CN114805108B - Preparation method of chiral beta-alkylamide compound - Google Patents
Preparation method of chiral beta-alkylamide compound Download PDFInfo
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- CN114805108B CN114805108B CN202210403991.2A CN202210403991A CN114805108B CN 114805108 B CN114805108 B CN 114805108B CN 202210403991 A CN202210403991 A CN 202210403991A CN 114805108 B CN114805108 B CN 114805108B
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- Prior art keywords
- butyl
- substituted
- aryl
- alkylene
- atoms
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 106
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- -1 iodo compound Chemical class 0.000 claims abstract description 144
- 239000003446 ligand Substances 0.000 claims abstract description 39
- 238000005859 coupling reaction Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 5
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 129
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical group I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 66
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 64
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical group [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 33
- 125000002947 alkylene group Chemical group 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 21
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 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 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 229940078494 nickel acetate Drugs 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 4
- SHWZFQPXYGHRKT-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;nickel Chemical compound [Ni].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O SHWZFQPXYGHRKT-FDGPNNRMSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 193
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
- 238000005481 NMR spectroscopy Methods 0.000 description 68
- 235000019439 ethyl acetate Nutrition 0.000 description 64
- 125000004429 atom Chemical group 0.000 description 38
- 230000002829 reductive effect Effects 0.000 description 36
- 239000003208 petroleum Substances 0.000 description 35
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000012074 organic phase Substances 0.000 description 32
- VHSVJTYBTJCDFL-UHFFFAOYSA-L 1,2-dimethoxyethane;nickel(2+);dibromide Chemical compound Br[Ni]Br.COCCOC VHSVJTYBTJCDFL-UHFFFAOYSA-L 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 239000000706 filtrate Substances 0.000 description 30
- 229940035429 isobutyl alcohol Drugs 0.000 description 30
- 239000012046 mixed solvent Substances 0.000 description 30
- 238000010898 silica gel chromatography Methods 0.000 description 30
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 239000012299 nitrogen atmosphere Substances 0.000 description 28
- 125000004432 carbon atom Chemical group C* 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 18
- KLZMBFVLCWOMPQ-UHFFFAOYSA-N 3-bromo-N-phenylbutanamide Chemical compound BrC(CC(=O)NC1=CC=CC=C1)C KLZMBFVLCWOMPQ-UHFFFAOYSA-N 0.000 description 17
- 229910052717 sulfur Inorganic materials 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- KVTHPKXDLVYNCH-UHFFFAOYSA-N 2-iodoethylbenzene Chemical compound ICCC1=CC=CC=C1 KVTHPKXDLVYNCH-UHFFFAOYSA-N 0.000 description 13
- 125000004122 cyclic group Chemical group 0.000 description 13
- 125000006413 ring segment Chemical group 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 125000004434 sulfur atom Chemical group 0.000 description 10
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 125000004430 oxygen atom Chemical group O* 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 4
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 4
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 4
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 4
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 4
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 4
- 125000005883 dithianyl group Chemical group 0.000 description 4
- 239000012039 electrophile Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000002632 imidazolidinyl group Chemical group 0.000 description 4
- 125000002636 imidazolinyl group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 4
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 4
- 125000002755 pyrazolinyl group Chemical group 0.000 description 4
- 238000006578 reductive coupling reaction Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 3
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 125000000532 dioxanyl group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003254 radicals Chemical group 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical group O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 3
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 3
- 125000002053 thietanyl group Chemical group 0.000 description 3
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 2
- RGCKJSPKMTWLLX-UHFFFAOYSA-N 3-iodopropylbenzene Chemical compound ICCCC1=CC=CC=C1 RGCKJSPKMTWLLX-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 150000001336 alkenes Chemical class 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 230000008901 benefit Effects 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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000000466 oxiranyl group Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000006407 thiazinanyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000001831 (C6-C10) heteroaryl group Chemical group 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- YCXFVLNWJDELGP-UHFFFAOYSA-N 1,2-dimethoxyethane hydrobromide Chemical compound Br.COCCOC YCXFVLNWJDELGP-UHFFFAOYSA-N 0.000 description 1
- CBPHUQIHJKGXHY-UHFFFAOYSA-N 1,2-dimethoxyethane;hydrochloride Chemical compound Cl.COCCOC CBPHUQIHJKGXHY-UHFFFAOYSA-N 0.000 description 1
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SEXZHJJUKFXNDY-UHFFFAOYSA-N 1-(bromomethyl)-2-phenylbenzene Chemical group BrCC1=CC=CC=C1C1=CC=CC=C1 SEXZHJJUKFXNDY-UHFFFAOYSA-N 0.000 description 1
- RZJGKPNCYQZFGR-UHFFFAOYSA-N 1-(bromomethyl)naphthalene Chemical compound C1=CC=C2C(CBr)=CC=CC2=C1 RZJGKPNCYQZFGR-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- LKCFNUWNIROFII-UHFFFAOYSA-N 1-iodo-3,7-dimethyloctane Chemical compound CC(C)CCCC(C)CCI LKCFNUWNIROFII-UHFFFAOYSA-N 0.000 description 1
- LMHCYRULPLGEEZ-UHFFFAOYSA-N 1-iodoheptane Chemical compound CCCCCCCI LMHCYRULPLGEEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- QFGHSJVNOHRSNT-UHFFFAOYSA-N 2-(2-iodoethyl)-1,3-dioxolane Chemical compound ICCC1OCCO1 QFGHSJVNOHRSNT-UHFFFAOYSA-N 0.000 description 1
- CZLVVNAEIJTRNL-UHFFFAOYSA-N 2-(2-iodoethyl)naphthalene Chemical compound C1=CC=CC2=CC(CCI)=CC=C21 CZLVVNAEIJTRNL-UHFFFAOYSA-N 0.000 description 1
- LXNKVDHVPNGONF-UHFFFAOYSA-N 2-(3-iodopropyl)thiophene Chemical compound ICCCC1=CC=CS1 LXNKVDHVPNGONF-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- HITDQIDBXIGRBU-UHFFFAOYSA-N 2-iodoethoxybenzene Chemical compound ICCOC1=CC=CC=C1 HITDQIDBXIGRBU-UHFFFAOYSA-N 0.000 description 1
- NYACRWGQRUIHSO-UHFFFAOYSA-N 2-iodoethoxymethylbenzene Chemical compound ICCOCC1=CC=CC=C1 NYACRWGQRUIHSO-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- LQNMGMMOHCDYPF-UHFFFAOYSA-N 4-iodobutylbenzene Chemical compound ICCCCC1=CC=CC=C1 LQNMGMMOHCDYPF-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005275 alkylenearyl group Chemical group 0.000 description 1
- 125000005218 alkyleneheteroaryl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- CXHHAWACKSPTFF-UHFFFAOYSA-N iodomethylcyclohexane Chemical compound ICC1CCCCC1 CXHHAWACKSPTFF-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 description 1
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003864 primary ammonium salts Chemical class 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 150000003865 secondary ammonium salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- CAAUZMMMFDVBFD-UHFFFAOYSA-N tert-butyl-(2-iodoethoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCI CAAUZMMMFDVBFD-UHFFFAOYSA-N 0.000 description 1
- 150000003866 tertiary ammonium salts Chemical class 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/847—Nickel
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
The invention discloses a preparation method of chiral beta-alkylamide compounds, which comprises the following steps: under the protection of inert gas, performing coupling reaction on an iodo compound and a bromo-alkylamide compound in an organic solvent in the presence of a catalyst, a ligand, a reducing agent and an additive to obtain a chiral beta-alkylamide compound; the preparation method has the characteristics of high enantioselectivity, small environmental pollution and high yield.
Description
Technical Field
The invention relates to the technical field of molecular synthesis of drug intermediates and organic chiral building blocks, and particularly discloses a preparation method of chiral beta-alkylamide compounds.
