CN113173854B - Preparation method of chiral beta-acyloxy carboxylic ester compound - Google Patents
Preparation method of chiral beta-acyloxy carboxylic ester compound Download PDFInfo
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- CN113173854B CN113173854B CN202110444041.XA CN202110444041A CN113173854B CN 113173854 B CN113173854 B CN 113173854B CN 202110444041 A CN202110444041 A CN 202110444041A CN 113173854 B CN113173854 B CN 113173854B
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- Prior art keywords
- alkyl
- substituted
- unsubstituted
- aryl
- hetero atom
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 154
- 238000006243 chemical reaction Methods 0.000 claims abstract description 113
- 239000002904 solvent Substances 0.000 claims abstract description 101
- 238000000034 method Methods 0.000 claims abstract description 98
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 79
- -1 carboxylic ester compound Chemical class 0.000 claims abstract description 56
- 238000007259 addition reaction Methods 0.000 claims abstract description 47
- 239000003446 ligand Substances 0.000 claims abstract description 45
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 39
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims abstract description 34
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 239000012634 fragment Substances 0.000 claims abstract description 26
- 239000007800 oxidant agent Substances 0.000 claims abstract description 23
- 230000001590 oxidative effect Effects 0.000 claims abstract description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 222
- 125000000217 alkyl group Chemical group 0.000 claims description 182
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 165
- 125000003118 aryl group Chemical group 0.000 claims description 140
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 124
- 229910052760 oxygen Inorganic materials 0.000 claims description 112
- 229910052717 sulfur Inorganic materials 0.000 claims description 111
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 98
- 125000001072 heteroaryl group Chemical group 0.000 claims description 80
- 229910052736 halogen Inorganic materials 0.000 claims description 77
- 150000002367 halogens Chemical class 0.000 claims description 77
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 47
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 125000003342 alkenyl group Chemical group 0.000 claims description 30
- 125000002950 monocyclic group Chemical group 0.000 claims description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 22
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
- 238000007069 methylation reaction Methods 0.000 claims description 22
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 19
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 229940046011 buccal tablet Drugs 0.000 claims description 16
- 239000006189 buccal tablet Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- 125000002619 bicyclic group Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical group O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000000732 arylene group Chemical group 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 239000011630 iodine Substances 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 230000011987 methylation Effects 0.000 claims description 7
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003158 alcohol group Chemical group 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- 239000012022 methylating agents Substances 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 claims description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims description 2
- PAGZTSLSNQZYEV-UHFFFAOYSA-L 2,2-dimethylpropanoate;palladium(2+) Chemical compound [Pd+2].CC(C)(C)C([O-])=O.CC(C)(C)C([O-])=O PAGZTSLSNQZYEV-UHFFFAOYSA-L 0.000 claims description 2
- JTXMVXSTHSMVQF-UHFFFAOYSA-N 2-acetyloxyethyl acetate Chemical compound CC(=O)OCCOC(C)=O JTXMVXSTHSMVQF-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 229940070710 valerate Drugs 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical group CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 10
- 239000007937 lozenge Substances 0.000 claims 7
- 230000035484 reaction time Effects 0.000 claims 3
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 84
- 239000000047 product Substances 0.000 description 58
- 238000004440 column chromatography Methods 0.000 description 51
- 239000003208 petroleum Substances 0.000 description 51
- 230000014759 maintenance of location Effects 0.000 description 45
- 238000001514 detection method Methods 0.000 description 44
- 239000007788 liquid Substances 0.000 description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 9
- PZVKSFBOPQYWGM-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;pyridine Chemical compound C1CN=CO1.C1=CC=NC=C1 PZVKSFBOPQYWGM-UHFFFAOYSA-N 0.000 description 7
- 150000001336 alkenes Chemical class 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012159 carrier gas Substances 0.000 description 3
- 238000005356 chiral GC Methods 0.000 description 3
- 239000013256 coordination polymer Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012263 liquid product Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910003445 palladium oxide Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 235000005749 Anthriscus sylvestris Nutrition 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QSRRZKPKHJHIRB-UHFFFAOYSA-N methyl 4-[(2,5-dichloro-4-methylthiophen-3-yl)sulfonylamino]-2-hydroxybenzoate Chemical compound C1=C(O)C(C(=O)OC)=CC=C1NS(=O)(=O)C1=C(Cl)SC(Cl)=C1C QSRRZKPKHJHIRB-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
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Abstract
The invention provides a preparation method of chiral beta-acyloxy carboxylic ester compounds. Specifically discloses a preparation method of a carboxylic ester compound, which comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound containing a fragment II, a compound containing a tablet section III and carbon monoxide (CO) to obtain a compound containing a fragment I-1 and/or a compound containing a tablet section I-2. The method has the advantages of high yield, wide substrate universality, good functional group compatibility, mild reaction conditions and simple operation.
