CN113861228B - Alkyl borane derivative and synthesis method thereof - Google Patents
Alkyl borane derivative and synthesis method thereof Download PDFInfo
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- CN113861228B CN113861228B CN202111192688.4A CN202111192688A CN113861228B CN 113861228 B CN113861228 B CN 113861228B CN 202111192688 A CN202111192688 A CN 202111192688A CN 113861228 B CN113861228 B CN 113861228B
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- carboxylic acid
- aliphatic carboxylic
- acid derivative
- ethyl
- hydrogen
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- -1 Alkyl borane derivative Chemical class 0.000 title claims abstract description 50
- 238000001308 synthesis method Methods 0.000 title claims abstract description 30
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000654 additive Substances 0.000 claims abstract description 11
- 150000002940 palladium Chemical class 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 230000004913 activation Effects 0.000 claims abstract description 5
- 239000007800 oxidant agent Substances 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 15
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 15
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000003570 air Substances 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 9
- 230000000996 additive effect Effects 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 4
- 229940071536 silver acetate Drugs 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- AKEXVWKYUAMNKL-UHFFFAOYSA-N 2,2-dimethylpropanoic acid;silver Chemical compound [Ag].CC(C)(C)C(O)=O AKEXVWKYUAMNKL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 8
- 238000010189 synthetic method Methods 0.000 claims 4
- 239000007805 chemical reaction reactant Substances 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 235000011181 potassium carbonates Nutrition 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 125000003368 amide group Chemical group 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 229910000085 borane Inorganic materials 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 11
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 10
- 238000012512 characterization method Methods 0.000 description 10
- 238000004896 high resolution mass spectrometry Methods 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- JDTWZSUNGHMMJM-UHFFFAOYSA-N N-acetylisoleucine Chemical compound CCC(C)C(C(O)=O)NC(C)=O JDTWZSUNGHMMJM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229910001923 silver oxide Inorganic materials 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 1
- NLEPLDKPYLYCSY-UHFFFAOYSA-N 2-fluoroquinoline Chemical compound C1=CC=CC2=NC(F)=CC=C21 NLEPLDKPYLYCSY-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- WXNXCEHXYPACJF-ZETCQYMHSA-N N-acetyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-N 0.000 description 1
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 1
- IHYJTAOFMMMOPX-LURJTMIESA-N N-acetyl-L-valine Chemical compound CC(C)[C@@H](C(O)=O)NC(C)=O IHYJTAOFMMMOPX-LURJTMIESA-N 0.000 description 1
- 125000001112 N-acetylglycine group Chemical group [H]C([H])([H])C(=O)N([H])C(C(=O)[*])([H])[H] 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 229960000669 acetylleucine Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical group [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 1
- 238000005885 boration reaction Methods 0.000 description 1
- BGECDVWSWDRFSP-UHFFFAOYSA-N borazine Chemical compound B1NBNBN1 BGECDVWSWDRFSP-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 238000005809 transesterification reaction 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention provides an alkyl borane derivative and a synthesis method thereof, wherein the method takes aliphatic carboxylic acid derivative and bis-pinacolato diborane as reaction initial raw materials, palladium salt is taken as a catalyst, silver salt is taken as an oxidant, C-H bond activation occurs in a solvent under the participation of alkali and additives, the reaction has good regioselectivity and functional group diversity, the method has wide applicability, amide groups in the skeleton structure of the alkyl borane derivative can be hydrolyzed to obtain corresponding carboxylic acid, and alkyl boron groups can be further functionalized and can be used as intermediates of structures of medicines and chemical products.
Description
Technical Field
The invention relates to an alkyl borane derivative and a synthesis method thereof, belonging to the field of chemical organic synthesis.