Background
Chiral C (sp3) -C (sp3) Bonds are widely present in natural products and drugs with biological activity, chiral C (sp3) -C (sp3) The construction of bonds has been a focus of research on organic synthesis. The enantioselective cross coupling reaction catalyzed by transition metal is efficient synthesis of chiral C (sp3) -C (sp3) One of the methods of bonding compounds, the limitation of which is the preparation and use of organometallic reagents. Another construction chiral C (sp3) -C (sp3) The bond is formed by asymmetric hydroalkylation of olefins, which is a major difficulty in the regioselectivity of the reaction from olefins via metal hydrogen species reactions to produce hydroalkylated products. The metal catalyzed reductive coupling reaction is an important method for constructing carbon-carbon bonds, and the reaction directly uses electrophiles for coupling, so that the preparation and the use of metal reagents are avoided, and the metal-catalyzed reductive coupling reaction is widely developed in recent years. Wherein an asymmetric reductive coupling reaction using a secondary electrophile can efficiently synthesize a series of chiral compounds, but the asymmetric reductive coupling reaction is mainly focused on the construction of chiral C (sp2) -C (sp3) Bond, so far metal catalytic reduction coupling reaction constructs chiral C (sp3) -C (sp3) Bonds have not been reported.
The main challenge of the asymmetric reduction coupling reaction of two molecules of alkyl electrophiles catalyzed by metal is the control of the reaction selectivity and chirality. Due to the similarity of raw materials and the high reactivity of alkyl electrophiles, a large number of self-coupling side reactions occur in the reaction, resulting in reduced selectivity of cross coupling, and chiral control of alkyl metal alkyl species is also a great difficulty. The present invention provides an efficient method for achieving this conversion process.
Chiral beta-alkylamides are an important class of organic synthons that contain such chiral backbones in many natural products as well as biological inhibitors. In the prior art, few synthesis methods of chiral beta-alkylamide compounds are reported, so that development of an effective synthesis route of chiral beta-alkylamide compounds with high stereoselectivity is urgently needed.
The invention comprises the following steps:
in one aspect, the invention discloses a preparation method of chiral beta-alkylamide compounds,
wherein: the preparation method comprises the following steps: under the protection of inert gas, carrying out coupling reaction on a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent in the presence of a catalyst, a ligand, a reducing agent and an additive to obtain a compound shown in a formula (I);
Each R is 1 And R is 2 Independently C 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 6-10 aryl-C 1-8 Alkylene or heteroaryl-C consisting of 5-12 atoms 1-8 Alkylene group, wherein the C 1-12 Alkyl, C 1-12 Hydroxyalkyl, C 6-10 aryl-C 1-8 Alkylene and heteroaryl-C consisting of 5 to 12 atoms 1-8 Alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, tert-butyldimethylsilyl, C 3-8 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl, C 6-10 aryl-C 1-6 Substitution of alkylene groups and heteroaryl groups of 5-12 atomsSubstituted by radicals;
R 3 independently C 1-6 Alkyl, C 3-8 Cycloalkyl or C 6-10 Aryl, wherein said C 1-6 Alkyl, C 3-8 Cycloalkyl and C 6-10 Aryl is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and C 6-10 The substituents of the aryl groups are substituted.
In some embodiments, wherein each R 1 And R is 2 Independently C 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 6-10 aryl-C 1-6 Alkylene or heteroaryl-C consisting of 5-12 atoms 1-6 Alkylene group, wherein the C 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 6-10 aryl-C 1-6 Alkyl and heteroaryl-C consisting of 5-12 atoms 1-6 Alkyl is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, t-butyldimethylsilane, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl, C 6-10 aryl-C 1-4 The substituents of the alkylene and heteroaryl consisting of 5 to 10 atoms are substituted;
R 3 independently C 1-4 Alkyl, C 3-6 Cycloalkyl or C 6-10 Aryl, wherein said C 1-4 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and C 6-10 The substituents of the aryl groups are substituted.
In some embodiments, wherein each R 1 And R is 2 Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene or heteroaryl-C consisting of 5-12 atoms 1-4 Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene and heteroaryl-C consisting of 5 to 12 atoms 1-4 Alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Substituted with a substituent selected from the group consisting of methoxy, ethylpropoxy, n-oxy, i-propoxy, t-butyldimethylsilyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, dioxacyclopentyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, phenylmethylene, phenylethenyl, benzofuranyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
R 3 independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, wherein the methyl, ethyl, n-propylIsopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Substituted with methoxy, ethylpropoxy, n-oxy, i-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and naphthyl.
In some embodiments, wherein the compound of formula (I) comprises at least one of the following compounds:
in some embodiments, wherein the catalyst for preparing the compound of formula (I) is zero-valent nickel or divalent nickel; preferably, the catalyst for the coupling reaction is Ni (cod) 2 Nickel chloride, nickel bromide, nickel iodide, ethylene glycol dimethyl ether chloride, ethylene glycol dimethyl ether bromide, nickel acetylacetonate or nickel acetate.
In some embodiments, wherein the ligand for preparing the compound of formula (I) is selected from the following compounds:
in some embodiments, the reducing agent for preparing the compound shown in the formula (I) is manganese metal, the characteristic is powder, and the particle mesh number is 100-500 mesh.
In some embodiments, wherein the additive for preparing the compound of formula (I) is zinc iodide.
In some embodiments, wherein the organic solvent used to prepare the compound of formula (I) is an alcoholic solvent; preferably, the organic solvent with the coupling reaction is ethanol, n-propanol, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, sec-amyl alcohol or n-hexanol.
In some embodiments, wherein the reaction temperature for preparing the compound of formula (I) is from 10℃to 40 ℃; preferably, the reaction temperature is 15-35 ℃.
In some embodiments, wherein the reaction time for preparing the compound of formula (I) is from 18 to 30 hours; preferably, the reaction time is 20 to 26 hours.
In some embodiments, the preparation method of chiral beta-alkylamide compounds and derivatives thereof provided by the invention adopts metal catalyzed coupling reaction, and has the advantages of high yield, excellent enantioselectivity of products, high atom economy and the like, and in addition, the catalyst dosage in a reaction system is small, and the catalytic efficiency is high.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise indicated, all patent publications cited throughout the disclosure of this invention are incorporated by reference in their entirety.
The invention will apply to the following definitions unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in terms of the periodic table of the elements, CAS version and handbook of chemicals, 75, th ed, 1994. In addition, the general principles of organic chemistry are found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999,and"March's Advanced Organic Chemistry", by Michael B.Smith and Jerry March, john Wiley&Sons, new York:2007, the entire contents of which are hereby incorporated by reference.
Many different aspects and embodiments of the disclosure will be described below, and each is not limiting on the scope of the disclosure. The terms "aspect" and "embodiment" are intended to be non-limiting, regardless of whether the terms "aspect" or "embodiment" appear anywhere in this specification. The transitional term "comprising" as used herein synonymously with "including," "containing," or "characterized by" is inclusive or open-ended and does not exclude additional, unrecited elements.
In the context of the present invention, all numbers disclosed herein are approximations. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, or 10%. Whenever a number is disclosed having a value of N, any number within the values of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, of a range of values is disclosed, any value falling within the disclosed range is explicitly disclosed.
All of the reaction steps described herein are reacted to an extent such as greater than about 70% raw material consumption, greater than 80%, greater than 90%, greater than 95%, or post-treatment such as cooling, collecting, extracting, filtering, separating, purifying, or a combination thereof, after detecting that the raw materials have been consumed. The degree of reaction can be detected by conventional methods such as Thin Layer Chromatography (TLC), high Performance Liquid Chromatography (HPLC), gas Chromatography (GC), etc. The reaction solution may be subjected to post-treatment by a conventional method, for example, by evaporating under reduced pressure or conventionally distilling the reaction solvent, and then collecting the crude product, and directly put into the next reaction; or directly filtering to obtain a crude product, and directly putting the crude product into the next reaction; or standing, pouring out supernatant to obtain crude product, and directly adding into the next reaction; or selecting proper organic solvent or combination thereof for extraction, distillation, crystallization, column chromatography, rinsing, pulping and other purification steps.
The dropping processes and the reactions of the steps are carried out under certain temperature conditions, and any temperature suitable for the dropping processes or the reactions is included in the invention. In addition, many similar modifications, equivalent substitutions, or equivalents in the art will be apparent to those skilled in the art to which the present invention pertains, and the temperature and temperature ranges described herein are deemed to be encompassed by the present invention. The invention provides the preferred temperature or temperature range of each dripping process and the preferred reaction temperature of each reaction.
The solvent used in each of the reaction steps described in the present invention is not particularly limited, and any solvent which dissolves the starting materials to some extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention. The present invention gives the preferred solvents to be used in each reaction step.
"room temperature" in the present invention means a temperature from about 10℃to about 40 ℃. In some embodiments, "room temperature" refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and so forth.