Description
Technical Field
The invention relates to a preparation method of chiral beta-acyloxy carboxylic ester compounds.
Background
Beta-acyloxycarboxylate compounds having optical activity and derivatives thereof such as beta-hydroxycarboxylic acid esters (acids) are widely present in pharmaceutical molecules as well as fine chemical products, and are synthetic building blocks widely used in organic synthesis. Thus, the development of methods for synthesizing such compounds is significant. The synthesis of such compounds by oxycarbonylation of inexpensive and readily available olefins as starting materials is the most straightforward and efficient process. Methods for synthesizing such compounds have been extensively studied over the last decades. Among them, asymmetric hydrogenation of beta-carbonyl carboxylates catalyzed by transition metals such as ruthenium, iridium, rhodium, etc. is the most frequently and widely used method for synthesizing chiral beta-hydroxycarboxylic esters at present (Noyori, R.Angew.Chem.Int.Ed.2002,41,2008;Xie,J.—h.; liu, x.—y.; yang, x.—h.; xie, j.—b.; wang, l.—x.; zhou, q.— L.Angew.Chem., int.Ed.2012,51,201;Jeulin,S.; duprat de Paule, s.; ratovelomanana Vidal, v.; genet, j.—p.; champion, n.; dellis, P.Angew.Chem., int.Ed.2004,43,320). However, such processes, while capable of achieving high enantioselective hydrogenation, require the preparation of complex β -carbonyl carboxylate precursors, poor functional group compatibility, and high pressure hydrogen conditions. In addition, asymmetric Aldol reactions of aldehydes and silyl enol ethers (Keck, g.e.; krishnamurthy, d.j.am.chem.soc.1995,117,2363; denmark, s.e.; wynn, t.; beuter, g.l.j.am.chem.soc.2002,124,13405; denmark, s.; beuter, g.l.; wynn, t.; eastgate, m.d.j.am.chem.soc.2005,127, 3774) are also a class of methods for synthesizing chiral β -hydroxycarboxylic acid esters, but their reaction precursors, aldehyde and silyl enol ethers, are not readily synthesized, have a very limited substrate range, and are sensitive to reaction conditions and are not useful. Therefore, there is an urgent need in the art for a preparation method of beta-acyloxycarboxylate compounds and derivatives thereof that can achieve high enantioselectivity with high efficiency, simplicity and mild conditions.
Although transition metal palladium catalyzed asymmetric oxycarbonylation has been reported earlier (Tietze, l.f.; zinnglebe, j.; spiegl, d.a.; stecker, f. Hetercycles 2007,74,473; tietze, l.f.; spiegl, d.a.; stecker, f.; major, j.; raith, c.; groβe, c.chem.; jacenkrol, s.; hierold, j.; ma, l.; waldecker, b.chem.; eur.j.2014,20,8628.; it is limited to intramolecular asymmetric oxycarbonylation and has not been reported for intermolecular asymmetric oxycarbonylation. The difficulty is that, firstly, the start-up of intermolecular palladium oxide is difficult, and secondly, the enantioselective control of the reaction is difficult to achieve in the presence of the strong ligand carbon monoxide. The desire to achieve palladium-catalyzed, highly enantioselective oxycarbonylation reactions therefore requires chiral ligands to increase Pd (OAc) 2 Lewis acidity of (C)So that the palladium oxide can be smoothly carried out, the enantioselectivity can be effectively controlled, and the asymmetric oxo-carbonylation reaction is finally realized.
Disclosure of Invention
The invention aims to overcome the defects of poor universality, harsh reaction conditions and poor functional group compatibility of an asymmetric hydrogenation substrate of beta-carbonyl carboxylate in the prior art, and provides a preparation method of chiral beta-acyloxy carboxylate compounds. The method has the advantages of high yield, wide substrate universality, good functional group compatibility, mild reaction conditions and simple operation.
The invention solves the technical problems through the following technical proposal.
