative and lithium metal, just corresponding
Borane reagent capture, solve the problems, such as that lithium reagent synthesize half-life period in different solvents, at the same expanded using lithium metal ginseng
With the use scope of reaction dissolvent.Select the halogen borane reagent of big steric hindrance, the reagent can a very convenient step be prepared, while boron
Nitrogen key stability is stronger, even if temperature reaction, after having carried out lithium reagent and the substitution of halogen boron, will not form secondary substituted pair
Product.
In conjunction with the advantages of both of the above, the inventive method substrate universality is strong, general cryogenic conditions and common suitable puts
Can all be carried out in big solvent, reaction yield is high, and product stability is strong, can also diversity derive, provide it is a kind of it is novel can
For the borane reagent of coupling reaction.
Specific implementation mode
Embodiment 1
Compound MeB (Ni-Pr2)2Synthesis：
Under argon gas protection, in the there-necked flask equipped with Dropping feeder, lithium metal (0.21 mole) and 2- methyl four is added
After 20 milliliters of hydrogen furans, -20 DEG C are cooled to, starts that bromomethane (0.1 mole) and bis- (N, N- diisopropyl) boron bromides is added dropwise
(0.11 mole) is dissolved in 150 milliliters of 2- methyltetrahydrofuran solution.After being initially added dropwise to 15-20 milliliters, continue stir about 10-
20 minutes, reacting liquid temperature rose to -15 DEG C from -20 DEG C, show at this time reaction caused, then maintain temperature be no more than -
10 DEG C are continued surplus stock being added dropwise, and system gradually has the generation of bromination lithium salts.Extracting reaction solution detection, there is no bromomethanes to remain
Yu Shi stops reaction.Saturated ammonium chloride is added to be quenched, adjusting solution pH value is 4-5.Liquid separation, water layer 2- methyltetrahydrofurans
Primary, merging organic layer, saturated common salt washing are extracted again.Evaporated under reduced pressure solvent obtains crude product, and 20.1 grams of MeB are obtained after rectifying
(Ni-Pr2)2.The product is colourless liquid, 98% or more GC purity, yield 89%.
Embodiment 2
Compound EtB (Ni-Pr2)2Synthesis：
Under argon gas protection, in the there-necked flask equipped with Dropping feeder, lithium metal (0.22 mole) and diethoxy first is added
After 20 milliliters of alkane, -20 DEG C are cooled to, starts that bromoethane is added dropwise（0.1 mole）(0.1 rubs with bis- (N, N- diisopropyl) boron bromides
You) it is dissolved in 150 milliliters of diethoxymethane solution.After being initially added dropwise to 15-20 milliliters, continue stir about 10-20 minutes, instead
Answer liquid temperature to rise to -16 DEG C from -20 DEG C, show at this time reaction caused, then maintain temperature continue no more than -10 DEG C by
Surplus stock is added dropwise, and system gradually has the generation of bromination lithium salts.It is anti-there is no when bromoethane residue, stopping to extract reaction solution detection
It answers.It is carefully added into saturated ammonium chloride to be quenched, adjusting solution pH value is 4-5.Liquid separation, water layer extract one again with diethoxymethane
It is secondary, merge organic layer, saturated common salt washing.Evaporated under reduced pressure solvent obtains crude product, and 20.4 grams of EtB (N are obtained after rectifyingi-Pr2)2。
The product is colourless to weak yellow liquid, 98% or more GC purity, yield 85%.
Embodiment 3
CompoundSynthesis：
Under argon gas protection, in the there-necked flask equipped with Dropping feeder, lithium metal (0.24 mole) and tetrahydrofuran 25 is added
After milliliter, -20 DEG C are cooled to, starts that Cyclopropyl Bromide (0.1 mole) is added dropwise and bis- (nafoxidine) boron chlorides (0.12 mole) is molten
Solution is in 150 milliliters of tetrahydrofuran solutions.After being initially added dropwise to 15-20 milliliters, continue stir about 10-20 minutes, reacting liquid temperature
- 16 DEG C are risen to from -20 DEG C, are shown that reaction has caused at this time, then temperature are maintained to continue surplus stock no more than -10 DEG C
It is added dropwise, system gradually has the generation of bromination lithium salts.Extracting reaction solution detection, the reaction was complete, and no Cyclopropyl Bromide is remaining, stops reaction.
It is carefully added into saturated ammonium chloride to be quenched, adjusting solution pH value is 5-6.Liquid separation after addition ethyl acetate, water layer use ethyl acetate again
Extraction is primary, merges organic layer, saturated common salt washing.Evaporated under reduced pressure solvent obtains 98% or more purity after continuing rectification under vacuum
23.7 grams of target product, yield 81%, HNMR structures meet.