The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". The terms "optionally," "optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally" whether or not prior to the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to F, cl, br, I, CN, N 3 、OH、OR a 、NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 3 to 6 atoms, (heterocyclyl of 3 to 6 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 Alkylene group, wherein R a 、R b And R is c Having the definition according to the invention.
The term "alkyl" or "alkyl group" as used herein refers to a saturated straight or branched chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms. Unless otherwise specified, an alkyl group contains 1 to 20 carbon atoms, some embodiments are where the alkyl group contains 1 to 12 carbon atoms, some embodiments are where the alkyl group contains 1 to 10 carbon atoms, some embodiments are where the alkyl group contains 1 to 8 carbon atoms, some embodiments are where the alkyl group contains 1 to 6 carbon atoms, some embodiments are where the alkyl group contains 1 to 4 carbon atoms, and some embodiments are where the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like, wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains.
The term "alkylene" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight or branched saturated hydrocarbon group. Unless otherwise specified, an alkylene group contains from 1 to 10 carbon atoms, and in other embodiments an alkylene group contains from 1 to 6 carbon atoms, and in other embodiments an alkylene group contains from 1 to 4 carbon atoms, and in other embodiments an alkylene group contains from 1 to 2 carbon atoms. Examples of this include methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), isopropylidene (-CH (CH) 3 )CH 2 (-) and the like, wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain from 1 to 20 carbon atoms, some embodiments are alkoxy groups containing from 1 to 10 carbon atoms, other embodiments are alkoxy groups containing from 1 to 8 carbon atoms, other embodiments are alkoxy groups containing from 1 to 6 carbon atoms, other embodiments are alkoxy groups containing from 1 to 4 carbon atoms, and other embodiments are alkoxy groups containing from 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy [ ]MeO,-OCH 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And the like, wherein the alkoxy groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group having one or more hydroxy substituents, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl (-CH) 2 CH 2 OH), 1-hydroxyethyl (-CH 2 OHCH 3 ) 1, 2-dihydroxyethyl, 2, 3-dihydroxypropyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, hydroxybutyl, and the like. The hydroxyalkyl group may optionally be substituted with one or more substituents described hereinSubstituted.
The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms that is saturated and has one or more points of attachment to the remainder of the molecule. The bicyclic ring system includes spirobicyclic and fused bicyclic rings. Some of these embodiments, cycloalkyl groups are ring systems containing 3 to 10 carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3 to 8 carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3 to 6 carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5 to 6 carbon atoms; examples of cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "cycloalkylalkylene" means that an alkyl group may be substituted with one or more cycloalkyl groups, where alkyl and cycloalkyl groups have the meanings as described herein. Some of these embodiments are where the cycloalkylalkylene group refers to a "lower cycloalkylalkylene" group, i.e., the cycloalkyl group is attached to C 1-6 Is present. Other embodiments are where the cycloalkyl group is attached to C 1-4 Is present. Other embodiments are where the cycloalkyl group is attached to C 1-3 Is present. Other embodiments are where the cycloalkyl group is attached to C 1-2 Is present. Examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. The cycloalkylalkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms, and wherein the ring system has one or more points of attachment to the remainder of the molecule. Unless otherwise indicated,the heterocyclic group may be a carbon or nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazanyl, homopiperazinyl, homopiperidinyl, oxaheptanyl, thietanyl, oxazanyl Radical, diaza->Radical, thiazal->Group, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1 ]]Hept-5-yl. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane groups and 1, 1-dioxothiomorpholinyl groups. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
In some embodiments, heterocyclyl is a heterocyclyl consisting of 3-6 atoms, meaning a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, at least one of which is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, heterocyclyl consisting of 3 to 6 atoms mayIs a carbon or nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclic groups consisting of 3 to 6 atoms include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazalkyl. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl and 3, 5-dioxopiperidyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane groups and 1, 1-dioxothiomorpholinyl groups. The 3-6 atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In some embodiments, heterocyclyl is a heterocyclyl consisting of 5-6 atoms, meaning a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, at least one of which is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, a heterocyclic group consisting of 5 to 6 atoms may be a carbon group or a nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclic groups consisting of 5 to 6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl Dioxanyl, dithianyl, thianyl. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl and 3, 5-dioxopiperidyl. Examples of sulfur atoms in the heterocyclyl group that are oxidized include, but are not limited to, 1-dioxothiomorpholinyl. The 5-6 atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In other embodiments, heterocyclyl is a 5 atom composition heterocyclyl, meaning a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, at least one of which is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, a heterocyclic group consisting of 5 atoms may be a carbon group or a nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclic groups consisting of 5 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl and oxo-1, 3-thiazolidinyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane groups. The 5 atom constituent heterocyclyl group may be optionally substituted with one or more substituents described herein.
In other embodiments, heterocyclyl is a 6 atom composition heterocyclyl, meaning a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, at least one of which is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, a heterocyclic group consisting of 6 atoms may be a carbon group or a nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Solid heterocyclic group composed of 6 atomsExamples include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazanyl. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-piperidonyl and 3, 5-dioxopiperidyl. Examples of sulfur atoms in the heterocyclyl group that are oxidized include, but are not limited to, 1-dioxothiomorpholinyl. The 6 atom constituent heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "heterocyclylalkylene" means that an alkyl group may be substituted with one or more heterocyclyl groups, where alkyl and heterocyclyl groups have the meanings as described herein. Some of these embodiments are where the heterocyclylalkylene group refers to a "lower heterocyclylalkylene" group, i.e., the heterocyclyl group is attached to C 1-6 Is present. Other embodiments are where the heterocyclyl group is attached to C 1-4 Is present. Other embodiments are where the heterocyclyl group is attached to C 1-2 Is present. Examples include, but are not limited to, 2-pyrrolidinoethyl, 3-azetidinomethyl, and the like. The heterocyclylalkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "heteroatom" refers to any oxidation state form of O, S, N, P and Si, including N, S and P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" refers to F, cl, br or I.
The term "aryl" may be used alone or as part of an "aralkyl", "aralkoxy" or "aryloxyalkyl" group, to denote monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring of 3 to 7 atoms, and one or more attachment points are attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "arylalkylene" means that an alkyl group may be substituted with one or more aryl groups, where alkyl and aryl groups have the meaning as described herein, and some embodiments are where arylalkylene groups refer to "lower arylalkylene" groups, i.e., aryl groups attached to C 1-6 Is present. In other embodiments, an arylalkylene group is meant to contain C 1-4 "phenylalkylene" of alkyl groups of (2). In other embodiments, an arylalkylene group means that the aryl group is attached to C 1-2 Is present. Specific examples thereof include benzyl, diphenylmethyl, phenethyl and the like. The arylalkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" to denote monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms, and one or more attachment points are attached to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a 5-12 atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5-10 atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5-6 atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 5-atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 6-atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
Still other embodiments are heteroaryl groups including, but not limited to, the following monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-oxadiazolyl, 1,2, 4-triazolyl, 1, 3-oxadiazolyl, 1, 3-triazolyl, 1, 4-oxadiazolyl, 1, 3-thiodiazolyl, 1, 4-triazolyl; the following bicyclic groups are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). The heteroaryl group is optionally substituted with one or more substituents described herein.
The term "heteroarylalkylene" means that an alkyl group may be substituted with one or more heteroaryl groups, where alkyl and heteroaryl groups have the meaning as described herein, some embodiments of which are that the heteroarylalkylene group refers to a "lower heteroarylalkylene" group, i.e., the heteroaryl group is attached to C 1-6 Is present. Other embodiments are where the heteroaryl group is attached to C 1-4 Alkyl group of (2)And (5) agglomerating. Other embodiments are where the heteroaryl group is attached to C 1-2 Is present. Specific examples thereof include 2-picolyl, 3-furanethyl, and the like. The heteroarylalkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.
The terms "cycloalkylalkylene", "heterocyclylalkylene", "arylalkylene", "heteroarylalkylene" refer to cycloalkyl, heterocyclyl, aryl and heteroaryl groups attached to the remainder of the molecule through an alkylene group, wherein the alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups all have the meanings as described herein. The alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups in the "alkylene cycloalkyl", "alkylene heterocyclyl", "alkylene aryl", "alkylene heteroaryl" groups are optionally substituted with one or more substituents described herein.