The invention provides a preparation method of a carboxylic ester compound, which comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound containing a fragment II, a compound containing a tablet section III and carbon monoxide (CO) to obtain a compound containing a fragment I-1 and/or a compound containing a tablet section I-2;
wherein the fragment II is
The fragment III is
The fragment I-1 is
Wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
the fragment I-2 is
Wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand
Wherein R is 5 And R is 6 Independently is hydrogen, R 5-1 Substituted or unsubstituted C 1 -C 10 Alkyl, R 5-2 Substituted or unsubstituted C 3 -C 8 Cycloalkyl, or R 5-3 Substituted or unsubstituted C 6 -C 30 An aryl group;
R 7 is hydrogen, R 7-1 Substituted or unsubstituted C 1 -C 10 Alkyl, or R 7-2 Substituted or unsubstituted C 6 -C 30 An aryl group;
when the oxazoline ligand is
When (I)>
Wherein the carbon noted is chiral carbon of the S configuration;
when the oxazoline ligand is
When (I)>
In this, the carbon marked by x is chiral carbon of the R configuration.
In the addition reaction, the solvent may be a conventional solvent in the art, and preferably, the solvent is one or more of an alkane solvent, a substituted aryl solvent, a nitrile solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, an ester solvent and an amide solvent. The alkane solvent is preferably n-hexane. The substituted aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, toluene and trifluoromethylbenzene. The nitrile solvent is preferably acetonitrile. The halogenated hydrocarbon solvent is preferably dichloromethane and chloroform. The ether solvent is preferably one or more of tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, ethyl tertiary butyl ether, anisole, ethylene glycol dimethyl ether and 1, 4-dioxane. The ketone solvent is preferably acetone. The ester solvent is preferably ethyl acetate and/or ethylene glycol diacetate. The amide solvent is preferably N, N-Dimethylformamide (DMF). More preferably, the solvent is an ether solvent and/or a halogenated hydrocarbon solvent; further, the solvent is diethyl ether and/or dichloromethane.
In the addition reaction, the amount of the solvent to be used is not particularly limited as long as the reaction is not affected. The solvent may be subjected to anhydrous treatment (the operation and method of anhydrous treatment are conventional in the art). Preferably, the concentration of the compound of the tablet segment II in the solvent may be conventional in the art, preferably 0.01 to 5.00mol/L (e.g. 0.625 or 2.00 mol/L), and may be preferably 0.01 to 0.20mol/L.
In the addition reaction, the palladium catalyst may be one or more of palladium acetate, palladium trifluoroacetate, palladium quaternary valerate, palladium dichlorodiacetonitrile, bis (benzonitrile) palladium chloride, palladium bromide, palladium iodide, palladium tetrafluoroborate, palladium hexafluoroacetylacetonate, bis (acetylacetonate), palladium tetrafluoroacetonitrile, palladium pivalate, (1 e,4 e) -bis (dibenzylideneacetone) palladium, bis (dibenzylideneacetone) dipalladium and tris (dibenzylideneacetone) dipalladium, which are conventional in the art; more preferably, the palladium catalyst is palladium acetate.
The palladium catalyst may be used in the addition reaction in amounts conventional in such reactions in the art. Preferably, the molar ratio of the palladium catalyst to the compound of the buccal tablet segment II is (1-50): 100; preferably (1 to 10): 100; for example 5:100 or 10:100.
The amount of oxazoline ligand used in the addition reaction may be that which is conventional in such reactions in the art. The mol ratio of the oxazoline ligand to the compound in the buccal tablet section II is (1-75): 100, e.g. 7.5:100 or 15:100.
In the addition reaction, the molar ratio of the palladium catalyst to the oxazoline ligand may be a molar ratio conventional in such reactions, preferably 1: (0.5-3), e.g., 1:1.5.
In the addition reaction, the oxidizing agent may be an oxidizing agent conventional in the art for such reactions, preferably the oxidizing agent is benzoquinone and/or PhI (OAc) 2 。
In the addition reaction, the molar ratio of the oxidizing agent to the compound of the buccal tablet segment II is preferably (1.0 to 5.0): 1, and may be (1.0 to 3.0): 1, for example, 1.2: 1. or 3:1.
In the addition reaction, the molar ratio of the compound of the buccal tablet stage III to the compound of the buccal tablet stage II is preferably (1.0 to 100): 1, more preferably (2.5 to 10): 1, for example 5:1 or 10:1.
In the addition reaction, the temperature of the addition reaction can be a temperature which is conventional in the art, preferably, the temperature of the addition reaction is-20-30 ℃, and can also be 0-20 ℃.
In the addition reaction, the addition reaction may be carried out under a protective gas. The shielding gas can be nitrogen and/or argon.
In the addition reaction, the progress of the addition reaction can be monitored by methods conventional in the art (e.g., TLC, HPLC, HNMR), preferably by the disappearance of the compound from segment II or by no longer reacting as an endpoint of the reaction. The time of the addition reaction may be 1 to 168 hours, preferably 10 to 72 hours, for example 16 hours, 24 hours, 36 hours, 48 hours or 72 hours.