Background
Boranes, particularly alkyl boranes, have become important intermediates for organic synthesis. The method is widely used for forming chemical bonds such as carbon hydrogen bonds, carbon-oxygen bonds, carbon halogen bonds, carbon-nitrogen bonds, carbon-carbon bonds and the like. Further protruding is that these reactions are all excellent stereoselectivity, especially for the stereosynthesis of many natural products such as steroids, terpenoids and hormones. Alkyl boranes are precursors of many functional molecules and occupy important roles in the fields of organic synthesis, pharmaceutical synthesis, synthesis of natural products, and the like (chem. Rev.2010,110,890; acc. Chem. Res.2012,45,864). The organoborides can also be used as enzyme inhibitors (Drug Discovery Today 2003,8,307) and in boron neutron capture therapeutics (J.org.chem.1997, 62,8730). In addition, many drug molecules also contain boron, such as the formula 1Bortezomib and the formula 2Ixazomib, which have good anticancer efficacy;
at present, the method for synthesizing alkyl borane is mainly realized by single electron transfer of halogenated alkane and a boration reagent under the action of metal and strong alkali, the conditions are more severe, and the substrate needs to be functionalized in advance, so that the application range of the substrate is greatly limited.
Patent document CN101198615 discloses a method for synthesizing dialkoxyorganoboranes by transesterification. However, the method uses the trimethyl borazine, diborane and poisonous gas carbon monoxide which are inflammable and easy to hydrolyze, has certain safety problem, and has the advantages of more reaction steps, complicated working procedures and relatively low reaction efficiency.
Thus, there is a need to develop a way to synthesize alkylboranes that is stable and readily available on a substrate, does not require pre-functionalization of the substrate, and is efficient.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an alkyl borane derivative which is an important organic synthesis intermediate for constructing bioactive molecules, and also provides a synthesis method of the alkyl borane derivative.
The synthesis method of the invention uses aliphatic carboxylic acid derivatives and bis-pinacolato diborane (B) 2 pin 2 ) As a raw material, alkyl borane derivatives are synthesized through C-H bond activation.
In order to solve the problems, the invention is realized by the following technical scheme:
an organic synthesis intermediate alkyl borane derivative has a structural formula shown in the following formula I:
R 1 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 2 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 3 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phenyl or aryl containing substituents;
R 4 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phenyl or aryl containing substituents; the substituent is one of hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, formyl, tertiary butyl and acetyl.
By variation of R in formula I 1 、R 2 、R 3 、R 4 The substituent groups are combined to obtain a series of alkyl borane derivatives with different structures.
The synthesis method of the alkyl borane derivative comprises the following steps:
aliphatic carboxylic acid derivative and bis-pinacolato diborane are used as reaction initial raw materials, palladium salt is used as a catalyst, silver salt is used as an oxidant, C-H bond activation is carried out in a solvent under the participation of alkali and additives, one-step synthesis reaction is carried out, and after the reaction is finished, the polysubstituted alkyl borane derivative is obtained through separation and purification.
The alkyl borane obtained by the invention can be further converted into a functionalized product.
The method has the advantages of easily available raw materials, mild reaction conditions and wide adaptability.
According to the present invention, the aliphatic carboxylic acid derivative has a molecular structural formula represented by the following formula II:
R 1 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 2 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 3 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phenyl or aryl containing substituents;
R 4 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phenyl or aryl containing substituents; the substituent is one of hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, formyl, tertiary butyl and acetyl.
According to the invention, the molar ratio of the aliphatic carboxylic acid derivative to the bis-pinacolatyldiborane is preferably 1: (1-10).
Further preferably, the molar ratio of the aliphatic carboxylic acid derivative to the bis-pinacolatyldiborane is 1: (2-4).
Preferably according to the invention, the palladium salt is selected from PdCl 2 、Pd(OAc) 2 、Pd(TFA) 2 、Pd(OPiv) 2 、Pd(CH 3 CN)Cl 2 、Pd(PhCN)Cl 2 、Pd(PPh 3 )Cl 2 One or two or more of them are mixed.
Further preferably, the catalyst is Pd (OPiv) 2 。Pd(OPiv) 2 The catalyst is most effective.
According to the invention, the molar ratio of the aliphatic carboxylic acid derivative to palladium salt is preferably 1: (0.01-0.5).
Further preferably, the molar ratio of the aliphatic carboxylic acid derivative to the palladium salt is 1: (0.05-0.15).
According to the present invention, preferably, the silver salt is one or a mixture of two or more of silver pivalate, silver acetate, silver carbonate, silver oxide and silver trifluoroacetate.
Further preferably, the silver salt is preferably silver carbonate. Silver carbonate works best as a silver salt.