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
"diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
The term "enantiomeric excess (enantiomeric excess)" or "ee%" is described. It represents the excess of one enantiomer over the other, usually expressed as a percentage.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by known methods, such as,by separating the diastereoisomeric salts thereof obtained. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The disclosed compounds may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to encompass all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, as part of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.
General synthetic procedure
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (II), unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin good Chemies, tianjin Fuchen Chemies, wuhan Xinhua Yuan technology development Co., ltd., qingdao Teng Chemies Co., and Qingdao sea chemical Co.
Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.
Nuclear magnetic resonance spectroscopy uses Bruker 400MHz or 600MHz nucleiMagnetic resonance spectrometer recording with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet), m (multiplet ), br (broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).
The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-M (column type: zorbax SB-C18,2.1x30mm,3.5 μm, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O), using electrospray ionization (ESI), at 210nm/254nm, using UV detection.
The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: agilent zorbax Eclipse Plus C), and detected by a DAD detector, and finally calculated by area normalization.
The following abbreviations are used throughout the present invention:
| MeOH | methanol | CDCl 3 | Deuterated chloroform |
| DCM | Dichloromethane (dichloromethane) | Mn | Manganese powder |
| PE | Petroleum ether | ZnI 2 | Zinc iodide |
| EtOAc | Acetic acid ethyl ester | NiBr 2 dme | Ethylene glycol dimethyl ether nickel bromide |
The following synthesis schemes list the experimental procedures for the preparation of the compounds of formula (I). Wherein R and n have the definitions as described herein.
Reaction scheme 1
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The compound represented by the formula (5) can be produced by the reaction scheme 1. The [ (x) ray ]1) The compound shown reacts under the action of sodium borohydride to obtain the compound shown in the formula2) The compounds shown. The [ (x) ray ]2) The shown compound reacts with simple substance bromine to obtain the formula3) The compounds shown. The [ (x) ray ]3) The compound shown in the formula4) The compound is subjected to coupling reaction under the action of a catalyst to obtain the compound with the formula of [ ]5) The compounds shown.
Reaction scheme 2
The [ (x) ray ]5) The compounds shown can be prepared by reaction scheme 2. The [ (x) ray ]6) The compounds and the formula are7) The compounds are condensed to obtain the formula4) The compounds shown. The [ (x) ray ]3) The compound shown in the formula4) The compound is subjected to coupling reaction under the action of a catalyst to obtain the compound with the formula of [ ]5) The compounds shown.
Reaction scheme 3
The compound represented by the formula (5) can be produced by the reaction scheme 3. The [ (x) ray ]8) The compound shown in the formula 9) The compounds shown react to obtain the formula2) The compounds shown. The [ (x) ray ]2) The shown compound reacts with simple substance bromine to obtain the formula3) The compounds shown. The [ (x) ray ]3) The compound shown in the formula4) The compound is subjected to coupling reaction under the action of a catalyst to obtain the compound with the formula of [ ]5) The compounds shown.
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Examples
Synthesis of ligand L1
Chiral oxazoline precursor (1.0 g,3.0 mmol) was dissolved in dry tetrahydrofuran (20 mL) under nitrogen protection, cooled to-40 ℃, liHMDS (9.0mL,9.0mmol,1M in THF) was added dropwise to the system, stirred for 30 minutes, bromomethyl-1, 1' -biphenyl (2.2 g,9.0 mmol) was added to the system, and stirred at room temperature for 12 hours. Saturated ammonium chloride was added to quench, ethyl acetate was extracted (3×50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate (v/v) =4:1) to give chiral oxazoline ligand L1. White solid, 1.0g, yield 50%.
1 H NMR(400MHz,CDCl 3 )δ7.60(dd,J＝15.1,7.8Hz,8H),7.49–7.40(m,8H),7.40–7.27(m,7H),7.24(t,J＝7.3Hz,2H),7.17(d,J＝7.1Hz,4H),4.39(dq,J＝9.2,5.5Hz,2H),4.21(t,J＝8.9Hz,2H),3.97(t,J＝8.0Hz,2H),3.47(d,J＝2.6Hz,4H),3.08(dd,J＝13.7,5.2Hz,2H),2.47(dd,J＝13.7,9.2Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ166.73,140.90,139.74,137.99,135.88,130.96,129.14,128.74,128.51,127.16,127.02,126.77,126.43,72.03,67.40,48.33,41.55,39.18.
Synthesis of ligand L2
1-bromomethylnaphthalene (12.2 g,55 mmol) and potassium carbonate (8.6 g,62.5 mmol) were added to a solution of malononitrile (1.7 g,25 mmol) in acetonitrile (50 mL) at room temperature and stirred at room temperature for 24 hours. Concentrated under reduced pressure, dichloromethane (100 mL) was added and washed three times with water (3X 50 mL). Concentrating under reduced pressure to obtain solid, washing with petroleum ether to obtain the dinaphthyl substituted malononitrile intermediate with equivalent yield, and directly carrying out the next step without further purification.
1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝8.3Hz,2H),7.91(d,J＝7.9Hz,4H),7.69(d,J＝6.8Hz,2H),7.60–7.47(m,6H),3.86(s,4H). 13 C NMR(101MHz,CDCl 3 )δ134.02,132.09,129.71,129.42,129.13,128.17,126.66,126.16,125.34,123.18,115.46,40.44,39.07.
Zinc chloride (4.1 g,30 mmol) was added to a solution of substituted malononitrile (3.5 g,10 mmol) in chlorobenzene (30 mL) at room temperature, followed by (S) -2-amino-3-phenylpropyl-1-ol (4.5 g,30 mmol) and stirring at 130℃for 24 hours. The reaction mixture was cooled to room temperature, and water (10 mL) and ethylenediamine (5 mL) were added thereto, followed by stirring at room temperature for 1 hour. Water (100 mL) and methylene chloride (50 mL) were added to the system and extracted three times with methylene chloride (3X 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate (v/v) =4:1) to give chiral oxazoline ligand L2. White solid, 4.7g, yield 77%.
1 H NMR(400MHz,CDCl 3 )δ8.35–8.20(m,2H),7.89(dd,J＝5.7,3.8Hz,2H),7.79(d,J＝8.1Hz,2H),7.70(d,J＝7.0Hz,2H),7.52(dd,J＝6.2,3.4Hz,4H),7.48–7.39(m,2H),7.29–7.17(m,6H),7.02(d,J＝7.0Hz,4H),4.24–3.94(m,6H),3.69(t,J＝8.9Hz,2H),3.51(t,J＝7.9Hz,2H),2.83(dd,J＝13.6,5.0Hz,2H),1.92(dd,J＝13.6,9.6Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ166.79,138.01,133.80,133.42,133.04,129.02,128.72,128.36,127.99,127.39,126.26,125.52,125.24,125.15,124.17,71.63,67.16,48.24,40.93,36.05.
Example 1 (R) -3-methyl-N, 5-diphenylvaleramide 3a
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To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirring was carried out at room temperature for 30 minutes, and to the reaction system, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and stirring was carried out at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3a,40mg (yield 76%), 92% ee.
1 H NMR(600MHz,CDCl 3 ))δ7.42(d,J＝7.7Hz,2H),7.24(t,J＝7.7Hz,2H),7.21–7.18(m,2H),7.07(dd,J＝47.6,7.1Hz,5H),2.71–2.48(m,2H),2.32(dd,J＝13.3,5.2Hz,1H),2.07(ddt,J＝20.2,13.6,7.6Hz,2H),1.73–1.63(m,1H),1.49(d,J＝6.3Hz,1H),1.00(d,J＝6.1Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ170.62,142.31,137.85,128.98,128.39,128.34,125.79,124.24,119.83,119.77,45.43,38.58,33.37,30.63,19.64.
EXAMPLE 2 (R) -N- (4-methoxyphenyl) -3-methyl-5-phenylpentanamide 3b
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirring was carried out at room temperature for 30 minutes, and to the reaction system, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N- (4-methoxyphenyl) butanamide 1b (54.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and stirring was carried out at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give the title compound as a white solid 3b,44mg (yield 74%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.35–7.27(m,2H),7.19(dd,J＝12.5,4.6Hz,3H),7.13–7.05(m,3H),6.80–6.71(m,2H),3.69(s,3H),2.57(dddd,J＝39.3,13.7,10.2,5.8Hz,2H),2.28(q,J＝9.5Hz,1H),2.10–1.97(m,2H),1.64(dt,J＝14.4,5.3Hz,1H),1.45(dddd,J＝13.2,10.5,7.4,5.7Hz,1H),0.97(d,J＝5.9Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.58,156.33,142.33,130.96,128.33,128.29,125.72,121.85,114.04,55.42,45.12,38.58,33.33,30.63,19.59.