Preferably, the addition reaction further comprises the following post-treatment steps: adding solvent into the reaction solution, concentrating, and purifying. In the post-treatment step, the solvent is an alcohol solvent (such as methanol), or a ketone solvent (such as acetone) and water.
In one embodiment of the invention, certain groups are defined as follows, undefined groups are as described above (hereinafter referred to as one of the schemes): r is R 5-1 、R 5-2 、R 5-3 、R 7-1 And R is 7-2 Independently 1 or more, when multipleAnd when the two are the same or different, the plurality of the two are 2, 3 or 4.
In one embodiment: when R is 5 And R is 6 Independently unsubstituted C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 4 Alkyl groups such as methyl or ethyl.
In one embodiment: when R is 5 And R is 6 Independently unsubstituted C 3 -C 8 In the case of cycloalkyl, said C 3 -C 8 Cycloalkyl radicals are C 3 -C 6 Monocyclic cycloalkyl groups, such as cyclopentyl or cyclohexyl.
In one embodiment: when R is 5 And R is 6 Independently unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl groups such as phenyl.
In one embodiment: when R is 7 Is unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl groups such as phenyl.
In one embodiment: r is R 5 And R is 6 Independently hydrogen, unsubstituted C 1 -C 10 Alkyl, unsubstituted C 3 -C 8 Cycloalkyl, or unsubstituted C 6 -C 30 Aryl groups.
In one embodiment: r is R 7 Is unsubstituted C 6 -C 30 Aryl groups.
In one embodiment: r is R 5 And R is 6 Identical, or R 5 And R is 6 Different, and one is H.
In one embodiment: r is R 5 And R is 6 Independently hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, or phenyl.
In one embodiment: r is R 7 Is phenyl.
In one embodiment:
R 5 and R is 6 Independently hydrogen, unsubstituted C 1 -C 10 Alkyl, unsubstitutedC of (2) 3 -C 8 Cycloalkyl, or unsubstituted C 6 -C 30 An aryl group;
R 7 is unsubstituted C 6 -C 30 Aryl groups.
In one embodiment: the oxazoline ligand is any one of the following compounds,
in one embodiment of the present invention, the preparation method of the carboxylic ester compound is the following method one or the following method two;
the method comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound shown in a formula II-A, a compound shown in a formula III' and carbon monoxide (CO) to obtain a compound shown in a formula I-1-A and/or a compound shown in a formula I-2-A;
the second method is as follows: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound shown in a formula II-B, a compound shown in a formula III' and carbon monoxide (CO) to obtain a compound shown in a formula I-1-B and/or a compound shown in a formula I-2-B;
In the first method and the second method, the operation and the conditions of the addition reaction are as described in any one of the previous claims;
wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
R 1 is hydrogen, or R 1-1 Substituted or unsubstituted C 1 -C 30 An alkyl group;
R 1-1 cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl, R 1-1a Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, C, wherein the hetero atoms are one or more selected from N, O and S 2 -C 10 Alkenyl, -O (CH) 2 ) n R 1-1b 、-S(＝O) 2 R 1-1c 、-OC(＝O)R 1-1d 、-C(＝O)OR 1-1e 、
-C(＝O)R 1-1h Or (b)
n is an integer of 0 to 10;
R 1-1a is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, cyano, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group;
R 1-1b is R 1-1b-1 Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, wherein the hetero atoms are one or more selected from N, O and S,
R 1-1b-1 Is nitro, aldehyde, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, -S (=o) 2 R 1-1b-1a 、
-C(＝O)OR 1-1b-1f or-C (=O) R 1-1b-1g ；
R 1-1b-1a 、R 1-1b-1b 、R 1-1b-1c 、R 1-1b-1d And R is 1-1b-1e Independently C 1 -C 10 An alkyl group;