According to a preferred embodiment of the present invention, the molar ratio of the aliphatic carboxylic acid derivative to silver salt is 1: (1-6).
Further preferably, the molar ratio of the aliphatic carboxylic acid derivative to the silver salt is 1: (2-4).
According to the invention, preferably, the alkali is one or more than two of sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium phosphate and potassium tert-butoxide;
further preferably, the base is sodium bicarbonate. Sodium bicarbonate works best as a base.
According to a preferred embodiment of the present invention, the molar ratio of the aliphatic carboxylic acid derivative to the base is 1: (1-6).
Further preferably, the molar ratio of the aliphatic carboxylic acid derivative to the base is 1: (2-4).
According to the invention, the additive is preferably one or more than two of N-acetylglycine, N-acetylvaline, N-acetylphenylalanine, N-acetylleucine, N-acetylisoleucine, N-acetyltertiary leucine, 2-chloropyridine, 2-chloroquinoline, 2-fluoroquinoline and 2-bromoquinoline.
Further preferably, the additive is N-acetylglycine or 2-chloroquinoline. N-acetylglycine or 2-chloroquinoline works best as an additive.
According to a preferred embodiment of the invention, the molar ratio of the aliphatic carboxylic acid derivative to the additive is 1: (0.01-0.5).
Further preferably, the molar ratio of the aliphatic carboxylic acid derivative to the additive is 1: (0.1-0.3).
According to the invention, the solvent is one or more than two of 1, 4-dioxane, tertiary butanol, toluene, 1, 2-dichloroethane, dichloromethane, tetrahydrofuran, benzotrifluoride, acetonitrile, chlorobenzene and 1, 2-dichlorobenzene;
further preferably, the solvent is acetonitrile. The reaction works best in acetonitrile.
According to the invention, the solvent is preferably used in an amount such that the molar concentration of the aliphatic carboxylic acid derivative is 0.01 to 1.0M,
it is further preferred that the solvent is used in an amount such that the molar concentration of the aliphatic carboxylic acid derivative is 0.05 to 0.2M.
According to the invention, the reaction atmosphere is preferably air, oxygen, nitrogen or argon.
Most preferably, the reaction atmosphere is oxygen.
Preferably, according to the invention, the reaction temperature is 50-150 ℃ and the reaction time is 10-48 hours;
further preferably, the reaction temperature is 80-150 ℃ and the reaction time is 16-48h;
most preferably, the reaction temperature is 100-140 ℃ and the reaction time is 20-48h;
the synthetic route of the alkyl borane derivative is shown in the following formula III:
the R is 1 、R 2 、R 3 、R 4 As described above.
The invention has the technical characteristics and advantages that:
1. the amide group in the skeleton structure of the alkyl borane derivative provided by the invention can be hydrolyzed to obtain corresponding carboxylic acid, and the alkyl borane group can be further functionalized and can be used as an intermediate of structures of medicines and chemical products.
2. The invention takes aliphatic carboxylic acid derivative and bis-pinacolato diborane as reaction initial raw materials, palladium salt as catalyst, silver salt as oxidant, and takes C-H bond activation in solvent under the participation of alkali and additive, and the reaction has good regioselectivity and functional group diversity, and wide applicability.
3. The aliphatic carboxylic acid derivative serving as a starting material in the synthesis method has structural diversity and can be used for synthesizing alkyl boranes with different types and structures.
4. The synthesis method has the advantages that the initial raw material aliphatic carboxylic acid derivative compound is easy to prepare, the preparation raw materials are cheap and easy to obtain, the cost is low, and the industrial production is easy.
5. The synthesis method utilizes the structural diversity of the aliphatic carboxylic acid derivative to efficiently synthesize the alkyl boranes with different types and structures, and compared with the reported synthesis method of the alkyl boranes, the synthesis method has the advantages of easily obtained raw materials, simple and convenient operation, mild synthesis reaction conditions, high reaction efficiency, high yield of target products and further functionalization.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The raw materials in the examples are all commercially available products unless otherwise specified.
Example 1
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, aliphatic carboxylic acid derivative compound 2a (0.2 mmol), bis-pinacolato diborane (0.6 mmol) and Pd (OPiv) were successively introduced under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, and stirred at 130℃for 24 hours. The resulting mixture was separated by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate as eluent, v/v=20:1) to give a polysubstituted alkylborane derivative designated as 1a (32.0 mg, yield 66%). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 a), yellow liquid.