Example 3 (R) -4- (3-methyl-5-phenylpentanamide) benzoic acid methyl ester 3c
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), methyl 4- (3-bromobutyramide) benzoate 1c (62.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give the title compound as a white solid 3c,52mg (yield 76%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.89(d,J＝8.4Hz,2H),7.80(s,1H),7.52(d,J＝8.4Hz,2H),7.17(t,J＝7.4Hz,2H),7.11–7.00(m,3H),4.26(q,J＝7.1Hz,2H),2.54(dddd,J＝41.5,13.7,10.2,5.9Hz,2H),2.32(dd,J＝13.9,5.8Hz,1H),2.07(ddd,J＝30.0,13.7,7.4Hz,2H),1.62(ddt,J＝15.8,10.9,5.6Hz,1H),1.51–1.39(m,1H),1.29(t,J＝7.1Hz,3H),0.96(d,J＝6.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.18,166.23,142.14,142.11,130.65,128.32,128.23,125.74,125.65,118.80,60.85,45.26,38.43,33.24,30.45,19.54,14.26.
Example 4 (R) -3-methyl-5-phenyl-N- (2-methylphenyl) pentanamide 3d
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirring was carried out at room temperature for 30 minutes, and to the reaction system, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N- (2-methylphenyl) butyramide 1d (51.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and stirring was carried out at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =20:1) to give the title compound as a white solid 3d,47mg (yield 83%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ8.25(d,J＝8.2Hz,1H),8.18(s,1H),7.39(d,J＝7.5Hz,1H),7.20(q,J＝7.0Hz,3H),7.13–7.05(m,3H),6.98(t,J＝7.6Hz,1H),2.60(dddd,J＝30.0,13.6,10.3,5.8Hz,2H),2.41(dd,J＝14.0,5.8Hz,1H),2.26(s,3H),2.12(ddd,J＝36.1,13.4,7.2Hz,2H),1.68(td,J＝10.9,9.1,5.0Hz,1H),1.59–1.45(m,1H),1.02(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.67,142.24,138.23,132.80,128.84,128.32,128.29,125.72,125.08,124.28,120.63,45.67,38.60,33.36,30.70,19.66,18.86.
Example 5 (R) -N- (2-methoxyphenyl) -3-methyl-5-phenylpentanamide 3e
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirring was carried out at room temperature for 30 minutes, and to the reaction system, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N- (2-methoxyphenyl) butyramide 1e (54.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and stirring was carried out at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =2:1) to give the title compound as a white solid 3e,38mg (yield 64%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝7.4Hz,1H),7.65(s,1H),7.22–7.16(m,2H),7.11(d,J＝7.8Hz,3H),6.96(t,J＝7.7Hz,1H),6.88(t,J＝7.7Hz,1H),6.79(d,J＝8.0Hz,1H),3.79(s,3H),2.60(dtd,J＝24.1,13.7,5.8Hz,2H),2.37(dd,J＝13.7,5.6Hz,1H),2.11(ddd,J＝26.5,13.3,7.2Hz,2H),1.68(ddt,J＝16.2,10.9,5.6Hz,1H),1.55–1.42(m,1H),1.00(d,J＝6.4Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.46,147.65,142.38,128.31,127.64,125.69,123.51,121.07,119.78,109.81,55.61,45.69,38.65,33.41,30.67,19.64.
Example 6 (R) -3-methyl-5-phenyl-N- (3, 4, 5-trimethoxyphenyl) pentanamide 3f
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N- (3, 4, 5-trimethoxyphenyl) butanamide 1f (66.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =2:1) to give the title compound as a colorless oil 3f,50mg (yield 70%), 92% ee.
1 H NMR(600MHz,CDCl 3 )δ7.27(s,1H),7.22–7.17(m,2H),7.12–7.06(m,3H),6.76(s,2H),3.73(s,9H),2.62(ddd,J＝13.7,10.5,5.6Hz,1H),2.53(ddd,J＝13.7,10.4,6.1Hz,1H),2.35–2.24(m,1H),2.05(tt,J＝13.8,7.9Hz,2H),1.68–1.61(m,1H),1.46(tt,J＝13.2,6.6Hz,1H),0.98(d,J＝6.2Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ170.73,153.20,142.22,134.40,134.14,128.33,128.30,128.26,125.74,97.35,60.89,55.98,45.32,38.51,33.31,30.53,19.58.
EXAMPLE 7 (R) -3-methyl-5-phenyl-N- (4- (trifluoromethyl) phenyl) pentanamide 3g
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N- (4- (trifluoromethyl) phenyl) butyramide 1g (62.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and the reaction system was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a white solid 3g,49mg (yield 73%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.5Hz,2H),7.47(d,J＝8.6Hz,2H),7.32(s,1H),7.20(dd,J＝8.3,6.4Hz,2H),7.14–7.05(m,3H),2.58(dddd,J＝41.0,13.7,10.1,6.0Hz,2H),2.33(dd,J＝13.9,5.8Hz,1H),2.17–1.98(m,2H),1.66(dddd,J＝13.4,10.2,6.3,5.2Hz,1H),1.48(dddd,J＝13.4,10.0,7.8,5.7Hz,1H),0.99(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.97,142.12,140.86,128.40,128.30,126.21(q,J＝4.0Hz),125.85,124.03(q,J＝270.0Hz),119.32,45.35,38.45,33.28,30.50,19.58.
19 F NMR(376MHz,CDCl 3 )δ-62.10.
Example 8 (R) -3-methyl-N- (naphthalen-1-yl) -5-phenylpentanamide 3h
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N- (naphthyl-L-yl) butyramide (58.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid for 3h,40mg (yield 63%), 85% ee.
1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝5.8Hz,2H),7.73–7.65(m,1H),7.60(d,J＝8.0Hz,1H),7.49(s,1H),7.45–7.33(m,3H),7.19(dd,J＝12.3,5.0Hz,2H),7.15–7.05(m,3H),2.74–2.50(m,2H),2.44(dd,J＝13.8,5.8Hz,1H),2.21(dd,J＝13.7,8.2Hz,1H),2.10(dd,J＝12.5,6.3Hz,1H),1.79–1.65(m,1H),1.55–1.46(m,1H),1.04(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.22,142.31,134.06,132.21,128.69,128.36,128.31,127.28,126.20,125.91,125.82,125.76,125.66,121.25,120.67,45.13,38.63,33.35,30.79,19.70.
Example 9 (R) -N-cyclohexyl-3-methyl-5-phenylpentanamide 3i
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-cyclohexylbutyramide 1i (49.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =2:1) to give the title compound as a white solid 3i,31mg (yield 58%), 84% ee.
1 H NMR(400MHz,CDCl 3 )δ7.24–7.16(m,2H),7.14–7.05(m,3H),5.28(s,1H),3.80–3.61(m,1H),2.56(ddp,J＝30.0,13.7,5.8Hz,2H),2.13(dd,J＝12.7,5.2Hz,1H),1.97–1.80(m,4H),1.69–1.51(m,4H),1.48–1.37(m,1H),1.34–1.22(m,2H),1.16–0.98(m,3H),0.93(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.35,142.46,128.31,128.30,125.68,48.06,44.65,38.65,33.34,33.25,33.18,30.64,25.50,24.84,19.51.
EXAMPLE 10 (R) -N-benzyl-3-methyl-5-phenylpentanamide 3j
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), N-benzyl-3-bromobutyramide 1j (51.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =2:1) to give the title compound as a white solid 3j,41mg (yield 73%), 87% ee.
1 H NMR(400MHz,CDCl 3 )δ7.27–7.15(m,7H),7.12–7.03(m,3H),5.73(s,1H),4.34(d,J＝5.7Hz,2H),2.65–2.44(m,2H),2.16(dt,J＝9.6,4.8Hz,1H),2.04–1.89(m,2H),1.61(ddt,J＝15.9,10.9,5.6Hz,1H),1.49–1.35(m,1H),0.93(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ172.14,142.37,138.35,128.64,128.30,128.27,127.78,127.43,125.68,44.37,43.52,38.59,33.31,30.57,19.59.