R 1-1b-1f and R is 1-1b-1g Independently C 2 -C 10 Alkenyl, or by one or more C 1 -C 10 An alkyl substituted or unsubstituted "heteroatom selected from one or more of N, O and S, a 5-to 15-membered heteroaryl having 1-4 heteroatoms;
R 1-1c 、R 1-1f and R is 1-1g Independently hydrogen, C 6 -C 30 Aryl or p-toluenesulfonyl;
R 1-1d Is R 1-1d-1 Substituted or unsubstituted C 1-10 Alkyl, R 1-1d-2 Substituted or unsubstituted C 2-10 Alkenyl, R 1-1d-3 Substituted or unsubstituted C 2-10 Alkynyl, R 1-1d-4 Substituted or unsubstituted C 6-30 Aryl, R 1-1d-5 A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R 1-1d-1 is-OR 1-1d-1a Or (b)
R 1-1d-1a Is R 1-1d-1a-1 Substituted or unsubstituted C 6 -C 30 An aryl group; r is R 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 Cycloalkyl;
R 1-1d-2 and R is 1-1d-3 Independently C 6 -C 30 An aryl group;
R 1-1d-4 is-C (=O) OR 1-1d-4a ；R 1-1d-4a Is C 2 -C 10 Alkenyl, or by one or more-OC (=o) R 1-1d-4a-1 Substituted C 1 -C 10 An alkyl group; r is R 1-1d-4a-1 Is C 1 -C 10 An alkyl group;
R 1-1d-5 to pair(s)Tosyl;
R 1-1e is hydrogen, C 1 -C 10 Alkyl or
R 1-1h Is C 2 -C 10 Alkenyl, or by one or more-OC (=o) R 1-1h-1 Substituted C 1 -C 10 An alkyl group; r is R 1-1h-1 Is C 1 -C 10 An alkyl group;
R 2 is hydrogen, R 2-1 Substituted or unsubstituted C 1 -C 30 Alkyl, R 2-2 Substituted or unsubstituted C 6 -C 30 Aryl, or C 2 -C 10 Alkenyl groups;
R 2-1 cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl, R 2-1a Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, C, wherein the hetero atoms are one or more selected from N, O and S 2 -C 10 Alkenyl, -O (CH) 2 ) n R 2-1b 、-S(＝O) 2 R 2-1c 、-OC(＝O)R 2-1d 、-C(＝O)OR 2-1e 、
-C(＝O)R 2-1h Or (b)
R 2-2 Is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, cyano, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group;
R 2-1a Is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, cyano, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group;
R 2-1b is R 2-1b-1 Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, wherein the hetero atoms are one or more selected from N, O and S,
R 2-1b-1 Is nitro, aldehyde, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, -S (=o) 2 R 2-1b-1a 、
-C(＝O)OR 2-1b-1f or-C (=O) R 2-1b-1g ；
R 2-1b-1a 、R 2-1b-1b 、R 2-1b-1c 、R 2-1b-1d And R is 2-1b-1e Independently C 1 -C 10 An alkyl group;
R 2-1b-1f and R is 2-1b-1g Independently C 2 -C 10 Alkenyl, or C 1 -C 10 An alkyl substituted or unsubstituted "heteroatom selected from one or more of N, O and S, a 5-to 15-membered heteroaryl having 1-4 heteroatoms;
R 2-1c 、R 2-1f and R is 2-1g Independently hydrogen, C 6 -C 30 Aryl or p-toluenesulfonyl;
R 2-1d is R 2-1d-1 Substituted or unsubstituted C 1-10 Alkyl, R 2-1d-2 Substituted or unsubstituted C 2-10 Alkenyl, R 2-1d-3 Substituted or unsubstituted C 2-10 Alkynyl, R 2-1d-4 Substituted or unsubstituted C 6-30 Aryl, R 2-1d-5 A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R 2-1d-1 is-OR 2-1d-1a Or (b)
R 2-1d-1a Is R 2-1d-1a-1 Substituted or unsubstituted C 6 -C 30 An aryl group; r is R 2-1d-1a-1 For C substituted by one or more halogens 3 -C 15 Cycloalkyl;
R 2-1d-2 and R is 2-1d-3 Independently C 6 -C 30 An aryl group;
R 2-1d-4 is-C (=O) OR 2-1d-4a ；R 2-1d-4a Is C 2 -C 10 Alkenyl groups;
R 2-1d-5 is p-toluenesulfonyl;
R 2-1e is hydrogen or C 1 -C 10 An alkyl group;
R 2-1h is C 2 -C 10 Alkenyl groups;
R 8 is C 1 -C 10 Alkylene group,
Or- (CH) 2 ) m3 -O(C＝O)-(C 6 -C 10 Arylene) - (c=o) O- (CH 2 ) m4 -；
m1, m2, m3 and m4 are independently 0, 1, 2, 3, 4, 5 or 6.
In one embodiment: r is R 1-1 、R 1-1a 、R 1-1b-1 、R 1-1d-1 、R 1-1d-2 、R 1-1d-3 、R 1-1d-4 、R 1-1d-5 、R 1-1d-1a-1 、R 8-1 And R is 8-1a - 1 Independently 1 or more, the same or different when plural, and preferably 2, 3 or 4 when plural.