1 H NMR(400MHz,CDCl 3 ) 1 H NMR(400MHz,CDCl 3 )δ9.87(s,1H),8.80(dd,J＝14.9and 5.2Hz,2H),8.13(d,J＝8.1Hz,1H),7.60–7.37(m,3H),2.58(s,2H),1.27(d,J＝7.9Hz,12H),1.21(s,6H),1.03(d,J＝10.1Hz,2H). 13 C{ 1 H}NMR(100MHz,CDCl3)δ171.2,148.1,138.7,136.4,135.0,128.1,127.5,121.6,121.4,116.8,83.2,51.8,33.1,30.4,25.1,25.0.HRMS Calcd for C 21 H 30 BN 2 O 3 [M+H] + :369.2344；Found:369.2348.
Example 2
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, aliphatic carboxylic acid derivative compound 2b (0.2 mmol), bis-pinacolato diborane (0.6 mmol), pd (OPiv) were successively introduced under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, and stirred at 130℃for 24 hours. The resulting mixture was separated by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate as eluent, v/v=20:1) to give a polysubstituted alkylborane derivative designated as 1b (48.0 mg, yield 62%). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 b), yellow solid.
1 H NMR(400MHz,CDCl 3 )δ 1 H NMR(400MHz,CDCl 3 )δ9.18(s,1H),8.98(m,1H),8.77(m,1H),8.18(m,1H),7.89(m,4H),7.68(s,1H),7.55(m,1H),7.43(m,1H),4.48(s,1H),1.14(s,12H),1.06(s,6H),0.43(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ166.2,164.7,148.5,138.1,136.5,135.9,134.0,131.1,128.2,127.5,126.7,124.2,123.3,121.3,86.5,59.8,39.0,26.9,24.3.HRMS Calcd for C 29 H 33 BN 3 O 5 [M+H] + :514.2508；Found:514.2510.
Example 3
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, aliphatic carboxylic acid derivative compound 2c (0.2 mmol), bis-pinacolato diborane (0.6 mmol), pd (OPiv) were successively introduced under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, and stirred at 130℃for 24 hours. The resulting mixture was separated by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate as eluent, v/v=20:1) to give a polysubstituted alkylborane derivative designated as 1c (62.0 mg, yield 75%). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 c), yellow solid. 1 H NMR(400MHz,CDCl 3 )δ 1 H NMR(400MHz,CDCl 3 )δ8.77–8.69(m,2H),8.45(m,1H),8.19(m,1H),7.62–7.53(m,2H),7.46(t,J＝7.8Hz,1H),2.19(t,J＝6.0Hz,1H),1.87(m,1H),1.68(m,1H),1.40–1.28(m,1H),1.19(d,J＝25.1Hz,12H),1.00(d,J＝14.6Hz,1H),1.00(s,3H),0.95(s,2H),0.83(t,J＝7.6Hz,3H),0.79(d,J＝14.7Hz,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ173.2,146.7,140.1,137.4,134.5,129.0,127.3,123.5,121.3,117.6,83.2,55.2,28.1,27.3,27.2,24.6,20.6,18.3,14.0.HRMS Calcd for C 24 H 36 BN 2 O 3 [M+H] + :411.2813；Found:411.2820.
Example 4
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, aliphatic carboxylic acid derivative compound 2d (0.2 mmol), bis-pinacolato diborane (0.6 mmol) and Pd (OPiv) were successively introduced under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, stirring at 130deg.CMix for 24 hours. The resulting mixture was separated by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate as eluent, v/v=20:1) to give a polysubstituted alkylborane derivative, which was designated 1d (67.0 mg, yield 73%). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 d), yellow solid.