EXAMPLE 11 (R) -3-phenyl-N-phenylhexanamide 3k
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (1148 mg,3.6mmol,18.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylhexanamide 1k (54.0 mg,0.2 mmol) and (2-iodoethyl) benzene 2a (139.2 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a white solid 3k,33mg (yield 56%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝7.9Hz,2H),7.26–7.15(m,5H),7.13–7.06(m,3H),7.01(t,J＝7.2Hz,1H),2.65–2.48(m,2H),2.23(d,J＝6.9Hz,2H),1.97(q,J＝6.0Hz,1H),1.66–1.51(m,2H),1.37–1.22(m,4H),0.82(t,J＝6.8Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.96,142.44,137.87,128.92,128.34,128.30,125.73,124.17,119.87,42.73,36.01,35.61,35.00,32.97,19.65,14.32.
EXAMPLE 12 (R) -3-phenyl-N-phenyldecanoamide 3l
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.0 mL) of ethylene glycol dimethyl ether nickel bromide (3.1 mg,0.01mmol,10 mol%), ligand L1 (8.0 mg,0.012mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (479.0 mg,1.5mmol,9.0 eq.), manganese powder (16.5 mg,0.3mmol,3.0 eq.), 3-bromo-N-phenyldecanoamide 1L (33.0 mg,0.1 mmol) and (2-iodoethyl) benzene 2a (70.0 mg,0.3mmol,3.0 eq.) and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a white solid 3l,21mg (yield 61%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝7.7Hz,2H),7.27–7.16(m,4H),7.11(d,J＝6.6Hz,3H),7.07–6.98(m,2H),2.58(t,J＝7.9Hz,2H),2.24(d,J＝6.9Hz,2H),1.97(dt,J＝12.6,6.0Hz,1H),1.69–1.58(m,2H),1.41–1.29(m,2H),1.19(s,10H),0.80(t,J＝6.6Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.84,142.46,137.85,128.96,128.37,128.33,125.76,124.20,119.81,42.81,35.61,35.24,33.71,33.02,31.82,29.84,29.27,26.50,22.64,14.08.
EXAMPLE 13 (R) -3-phenyl-N, 6-diphenylhexanamide 3m
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.0 mL) of ethylene glycol dimethyl ether nickel bromide (3.1 mg,0.01mmol,10 mol%), ligand L1 (8.0 mg,0.012mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, and zinc iodide (479.0 mg,1.5mmol,9.0 eq.), manganese powder (16.5 mg,0.3mmol,3.0 eq.), 3-bromo-N, 5-diphenylvaleramide 1m (33.0 mg,0.1 mmol) and 3-iodopropylbenzene 2b (74.0 mg,0.3mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a pale yellow oil 3m,20mg (yield 53%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝7.9Hz,2H),7.27–7.15(m,6H),7.14–6.96(m,8H),2.53(q,J＝7.3Hz,4H),2.31–2.12(m,2H),1.98(dq,J＝12.4,6.2Hz,1H),1.58(d,J＝9.3Hz,4H),1.40(dt,J＝12.1,6.4Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ170.74,142.35,142.31,137.79,128.94,128.36,128.31,128.27,125.78,125.71,124.24,119.88,42.65,36.01,35.50,35.02,33.22,32.96,28.34.
EXAMPLE 14 (S) -6- (5-methylfuran-2-yl) -3-phenyl-N-phenylhexanamide 3N
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.0 mL) of ethylene glycol dimethyl ether nickel bromide (3.1 mg,0.01mmol,10 mol%), ligand L1 (8.0 mg,0.012mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (479 mg,1.5mmol,15.0 eq.), manganese powder (16.5 mg,0.3mmol,3.0 eq.), 3-bromo-5- (5-methylfuran-2-yl) -N-phenylpentanamide 1N (34.0 mg,0.1 mmol) and (2-iodoethyl) benzene 2a (70.0 mg,0.3mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =11:1) to give the title compound as a white solid 3n,24mg (yield 67%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.38(d,J＝7.9Hz,2H),7.29(s,1H),7.18(dt,J＝11.5,7.3Hz,4H),7.07(t,J＝8.6Hz,3H),6.99(t,J＝7.2Hz,1H),5.75(s,2H),2.54(q,J＝7.7,6.5Hz,4H),2.24(d,J＝6.9Hz,2H),2.13(s,3H),1.99(dt,J＝12.7,6.3Hz,1H),1.67(ddd,J＝25.4,14.7,6.4Hz,4H).
13 C NMR(101MHz,CDCl 3 )δ170.69,153.87,150.27,142.17,137.80,128.87,128.33,128.29,125.75,124.20,119.96,105.83,105.51,42.25,35.43,34.69,32.86,31.88,25.14,13.44.
EXAMPLE 15 (R) -3-methyl-N-phenylpentanamide 3o
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, and zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and ethyl iodide 2c (94.0 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3o,35mg (yield 93%), 89% ee.
1 H NMR(600MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.49(s,1H),7.30(t,J＝7.9Hz,2H),7.09(t,J＝7.4Hz,1H),2.36(dd,J＝14.0,6.1Hz,1H),2.11(dd,J＝14.0,8.2Hz,1H),1.99(dq,J＝14.0,7.0Hz,1H),1.43(tt,J＝13.2,7.4Hz,1H),1.26(dq,J＝13.9,7.4,6.2Hz,1H),0.98(d,J＝6.6Hz,3H),0.91(t,J＝7.4Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ171.18,137.94,128.89,124.14,119.89,45.12,32.41,29.38,19.17,11.31.
EXAMPLE 16 (R) -3-methyl-N, 6-diphenylhexanamide 3p
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, and zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 3-iodopropylbenzene 2d (148.0 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3p,34mg (yield 61%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝7.9Hz,2H),7.26–7.17(m,4H),7.15–7.05(m,4H),7.02(t,J＝7.4Hz,1H),2.53(h,J＝6.9Hz,2H),2.26(q,J＝9.3Hz,1H),2.03(q,J＝7.8Hz,2H),1.64–1.53(m,2H),1.37(td,J＝11.9,10.3,5.4Hz,1H),1.21(dd,J＝10.5,6.8Hz,1H),0.92(d,J＝6.1Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.80,142.48,137.84,128.96,128.35,128.26,125.67,124.22,119.84,45.50,36.37,35.98,30.75,28.86,19.64.
EXAMPLE 17 (R) -3-methyl-N, 7-diphenylvaleramide 3q
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirring was carried out at room temperature for 30 minutes, and to the reaction system, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and (4-iodobutyl) benzene 2e (156.0 mg,0.6mmol,3.0 eq.) were added, and stirring was carried out at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3q,38mg (yield 56%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝7.9Hz,2H),7.28(s,1H),7.20(dt,J＝14.7,7.3Hz,4H),7.09(t,J＝6.7Hz,3H),7.01(t,J＝7.4Hz,1H),2.52(t,J＝7.7Hz,2H),2.30–2.19(m,1H),2.07–1.93(m,2H),1.53(p,J＝7.2,6.5Hz,2H),1.32(dt,J＝12.8,6.0Hz,2H),1.21–1.13(m,2H),0.89(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.99,142.59,137.88,128.92,128.35,128.20,125.58,124.18,119.87,45.46,36.59,35.84,31.51,30.79,26.57,19.66.
EXAMPLE 18 (R) -3-methyl-N-phenyldecanoamide 3R
To a 10mL reaction tube, under nitrogen protection, was added a mixed solvent of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol (1:3, 1.5 mL), stirred at room temperature for 30 minutes, and to the reaction system was added zinc iodide (957.0 mg,3.0mmol,15.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 1-iodoheptane 2f (144.0 mg,0.6mmol,3.0 eq.) stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a white solid 3r,33mg (yield 59%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.31(q,J＝8.1,6.9Hz,3H),7.09(t,J＝7.4Hz,1H),2.35(dd,J＝13.3,5.3Hz,1H),2.08(ddd,J＝19.1,12.5,6.3Hz,2H),1.44–1.19(m,14H),0.98(d,J＝6.3Hz,3H),0.88(t,J＝6.8Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ171.05,137.93,128.93,124.15,119.85,45.59,36.84,31.86,30.89,29.77,29.58,29.27,26.97,22.64,19.67,14.08.