In one embodiment: when R is 1 Is R 1-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is C 1 -C 10 Alkyl, preferably C 1 -C 8 Alkyl groups, e.g. methyl,
In one embodiment: when R is 1-1 In the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
In one embodiment: when R is 1-1 Is C 3 -C 15 When cycloalkyl is a cycloalkyl group, C 3 -C 15 Cycloalkyl of (2) is monocyclic C 3 -C 15 Cycloalkyl, condensed ring C 3 -C 15 Cycloalkyl, spiro C 3 -C 15 Cycloalkyl or bridged ring C of (C) 3 -C 15 Cycloalkyl of (C), preferably monocyclic C 3 -C 15 Cycloalkyl of (c);
said single ring C 3 -C 15 Cycloalkyl radicals of (C) are preferred 3 -C 6 For example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably cyclohexyl.
In one embodiment: when R is 1-1 Is R 1-1a Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl, preferably phenyl or naphthyl.
In one embodiment: when R is 1-1 Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 6 Alkenyl groups, e.g.
In one embodiment: when R is 1-1a In the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or iodine.
In one embodiment: when R is 1-1a Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 Alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl.
In one embodiment: when R is 1-1a Is C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl, preferably phenyl.
In one embodiment: when R is 1-1b Is R 1-1b-1 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl, preferably phenyl or naphthyl.
In one embodiment: when R is 1-1b When the hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 ", the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4, and the hetero atom of 5-15 is selected from one or more of N, O and S, the hetero atom number is 1-4, and the hetero atom is 5-15, or 5-15, preferably the hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4, and the hetero atom is 5-15;
the "hetero atom is selected from one or more of N, O and S, and the 5-15 membered monocyclic heteroaryl group having 1-4 hetero atoms" is preferably "hetero atom is selected from one or more of N, O and S, and the 5-6 membered monocyclic heteroaryl group having 1 or 2 hetero atoms" is preferably selected from the group consisting of thienyl 
In one embodiment: n is 0, 1, 2, 3, 4, 5 or 6, preferably n is 0 or 1.
In one embodiment: when R is 1-1b-1 Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 Alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl.
In one embodiment: when R is 1-1b-1 Is C 2 -C 10 In the case of alkenyl, the alkenyl is C 2 -C 4 Alkenyl groups, e.g.
In one embodiment: when R is 1-1b-1a 、R 1-1b-1b 、R 1-1b-1c 、R 1-1b-1d And R is 1-1b-1e Independently C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is independently C 1 -C 6 Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
In one embodiment: when R is 1-1b-1f Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl groups being
In one embodiment: when R is 1-1b-1g Is one or more C 1 -C 10 When the alkyl substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4' 5-15 membered heteroaryl, C 1 -C 10 The number of alkyl groups is 1, 2 or 3.
In one embodiment: when R is 1-1b-1g Is C 1 -C 10 When the alkyl substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 ' 5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4 ' 5-15 membered heteroaryl is selected from one or more of N, O and S, and the hetero atom number is 1-4 ' A 5-15 membered monocyclic heteroaryl or a 5-15 membered bicyclic heteroaryl, preferably a 5-15 membered bicyclic heteroaryl wherein the "heteroatom is selected from one or more of N, O and S and the number of heteroatoms is 1-4";
the "hetero atom is selected from one or more of N, O and S, and the 5-15 membered bicyclic heteroaryl group with 1-4 hetero atoms" is preferably "hetero atom is selected from one or more of N, O and S, and the 8-10 membered bicyclic heteroaryl group with 1 or 2 hetero atoms" is preferably selected from benzofuranyl group
In one embodiment: when R is 1-1b-1g Is one or more C 1 -C 10 When the alkyl substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4, the C is 5-15 membered heteroaryl 1 -C 10 Alkyl is C 1 -C 6 Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably ethyl.
In one embodiment: when R is 1-1c 、R 1-1f And R is 1-1g Independently C 6 -C 30 Aryl, the C 6 -C 30 Aryl is independently C 6 -C 10 Aryl, preferably phenyl.
In one embodiment: when R is 1-1d Is R 1-1d-1 Substituted or unsubstituted C 1-10 In the case of alkyl, said C 1-10 Alkyl is C 1 -C 6 Alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or isopropyl.
In one embodiment: when R is 1-1d Is R 1-1d-2 Substituted or unsubstituted C 2-10 In the case of alkenyl, said C 2-10 Alkenyl group is C 2-4 Alkenyl groups, e.g.
In a certain schemeIn (a): when R is 1-1d Is R 1-1d-3 Substituted or unsubstituted C 2-10 In the case of alkynyl, said C 2-10 Alkynyl is C 2-4 Alkynyl radicals, e.g.