1 H NMR(400MHz,CDCl 3 )δ8.78–8.71(m,2H),8.46(m,1H),8.25(m,1H),7.61(m,1H),7.56(m,1H),7.49(t,J＝7.8Hz,1H),7.32–7.24(m,2H),7.28–7.18(m,3H),3.08(ddt,J＝13.5,7.8,1.0Hz,1H),2.87(ddt,J＝13.6,7.9,0.9Hz,1H),2.70–2.63(m,1H),1.20(s,4H),1.15(s,4H),1.08–0.98(m,6H),0.82(d,J＝14.5Hz,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ172.8,146.7,140.2,137.7,137.4,134.5,129.4,129.2,128.9,127.2,126.8,123.7,121.3,117.5,83.1,55.9,29.2,28.3,27.6,24.6,18.3.HRMS Calcd for C 28 H 36 BN 2 O 3 [M+H] + :459.2813；Found:459.2821.
Example 5
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, aliphatic carboxylic acid derivative compound 2e (0.2 mmol), bis-pinacolato diborane (0.6 mmol) and Pd (OPiv) were successively introduced under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, and stirred at 130℃for 24 hours. The resulting mixture was separated by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate as eluent, v/v=20:1) to give a polysubstituted alkylborane derivative designated 1e (70.0 mg, yield 70%). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 e), yellow solid.
1 H NMR(400MHz,CDCl 3 )δ9.46(s,1H),8.74(m,1H),8.43m,1H),8.25(m,1H),7.88(m,2H),7.72(m,2H),7.63–7.52(m,2H),7.49(t,J＝7.8Hz,1H),4.60(d,J＝6.6Hz,1H),2.54(pt,J＝6.8,5.3Hz,1H),1.21(s,4H),1.16(s,4H),1.07(d,J＝6.8Hz,3H),0.78(m,1H),0.69(m,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ169.0,167.6,146.7,139.7,137.6,134.5,134.1,132.0,131.1,127.0,123.7,123.4,121.2,117.6,83.2,59.8,31.5,31.2,24.6,19.3.Calcd for C 28 H 31 BN 3 O 5 [M+H] + :500.2351；Found:500.2356.
Example 6
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, aliphatic carboxylic acid derivative compound 2f (0.2 mmol), bis-pinacolato diborane (0.6 mmol), pd (OPiv) were successively introduced under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, and stirred at 130℃for 24 hours. The resulting mixture was separated by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v=20:1) to give a polysubstituted alkylborane derivative, designated 1f (73.0 mg, yield 72%). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 f), yellow solid.
1 H NMR(400MHz,CDCl 3 )δ9.63(s,1H),8.74(m,1H),8.47(m,1H),8.27(m,1H),7.88(m,2H),7.72(m,2H),7.61(m,1H),7.56(m,1H),7.49(t,J＝7.7Hz,1H),4.78(d,J＝6.6Hz,1H),2.75–2.65(m,1H),1.60(m,1H),1.46(m,1H),1.20(s,4H),1.15(s,4H),0.96(t,J＝7.3Hz,3H),0.84(m,1H),0.74(m,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ169.1,167.5,146.7,139.7,137.6,134.5,134.1,132.0,131.1,127.0,123.7,123.4,121.2,117.6,83.2,59.1,37.7,29.4,24.6,24.0,11.9.Calcd for C 29 H 33 BN 3 O 5 [M+H] + :514.2508；Found:514.2510.
Example 7
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, 2g (0.2 mmol) of an aliphatic carboxylic acid derivative compound, 0.6mmol of bis-pinacolato diborane and Pd (OPiv) were successively charged under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, and stirred at 130℃for 24 hours. The resulting mixture was separated by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v=20:1) to give a polysubstituted alkylborane derivative (1 g; 74.0 mg; yield: 70%). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 g), yellow solid.
1 H NMR(400MHz,CDCl 3 )δ9.77(s,1H),8.74(m,1H),8.43(m,1H),8.27(m,1H),7.87(m,2H),7.72(m,2H),7.62(m,1H),7.56(m,1H),7.49(t,J＝7.8Hz,1H),4.66(s,1H),1.65(m,1H),1.53(m,1H),1.16(d,J＝24.9Hz,11H),1.08(s,2H),0.92–0.83(m,4H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ168.1,167.5,146.7,139.7,138.0,134.5,134.1,132.6,131.1,127.0,123.7,123.4,121.2,117.6,83.1,63.1,38.4,32.3,24.6,23.3,17.8,8.3.Calcd for C 30 H 35 BN 3 O 5 [M+H] + :528.2664；Found:528.2670.