EXAMPLE 19 (R) -3-methyl-5-phenoxy-N-phenylpentanamide 3s
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and (2-iodoethoxy) benzene 2g (149.0 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give the title compound as a white solid 3s,38mg (yield 67%), 92% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(s,1H),7.44(d,J＝7.9Hz,2H),7.25–7.15(m,4H),7.02(t,J＝7.3Hz,1H),6.93–6.76(m,3H),3.97(ddt,J＝15.8,9.4,5.2Hz,2H),2.46–2.10(m,3H),1.77(ddq,J＝57.8,13.0,6.1Hz,3H),1.01(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.54,158.68,137.87,129.49,128.94,124.20,120.81,119.85,114.42,65.90,44.97,35.39,28.54,19.84.
EXAMPLE 20 (R) -3-methyl-5- (naphthalen-2-yl) -N-phenylpentanamide 3t
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 2- (2-iodoethyl) naphthalene 2h (169.0 mg,0.6mmol,3.0 eq.) were added, and the reaction system was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a white solid 3t,38mg (yield 59%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.93(d,J＝8.6Hz,1H),7.80–7.72(m,1H),7.62(d,J＝8.1Hz,1H),7.48–7.33(m,4H),7.34–7.27(m,1H),7.27–7.16(m,3H),7.13(s,1H),7.01(t,J＝7.3Hz,1H),3.03(dddd,J＝47.6,13.9,10.8,5.5Hz,2H),2.35(dd,J＝13.2,5.1Hz,1H),2.25–2.05(m,2H),1.77(ddt,J＝16.1,10.8,5.4Hz,1H),1.59(dddd,J＝13.2,10.8,7.6,5.5Hz,1H),1.07(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.62,138.44,137.78,133.88,131.71,128.94,128.79,126.60,125.84,125.79,125.57,125.43,124.25,123.65,119.88,45.37,37.95,31.12,30.59,19.70.
EXAMPLE 21 (R) -5- (2, 3-Dihydrobenzofuran-6-yl) -3-methyl-N-phenylpentanamide 3u
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%) of ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 6- (2-iodoethyl) -2, 3-dihydrobenzofuran 2i (164.0 mg,0.6mmol,3.0 eq.) were added, and the reaction system was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3u,42mg (yield 68%), 87% ee.
1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝7.9Hz,2H),7.31(t,J＝7.8Hz,2H),7.23(s,1H),7.10(t,J＝7.3Hz,1H),7.01(s,1H),6.90(d,J＝7.9Hz,1H),6.69(d,J＝8.1Hz,1H),4.53(t,J＝8.7Hz,2H),3.14(t,J＝8.6Hz,2H),2.72–2.48(m,2H),2.38(dd,J＝13.4,5.5Hz,1H),2.13(ddt,J＝20.2,13.6,7.6Hz,2H),1.70(ddt,J＝15.5,10.7,5.7Hz,1H),1.52(dq,J＝11.5,6.7,5.8Hz,1H),1.06(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.69,158.16,137.85,134.27,128.94,127.62,127.01,124.80,124.19,119.81,108.90,71.10,45.42,39.06,32.70,30.51,29.75,19.63.
EXAMPLE 22 (R) -3-methyl-N-phenyl-6- (thiophen-2-yl) hexanamide 3v
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirring was carried out at room temperature for 30 minutes, and to the reaction system, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 2- (3-iodopropyl) -thiophene 2j (151.0 mg,0.6mmol,3.0 eq.) were added, and stirring was carried out at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3v,45mg (yield 78%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.51(d,J＝7.8Hz,2H),7.31(t,J＝7.9Hz,2H),7.23(s,1H),7.15–7.06(m,2H),6.90(dd,J＝5.1,3.4Hz,1H),6.80–6.69(m,1H),2.92–2.73(m,2H),2.35(q,J＝9.3Hz,1H),2.20–2.04(m,2H),1.82–1.67(m,2H),1.48(ddt,J＝15.7,10.5,5.2Hz,1H),1.32(dt,J＝10.3,6.3Hz,1H),1.00(d,J＝6.1Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.75,145.34,137.83,128.96,126.66,124.24,124.07,122.83,119.86,45.40,36.11,30.63,29.95,29.17,19.62.
EXAMPLE 23 (R) -5- (3-chlorophenyl) -3-methyl-N-phenylpentanamide 3w
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirring was carried out at room temperature for 30 minutes, and to the reaction system, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 1-chloro-3- (2-iodoethyl) phenyl 2k (160.0 mg,0.6mmol,3.0 eq.) were added, and stirring was carried out at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3w,41mg (yield 68%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝7.8Hz,2H),7.31(t,J＝7.9Hz,3H),7.22–7.13(m,3H),7.10(t,J＝7.4Hz,1H),7.05(d,J＝7.1Hz,1H),2.74–2.51(m,2H),2.38(dd,J＝13.5,5.5Hz,1H),2.14(ddt,J＝19.0,12.6,7.1Hz,2H),1.72(dq,J＝15.9,5.4Hz,1H),1.58–1.47(m,1H),1.06(d,J＝6.3Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.51,144.32,137.77,134.06,129.60,128.97,128.40,126.52,125.96,124.29,119.87,45.31,38.29,33.07,30.53,19.57.
EXAMPLE 24 (R) -4- (3-methyl-5-oxo-5- (anilinopentyl) phenylacetate 3x
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and stirred at room temperature for 30 minutes, and to the reaction system were added zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 2L 4- (2-iodoethyl) phenylacetate (174.0 mg,0.6mmol,3.0 eq.) and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3x,33mg (yield 51%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝8.0Hz,2H),7.31(t,J＝7.8Hz,2H),7.24(s,1H),7.17(d,J＝8.3Hz,2H),7.10(t,J＝7.4Hz,1H),6.98(d,J＝8.4Hz,2H),2.65(dtt,J＝24.0,13.8,5.8Hz,2H),2.36(td,J＝9.3,4.2Hz,1H),2.29(s,3H),2.13(tt,J＝13.4,7.5Hz,2H),1.73(ddt,J＝15.5,10.6,5.5Hz,1H),1.59–1.48(m,1H),1.06(d,J＝6.2Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.57,169.73,148.67,139.89,137.84,129.21,128.95,124.21,121.35,119.82,45.35,38.49,32.73,30.55,21.11,19.58.
EXAMPLE 25 (R) -4-methyl-6-oxo-6- (aniline) hexyl benzyl ester 3y
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L2 (15.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 3-iodopropylbenzyl ester 2m (174.0 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give the title compound as a white solid 3y,33mg (yield 50%), 90% ee.
1 H NMR(400MHz,CDCl 3 )δ8.09–7.99(m,2H),7.56–7.50(m,3H),7.43(t,J＝7.7Hz,2H),7.30(t,J＝7.9Hz,2H),7.09(t,J＝7.4Hz,1H),4.50(dt,J＝11.4,6.5Hz,1H),4.35(dt,J＝11.2,6.6Hz,1H),2.50(dd,J＝13.5,5.3Hz,1H),2.24(ddd,J＝32.7,13.6,7.5Hz,2H),1.88(dq,J＝12.9,6.4Hz,1H),1.73(dq,J＝13.8,6.7Hz,1H),1.09(d,J＝6.5Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.40,166.91,137.90,133.00,130.13,130.07,129.56,128.94,128.38,124.20,119.78,62.86,44.79,35.38,28.23,19.76.
EXAMPLE 26 (R) -5- (1, 3-Dioxolan-2-yl) -3-methyl-N-phenylpentanamide 3z
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%) of ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and 2- (2-iodoethyl) -1, 3-dioxolane 2N (137.0 mg,0.6mmol,3.0 eq.) were added, and the mixture was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give the title compound as a colorless oil 3z,33mg (yield 62%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.51(d,J＝7.9Hz,2H),7.40(s,1H),7.30(t,J＝7.9Hz,2H),7.09(t,J＝7.4Hz,1H),4.85(t,J＝4.7Hz,1H),4.02–3.90(m,2H),3.90–3.79(m,2H),2.38(q,J＝9.2Hz,1H),2.18–2.04(m,2H),1.71(ddt,J＝19.0,13.6,7.1Hz,2H),1.52(ddt,J＝15.8,10.6,5.4Hz,1H),1.37(dq,J＝17.9,6.5Hz,1H),1.01(d,J＝6.1Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.71,137.93,128.93,124.14,119.81,104.58,64.83,64.81,45.10,31.13,30.72,30.66,19.63.