Embodiment 4
CompoundSynthesis：
Under argon gas protection, in the there-necked flask equipped with Dropping feeder, lithium metal (0.2 mole) and glycol dimethyl ether is added
After 20 milliliters, -15 DEG C are cooled to, starts that (0.11 mole) dissolving of bromobenzene (0.1 mole) and bis- (hexahydro piperidines) boron bromides is added dropwise
In 150 milliliters of ethylene glycol dimethyl ether solutions.After being initially added dropwise to 15-20 milliliters, continue stir about 10-20 minutes, reaction solution temperature
Degree rises to -11 DEG C from -15 DEG C, shows that reaction has caused at this time, and then maintaining temperature to continue no more than -5 DEG C will be remaining former
Material is added dropwise, and system gradually has the generation of bromination lithium salts.Detection is extracted reaction solution there is no when bromobenzene residue, stops reaction.It is added
Saturated ammonium chloride is quenched, and adjusting solution pH value is 4-5.Liquid separation after addition ethyl acetate, water layer are extracted with ethyl acetate once again,
Merge organic layer, saturated common salt washing.Evaporated under reduced pressure solvent, after being then evaporated under reduced pressure, oil pump is further continued for vacuumizing 1-2 hours,
19.7 grams of 98% or more target product of purity is obtained, yield 77%, HNMR structures meet.
Embodiment 5
CompoundSynthesis：
Under argon gas protection, in the there-necked flask equipped with Dropping feeder, lithium metal (0.21 mole) and methyl tertbutyl is added
After 20 milliliters of ether, -20 DEG C are cooled to, starts that 3 bromo thiophene (0.1 mole) is added dropwise and bis- (morpholine) boron chlorides (0.12 mole) is molten
Solution is in 150 milliliters of t-butyl methyl ether solutions.After being initially added dropwise to 15-20 milliliters, continue stir about 10-20 minutes, reaction solution
Temperature rises to -14 DEG C from -20 DEG C, shows that reaction has caused at this time, then temperature is maintained to continue no more than -10 DEG C will be remaining
Raw material is added dropwise, and system gradually has the generation of bromination lithium salts.It is anti-there is no when 3 bromo thiophene residue, stopping to extract reaction solution detection
It answers.Saturated ammonium chloride is added to be quenched, adjusting solution pH value is 4-5.Liquid separation after addition ethyl acetate, water layer are extracted with ethyl acetate again
Take primary, merging organic layer, saturated common salt washing.Evaporated under reduced pressure solvent, after being then evaporated under reduced pressure, oil pump is further continued for vacuumizing 1-
2 hours, 20.7 grams of 98% or more target product of purity is obtained, yield 78%, HNMR structures meet.
Embodiment 6
The synthesis (application example) of ethyl-boron dihydroxide：
Under nitrogen protection, the EtB (N that will be obtained in above-described embodiment 2i-Pr2)2It is dissolved in 65 milliliters of 2- methyltetrahydrofurans
In, 40 DEG C to 50 DEG C of temperature is controlled, is gradually added dropwise in the aqueous solution of 10% hydrochloric acid, after being added dropwise, insulated and stirred reaction 1 is small
When, it is 2-3 to detect pH at this time.Cooling layering, water layer are extracted once again with 2- methyltetrahydrofurans, are merged organic layer, are evaporated molten
After agent, normal heptane mashing is added, after filtering, naturally dry obtains 5.9 grams of white plates crystal ethyl-boron dihydroxide, yield 94%, HNMR
Purity 97%.
Embodiment 7
The synthesis (application example) of cyclopropylboronic acid pinacol ester：
Under nitrogen protection, the product obtained in above-described embodiment 3 is dissolved in 70 milliliters of tetrahydrofurans, is warming up to back
Stream starts the tetrahydrofuran solution for being gradually added dropwise to pinacol (0.85 mole).In whole process, the weak reflux of solution is kept.Drop
During adding, gradually there is nafoxidine generation, after being added dropwise, continues stirred at reflux condition and react 1 hour, GC detects raw material
Reaction finishes.After cooling, after being evaporated under reduced pressure solvent and nafoxidine, colourless transparent liquid ring third is obtained after continuing heating distillation
12.4 grams of ylboronic acid pinacol ester, yield 91%, GC:99.2%, HNMR structure meet.
Embodiment 8
The synthesis (application example) of 3- tolylthiophenes：
Under nitrogen protection, 220 milliliters of dioxane, the production that will then be obtained in above-described embodiment 5 are added in reaction bulb
(0.80 mole) object, acetic anhydride potassium (1.95 moles) and bromobenzene addition, after stirring evenly, finally by 3% mol catalyst
PdCl2Dppf is added.Then, reaction mixture is gradually heating to 100 DEG C, and the temperature is maintained to be stirred to react 3-5 hours.On
State reaction solution during the reaction, color gradually becomes aterrimus, and GC detection raw material reactions finish.After cooling, diatomite filtering, filter
Liquid is evaporated under reduced pressure to doing, and 7.7 grams of 3- tolylthiophenes is obtained after rapid column chromatography, yield 62%, HNMR structures meet.