Example 8
The synthesis method of the alkyl borane derivative comprises the following steps:
in a 25mL schlenk tube, aliphatic carboxylic acid derivative compound 2h (0.2 mmol), bis-pinacolato diborane (0.6 mmol), pd (OPiv) were added sequentially under air 2 (0.02 mmol), silver carbonate (0.6 mmol), sodium bicarbonate (0.4 mmol), 2-chloroquinoline (0.04 mmol) and 2.0mL acetonitrile, and stirred at 130℃for 24 hours. The polysubstituted alkylborane derivative was obtained by column chromatography on silica gel (petroleum ether (60-90 ℃)/ethyl acetate, v/v=20:1) and was recorded as 1h (87.0 mg, 76% yield). The target product is confirmed by nuclear magnetic resonance spectrum and high-resolution mass spectrometry; the synthetic route is as follows:
data on characterization of the Compounds
Alkyl borane (1 h), yellow solid.
1 H NMR(400MHz,CDCl 3 )δ9.77(s,1H),8.74(m,1H),8.43(m,1H),8.28(m,1H),7.88(m,2H),7.71(m,2H),7.63(m,1H),7.60–7.49(m,2H),7.40–7.32(m,2H),7.26–7.17(m,3H),4.68(s,1H),2.93(m,1H),2.48(m,1H),1.25–1.16(m,9H),1.13(s,5H),0.93(d,J＝14.5Hz,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ168.0,167.2,146.7,139.7,138.0,137.6,134.5,134.0,132.6,131.1,129.9,128.6,127.1,127.1,123.8,123.4,121.2,117.7,82.9,61.7,44.9,41.4,24.6,23.8,18.9.Calcd for C 35 H 37 BN 3 O 5 [M+H] + :590.2821；Found:590.2826.
Example 9
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
with Pd (OAc) 2 Instead of Pd (OPiv) 2 The other operations were conducted as in example 1 to give the desired product (39.0 mg, yield 50%).
Example 10
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
with PdCl 2 Instead of Pd (OPiv) 2 The other operations were conducted as in example 1 to give the desired product (10.0 mg, yield 13%).
Example 11
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
the procedure of example 1 was followed except for using silver acetate instead of silver carbonate to give the desired product (15.0 mg, yield 20%).
Example 12
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
the procedure of example 1 was followed except for using silver oxide instead of silver carbonate to give the desired product (8.0 mg, yield 10%).
Example 13
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
the procedure of example 1 was followed except for using 0.4mmol of dipyruvyldiborane to give the desired product (41.0 mg, yield 55%).
Example 14
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
the procedure of example 1 was followed except for using 0.8mmol of dipyruvyldiborane to give the desired product (50.0 mg, yield 68%).
Example 15
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
the procedure of example 1 was followed except for using sodium carbonate instead of sodium hydrogencarbonate, to give the desired product (50.0 mg, yield 68%).
Example 16
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
the procedure of example 1 was followed except for using 1, 4-dioxane instead of acetonitrile in an amount of 2.0mL to give the desired product (50.0 mg, yield 68%).
Example 17
The synthesis method of the alkyl borane derivative described in example 1 is different in that,
the procedure of example 1 was followed except for using 2-chloropyridine instead of chloroquinoline in an amount of 2.0mL to give the desired product (17.0 mg, yield 23%).
Application example 1
In a 25mL schlenk tube, alkylboron compound 1a (0.2 mmol), boron trifluoride etherate (2 mmol) and 2.0mL methanol were added in this order under air and stirred at 110℃for 10 hours. The product was isolated by column chromatography on silica gel (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v=20:1) to give the desired product 4 (44.0 mg, 85% yield). The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
Data on characterization of the Compounds
Esterification product (4), yellow solid. 1 H NMR(400MHz,CDCl 3 )δ3.60(s,1H),2.37(s,1H),1.16(s,6H),1.04(s,3H),0.74(s,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ172.3,82.9,51.7,47.2,31.2,26.4,24.6,15.3.Calcd for C 13 H 26 BO 4 [M+H] + :257.1919；Found:257.1925.