In one embodiment: when R is 1-1d Is R 1-1d-4 Substituted or unsubstituted C 6-30 Aryl, the C 6-30 Aryl is C 6-10 Aryl, preferably phenyl.
In one embodiment: when R is 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 ' 5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4 ' 5-15 membered heteroaryl is selected from one or more of N, O and S, and the hetero atom number is 1-4 ' 5-15 membered monocyclic heteroaryl or 5-15 membered bicyclic heteroaryl.
The "hetero atom is selected from one or more of N, O and S, and the 5-15 membered monocyclic heteroaryl group with 1-4 hetero atoms" is preferably "hetero atom is selected from one or more of N, O and S, and the 5-6 membered monocyclic heteroaryl group with 1 or 2 hetero atoms" is preferably selected from furyl, such as furyl
The "hetero atom is selected from one or more of N, O and S, and the 5-15 membered bicyclic heteroaryl group with 1-4 hetero atoms" is preferably "hetero atom is selected from one or more of N, O and S, and the 8-10 membered bicyclic heteroaryl group with 1 or 2 hetero atoms" is preferably selected from benzofuranyl group 
Benzothienyl->
Or indolyl->
In one embodiment: when R is 1-1d-1a Is R 1-1d-1a-1 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl, preferably phenyl.
In one embodiment: when R is 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 In the case of cycloalkyl, the number of halogens is 1, 2 or 3.
In one embodiment: when R is 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 In the case of cycloalkyl, the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine.
In one embodiment: when R is 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 In the case of cycloalkyl, said C 3 -C 15 Cycloalkyl radicals are C 3 -C 15 Monocyclic cycloalkyl, C 3 -C 15 Condensed ring cycloalkyl, C 3 -C 15 Spiro cycloalkyl or C 3 -C 15 Bridged cycloalkyl radicals, preferably C 3 -C 15 A monocyclic cycloalkyl group.
The C is 3 -C 15 Monocyclic cycloalkyl groups are preferably C 3 -C 6 Monocyclic cycloalkyl groups such as cyclopropyl.
In one embodiment: when R is 1-1d-2 And R is 1-1d-3 Independently C 6 -C 30 Aryl, the C 6 -C 30 Aryl is independently C 6 -C 10 Aryl, preferably phenyl.
In one embodiment: when R is 1-1d-4a Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 4 Alkenyl groups, e.g.
In one embodiment: when R is 1-1e Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 Alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
In one embodiment: when R is 1-1h Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 6 Alkenyl groups, e.g.
In one embodiment: r is R 2-1 、R 2-2 、R 2-1a 、R 2-1b-1 、R 2-1d-1 、R 2-1d-2 、R 2-1d-3 、R 2-1d-4 、R 2-1d-5 And R is 2 -1d-1a-1 Independently 1 or more, the same or different when plural, and preferably 2, 3 or 4 when plural.
In one embodiment: when R is 2 Is R 2-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is C 1 -C 10 Alkyl, preferably C 1 -C 6 Alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl.
In one embodiment: when R is 2 Is R 2-2 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl, preferably phenyl or naphthyl.
In one embodiment: when R is 2 Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 4 Alkenyl groups such as vinyl.
In one embodiment: when R is 2-2 In the case of halogen, saidHalogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
In one embodiment: when R is 2-2 Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one embodiment: when R is 2-2 Is C 1 -C 10 In the case of alkoxy, said C 1 -C 10 Alkoxy is C 1 -C 4 Alkoxy groups such as methoxy.
In one embodiment: when R is 2-2 Is C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl, preferably phenyl.
In one embodiment: when R is 2-2 For C substituted by one or more halogens 1 -C 10 In the case of alkyl, the number of halogens is 1, 2 or 3.
In one embodiment: when R is 2-2 For C substituted by one or more halogens 1 -C 10 In the case of alkyl, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
In one embodiment: when R is 2-2 For C substituted by one or more halogens 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
In one embodiment: when R is 8 Is R 8-1 Substituted or unsubstituted C 1 -C 10 R in the case of alkylene 8-1 The number of (2) is 1, 2 or 3.
In one embodiment: when R is 8 Is R 8-1 Substituted or unsubstituted C 1 -C 10 In the case of alkylene, said C 1 -C 10 Alkylene is C 1 -C 6 Alkylene groups such as methylene, ethylene, propylene, isopropylene, n-butylene, isobutyleneSec-or tert-butyl, for example, in turn methylene or ethylene.
In one embodiment: when R is 8 Is- (CH) 2 ) m3 -O(C＝O)-(C 6 -C 10 Arylene) - (c=o) O- (CH 2 ) m4 -wherein C 6 -C 10 Arylene groups are preferably phenylene groups (e.g
)。
In one embodiment: m1, m2, m3 and m4 are independently 1, 2 or 3.