Claims (5)
1. the method for one pot process boron aminated compounds, it is characterised in that：By anhydrous solvent, bromo-derivative RBr and XBY2Three is mixed
It after conjunction, is slowly dropped into the anhydrous solvent containing lithium metal, maintains temperature at -20~20 DEG C during being added dropwise, in reaction solution
When temperature increases to over 3 DEG C or more, by remaining, all addition finishes, and -20~40 DEG C of reaction 3-8h, detection is then maintained to react
Entirely, saturated ammonium chloride tune pH=4-6 is added, separates organic layer, water layer extracts once again, merges organic layer, saturated common salt washing
It washs, the boron amide class compound R BY of 98% or more purity is obtained after being evaporated under reduced pressure solvent2；The R is alkyl or aryl；Alkyl is selected from
Methyl, ethyl, isopropyl, cyclopropyl, normal-butyl, isobutyl group, cyclopenta or cyclohexyl；Aryl be selected from phenyl, neighbour// to first
Base phenyl, neighbour// p-methoxyphenyl, neighbour// p-fluorophenyl, neighbour// rubigan, neighbour// p-bromophenyl, 2/3-
Furans, 2/3- thiophene, N- methyl -4- pyrazoles or N- benzyl -4- pyrazoles；The XBY2Middle X be chlorine or bromine, Y be diisopropylamine,
Di-iso-butylmanice, two cyclopropylamines, nafoxidine, hexahydro piperidines or morpholine.
2. the method for one pot process boron aminated compounds according to claim 1, it is characterised in that：Anhydrous solvent is selected from four
Hydrogen furans, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE), cyclopentyl-methyl ether, glycol dimethyl ether or diethoxymethane.
3. the method for one pot process boron aminated compounds according to claim 1, it is characterised in that：Described RBr, XBY2With
The molar ratio of lithium metal is 1:1-1.2:2-2.4.
4. according to the application of the boron aminated compounds of claim 1-3 any one the methods synthesis, it is characterised in that：Boron amide
Class compound R BY2It is reacted with glycol and generates borate, glycol is selected from：Pinacol or neopentyl glycol；Operating condition is：By RBY2Add
Enter 1-1.1 equivalent weight diols, be to slowly warm up to back flow reaction 1-3 hours, corresponding borate is obtained after distillation.
5. according to the application of the boron aminated compounds of claim 1-3 any one the methods synthesis, it is characterised in that：Boron amide
Class compound R BY2With 1-1.05 equivalents bromobenzene or iodobenzene in the presence of 1-3% moles of palladium catalyst and 1.5-3.0 equivalent alkali, 80
~120 DEG C of coupling reactions obtain PhR；Alkali is selected from：KOAc；Solvent is selected from：Dioxane, dimethyl sulfoxide (DMSO), tetrahydrofuran or second
Glycol dimethyl ether；Palladium catalyst is selected from Pd (OAc)2/Pt-Bu3、Pd(OAc)2/PCy3、PdCl2Dppf or Pd (PPh4)3。
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| CN105566368B (en) * | 2016-01-11 | 2017-09-15 | 沧州普瑞东方科技有限公司 | A kind of method of the borate of synthesis N substituted piperidines 4 |
| CN107987097B (en) * | 2017-12-17 | 2019-11-29 | 沧州普瑞东方科技有限公司 | The synthesis technology of 2,6- dichloropyridine -4- boric acid pinacol ester |
| CN107892699B (en) * | 2017-12-17 | 2019-08-23 | 沧州普瑞东方科技有限公司 | A kind of synthesis technology of pyridine -4- boric acid |
| CN107987096B (en) * | 2017-12-17 | 2020-06-05 | 沧州普瑞东方科技有限公司 | Method for synthesizing 2-aldehyde furan-4-boronic acid pinacol ester |
| CN109456350B (en) * | 2018-12-23 | 2021-04-16 | 沧州普瑞东方科技有限公司 | Synthetic method of dibenzofuran/thiophene-4-boric acid |
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| CN103030660A (en) * | 2012-12-20 | 2013-04-10 | 大连联化化学有限公司 | Technological method for synthesizing methylboronic acid |
| CN104478918A (en) * | 2014-12-31 | 2015-04-01 | 大连联化化学有限公司 | Synthesis method of cycloalkene-1-boronic acid pinacol ester |
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| CN101440100A (en) * | 2008-12-19 | 2009-05-27 | 大连联化医药技术有限公司 | Novel process for synthesizing cyclopropylboronic acid |
| CN103030660A (en) * | 2012-12-20 | 2013-04-10 | 大连联化化学有限公司 | Technological method for synthesizing methylboronic acid |
| CN104478918A (en) * | 2014-12-31 | 2015-04-01 | 大连联化化学有限公司 | Synthesis method of cycloalkene-1-boronic acid pinacol ester |
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