Application example 2
In a 25mL schlenk tube, alkylboron compound 1a (0.2 mmol), iodobenzene (0.4 mmol), palladium acetate (0.02 mmol), silver acetate (0.4 mmol) and 2.0mL t-butanol were added sequentially under air and stirred at 110℃for 24 hours. The product was isolated by column chromatography on silica gel (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v=20:1) to give the desired product 5 (50.0 mg, 78% yield). The target product is confirmed by nuclear magnetic resonance spectroscopy and high resolution mass spectrometry.
Data on characterization of the Compounds
Amide product (5), yellow solid. 1 H NMR(400MHz,CDCl 3 )δ9.60(s,1H),8.84(m,1H),8.46(m,1H),8.29(m,1H),7.64–7.50(m,3H),7.38–7.30(m,2H),7.25–7.17(m,3H),2.73(t,J＝0.9Hz,2H),2.48(s,1H),1.05(s,4H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ170.8,146.6,139.5,138.4,137.9,134.5,130.0,128.8,128.6,127.1,127.0,123.5,121.6,117.2,47.8,47.5,35.9,28.2.Calcd for C 21 H 23 N 2 O[M+H] + :319.1805；Found:319.1809。
Claims (9)
1. An organic synthesis intermediate alkyl borane derivative has a structural formula shown in the following formula I:
a method for preparing the compound of formula I,
R 1 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 2 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 3 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl;
R 4 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl.
2. The method for synthesizing an alkyl borane derivative according to claim 1, comprising the steps of:
aliphatic carboxylic acid derivatives and bis-pinacolato diborane are used as reaction starting materials, palladium salt is used as a catalyst, silver salt is used as an oxidant, C-H bond activation is carried out in a solvent under the participation of alkali and additives, one-step synthesis reaction is carried out, and after the reaction is finished, separation and purification are carried out, so as to obtain the polysubstituted alkyl borane derivatives;
the molecular structural formula of the aliphatic carboxylic acid derivative is shown as the following formula II:
II, the step of setting the position of the base plate,
R 1 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 2 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl, phthalamide;
R 3 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl;
R 4 one selected from the following groups:
hydrogen, methyl, ethyl, propyl, benzyl;
the palladium salt is selected from PdCl 2 、Pd(OAc) 2 、Pd(TFA) 2 、Pd(OPiv) 2 、Pd(CH 3 CN)Cl 2 、Pd(PhCN)Cl 2 、Pd(PPh 3 )Cl 2 One or more than two of them are mixed;
the silver salt is one or more than two of silver pivalate, silver acetate, silver carbonate and silver trifluoroacetate;
the alkali is one or more than two of sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and potassium phosphate; the additive isN-acetylglycine or 2-chloroquinoline.
3. The synthetic method according to claim 2, wherein the molar ratio of the aliphatic carboxylic acid derivative to the bis-pinacolatyldiborane is 1: (1-10).
4. The synthesis method according to claim 2, which comprisesCharacterized in that the palladium salt is Pd (OPiv) 2 The method comprises the steps of carrying out a first treatment on the surface of the The molar ratio of the aliphatic carboxylic acid derivative to the palladium salt is 1: (0.01-0.5).
5. The method of synthesis according to claim 2, wherein the silver salt is silver carbonate; the molar ratio of the aliphatic carboxylic acid derivative to the silver salt is 1: (1-6).
6. The synthetic method of claim 2 wherein the base is sodium bicarbonate; the molar ratio of the aliphatic carboxylic acid derivative to the base is 1: (1-6).
7. The method of synthesis according to claim 2, wherein the molar ratio of the aliphatic carboxylic acid derivative to the additive is 1: (0.01-0.5).
8. The synthetic method according to claim 2, wherein the solvent is one or a mixture of any two or more of 1, 4-dioxane, tertiary butanol, toluene, 1, 2-dichloroethane, dichloromethane, tetrahydrofuran, benzotrifluoride, acetonitrile, chlorobenzene, and 1, 2-dichlorobenzene; the solvent is used in an amount such that the molar concentration of the aliphatic carboxylic acid derivative is 0.01 to 1.0. 1.0M.
9. The synthetic method of claim 2 wherein the reaction atmosphere is air, oxygen, nitrogen or argon; the synthesis reaction temperature is 50-150 ℃ and the reaction time is 10-48h.
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