EXAMPLE 27 (R) -5- (benzyloxy) -3-methyl-N-phenylpentanamide 3aa
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol (1:3, 1.5 mL) was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and ((2-iodoethoxy) methyl) benzene 2o (157.0 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give the title compound as a white solid 3aa,45mg (yield 75%), 93% ee.
1 H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.32–7.19(m,7H),7.19–7.10(m,2H),6.95(t,J＝7.3Hz,1H),4.43(s,2H),3.53(dddd,J＝37.3,9.5,6.7,5.1Hz,2H),2.37–2.07(m,3H),1.60(hept,J＝8.2Hz,2H),0.95(d,J＝6.6Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ170.77,138.09,137.89,128.72,128.49,128.00,127.85,123.78,119.57,73.38,68.66,44.63,35.24,29.18,20.05.
Example 28 (R) -5- ((tert-Butyldimethylsilanyloxy) -3-methyl-N-phenylpentanamide 3ab
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.0 mL) of ethylene glycol dimethyl ether nickel bromide (3.1 mg,0.01mmol,10 mol%), ligand L1 (8.0 mg,0.012mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, zinc iodide (574.2 mg,1.8mmol,9.0 eq.), manganese powder (16.5 mg,0.3mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (24.0 mg,0.1 mmol) and tert-butyl- (2-iodoethoxy) dimethylsilane 2p (103.0 mg,0.3mmol,3.0 eq.) were added, and the reaction system was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a colorless oil 3ab,21mg (yield 56%), 89% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.35–7.24(m,3H),7.09(t,J＝7.4Hz,1H),3.59(t,J＝6.6Hz,2H),2.42–2.29(m,1H),2.16–1.98(m,2H),1.56–1.44(m,2H),1.42–1.18(m,8H),0.98(d,J＝6.3Hz,3H),0.89(s,9H),0.04(s,6H).
13 C NMR(101MHz,CDCl 3 )δ170.96,137.92,128.94,124.16,119.81,63.27,45.58,36.78,32.81,30.87,29.56,26.96,25.97,25.77,19.66,18.36,5.27.
EXAMPLE 29 (R) -4-cyclohexyl-3-methyl-N-phenylpentanamide 3ac
To a 10mL reaction tube under nitrogen atmosphere, a mixed solvent (1:3, 1.5 mL) of ethylene glycol dimethyl ether nickel bromide (6.2 mg,0.02mmol,10 mol%), ligand L1 (16.0 mg,0.024mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol was added, and the reaction system was stirred at room temperature for 30 minutes, and zinc iodide (1148.0 mg,3.6mmol,18.0 eq.), manganese powder (33.0 mg,0.6mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (48.0 mg,0.2 mmol) and (iodomethyl) cyclohexane 2q (134.0 mg,0.6mmol,3.0 eq.) were added, and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a colorless oil 3ac,25mg (yield 49%), 87% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝7.9Hz,2H),7.31(t,J＝7.8Hz,3H),7.09(t,J＝7.4Hz,1H),2.33(dd,J＝13.6,5.5Hz,1H),2.18(dq,J＝13.7,6.9,6.2Hz,1H),2.08(dd,J＝13.6,8.2Hz,1H),1.67(q,J＝14.9,11.5Hz,5H),1.33–1.04(m,6H),0.97(d,J＝6.5Hz,3H),0.84(dt,J＝20.5,11.3Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ170.98,137.92,128.94,124.15,119.85,45.94,44.83,34.83,34.04,32.90,27.78,26.62,26.38,26.27,19.88.
Example 30 (3R) -3,6, 10-trimethyl-N-phenylundecanamide 3ad
To a 10mL reaction tube, under nitrogen protection, was added a mixed solvent of ethylene glycol dimethyl ether nickel bromide (3.1 mg,0.01mmol,10 mol%), ligand L1 (8.0 mg,0.012mmol,12 mol%), isobutyl alcohol and sec-amyl alcohol (1:3, 1.0 mL), stirred at room temperature for 30 minutes, zinc iodide (479.0 mg,1.5mmol,15.0 eq.), manganese powder (16.5 mg,0.3mmol,3.0 eq.), 3-bromo-N-phenylbutyramide 1a (24.0 mg,0.1 mmol) and 1-iodo-3, 7-dimethyloctane 2r (80.0 mg,0.3mmol,3.0 eq.) were added and stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction system to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =15:1) to give the title compound as a white solid 3ad,21mg (yield 70%), 87%/88% ee.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝8.0Hz,3H),7.30(t,J＝7.8Hz,2H),7.09(t,J＝7.4Hz,1H),2.37(ddd,J＝14.2,8.7,5.7Hz,1H),2.07(ddt,J＝33.0,18.5,7.3Hz,2H),1.51(dp,J＝13.2,6.6Hz,1H),1.40–1.07(m,11H),0.98(dd,J＝6.4,2.7Hz,3H),0.93–0.79(m,9H).
13 C NMR(101MHz,CDCl 3 )δ171.15,137.94,128.89,124.14,119.92,45.63,45.41,39.30,39.28,37.37,37.07,34.30,34.27,34.22,34.18,32.98,32.85,31.25,31.13,27.92,24.75,24.69,22.68,22.58,19.81,19.72,19.62,19.56.
While the methods of this invention have been described in terms of several embodiments, it will be apparent to those of skill in the relevant art that variations and combinations of the methods and applications described herein can be made to practice and use the techniques of this invention within the spirit and scope of the invention. Those skilled in the art can, given the benefit of this disclosure, suitably modify the reaction parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (6)
1. A preparation method of chiral beta-alkylamide compounds,
wherein: the preparation method comprises the following steps: under the protection of inert gas, carrying out coupling reaction on a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent in the presence of a catalyst, a ligand, a reducing agent and an additive to obtain a compound shown in a formula (I);
wherein each R is 1 And R is 2 Independently C 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 6-10 aryl-C 1-6 Alkylene or heteroaryl-C consisting of 5-12 atoms 1-6 Alkylene group, wherein the C 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 6-10 aryl-C 1-6 Alkylene and heteroaryl-C consisting of 5 to 12 atoms 1-6 Alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, tert-butyldimethylsilyl, C 3-6 Cycloalkyl, heterocyclyl of 3-6 atoms, C 6-10 Aryl, C 6-10 aryl-C 1-4 The substituents of the alkylene and heteroaryl consisting of 5 to 10 atoms are substituted;
R 3 independently C 1-4 Alkyl, C 3-6 Cycloalkyl or C 6-10 Aryl, wherein said C 1-4 Alkyl, C 3-6 Cycloalkyl and C 6-10 Aryl is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and C 6-10 Aryl substituents are substituted;
wherein the catalyst is zero-valent nickel or divalent nickel, and the ligand is selected from the following compounds:
the additive is zinc iodide, the reducing agent is manganese metal, the property is powder, and the mesh number of the particles is 200-500 meshes.
2. The method of claim 1, wherein each R 1 And R is 2 Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene or heteroaryl-C consisting of 5-12 atoms 1-4 Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, C 6-10 aryl-C 1-4 Alkylene and heteroaryl-C consisting of 5 to 12 atoms 1-4 Alkylene is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 、-OC(O)CH 3 、-OC(O)C 6 H 5 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy, isopropoxy, tert-butyldimethylsilyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, dioxacyclopentyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,Substituted with piperazinyl, morpholinyl, phenyl, naphthyl, phenylmethylene, phenylethenyl, benzofuranyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl;
R 3 independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from D, F, cl, br, I, oxo, -CN, -OH, -NH 2 、-COOCH 3 、-COOCH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 Substituted with methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and naphthyl.
3. The production method according to claim 1, wherein the compound represented by the formula (I) comprises at least one of the following compounds:
4. the preparation method according to claim 1, wherein the catalyst is Ni (cod) 2 Nickel chloride, nickel bromide, nickel iodideNickel chloride of ethylene glycol dimethyl ether, nickel bromide of ethylene glycol dimethyl ether, nickel acetylacetonate or nickel acetate.
5. The process according to claim 1, wherein the organic solvent is an alcohol solvent, and the organic solvent is ethanol, n-propanol, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, sec-amyl alcohol or n-hexanol.
6. The preparation method according to claim 1, wherein the reaction temperature is 15-35 ℃; the reaction time is 18-30 h.
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| CN106317055A (en) * | 2015-07-02 | 2017-01-11 | 中国科学院上海药物研究所 | Compound with kinase inhibition activity and its preparation method and use |
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