In one embodiment: when R is 1-1 Is R 1-1a Substituted or unsubstituted C 6 -C 30 In the case of aryl radicals, R 1-1 In any one of the structures described in the following,
in one embodiment: when R is 1-1 is-O (CH) 2 ) n R 1-1b When R is 1-1 In any one of the structures described in the following,
in one embodiment: when R is 1-1 is-OC (=O) R 1-1d When R is 1-1 In any one of the structures described in the following,
in one embodiment: when R is 1-1 is-C (=O) OR 1-1e When R is 1-1 In any one of the structures described in the following,
in one embodiment:R 1 is R 1-1 Substituted or unsubstituted C 1 -C 30 An alkyl group.
In one embodiment: r is R 1-1 Cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl, R 1-1a Substituted or unsubstituted C 6 -C 30 Aryl, C 2 -C 10 Alkenyl, -O (CH) 2 ) n R 1-1b 、-S(＝O) 2 R 1-1c 、-OC(＝O)R 1-1d 、-C(＝O)OR 1-1e 、
-C(＝O)R 1-1h Or->
In one embodiment: r is R 1-1 Cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl, C 2 -C 10 Alkenyl, -O (CH) 2 ) n R 1-1b 、-S(＝O) 2 R 1-1c 、-OC(＝O)R 1-1d 、-C(＝O)OR 1-1e 、
-C(＝O)R 1-1h Or->
In one embodiment: r is R 1-1a Is halogen, C 1 -C 10 Alkyl or C 6 -C 30 Aryl groups.
In one embodiment: r is R 1-1d Is R 1-1d-1 Substituted or unsubstituted C 1-10 Alkyl, R 1-1d-2 Substituted or unsubstituted C 2-10 Alkenyl, R 1-1d-3 Substituted or unsubstituted C 2-10 Alkynyl, unsubstituted C 6-30 Aryl, R 1-1d-5 The substituted or unsubstituted hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4 and 5-15 membered heteroaryl.
In one embodiment: r is R 1-1h Is C 2 -C 10 Alkenyl groups.
In one embodiment: r is R 1-1 In any one of the structures described in the following,
In one embodiment: the compound shown in the formula II-A is selected from any one of the following compounds:
in one embodiment: the compound shown in the formula II-B is selected from any one of the following compounds:
in one embodiment: r is R 2 Is hydrogen, unsubstituted C 1 -C 30 Alkyl, or R 2-2 Substituted or unsubstituted C 6 -C 30 Aryl groups.
In one embodiment: r is R 2-2 Is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group.
In one embodiment: the compound shown in the formula III' is selected from any one of the following compounds:
in one embodiment, the compound of formula I-2-A is:
the invention also provides a preparation method of the chiral beta-acyloxy carboxylic ester compound, which comprises the following steps:
(1) In a solvent, carrying out addition reaction on a compound containing a fragment II, a compound containing a fragment III and carbon monoxide (CO) in the presence of a palladium catalyst, an oxazoline ligand and an oxidant;
(2) In a solvent, carrying out methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound containing a fragment I;
wherein the fragment II is
The fragment III is
/>
The fragment I is 
Wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand
When the oxazoline ligand is
When (I)>
Wherein the carbon noted is chiral carbon of the S configuration;
when the oxazoline ligand is
When (I)>
Wherein the carbon noted is chiral carbon of the R configuration;
wherein R is 5 、R 6 And R is 7 Is as defined in any one of the preceding claims;
the reaction operation and conditions of step (1) are as described in any one of the preceding claims.
The operation and conditions of the methylation reaction in step (2) may be conventional in the art for such reactions. Specific:
in step (2), the solvent may be a conventional reaction of the type in the art, and preferably, the solvent is an alcoholic solvent and/or a substituted aromatic solvent. The alcohol solvent is preferably methanol and/or ethanol. The substituted aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, toluene and trifluoromethylbenzene. More preferably, the solvent is a mixed solvent of methanol and/or toluene.
In the step (2), the amount of the solvent to be used is not particularly limited as long as the reaction is not affected.
In step (2), the methylating agent may be a methylating agent conventional in such reactions in the art, preferably TMSCHN 2 。
In step (2), the amount of the methylating agent may be that conventionally used in such reactions in the art, and preferably, the molar ratio of the methylating agent to the compound of segment II in step (1) is from (2 to 10): 1, e.g., 4:1.
In step (2), the temperature of the methylation reaction may be a temperature conventional in such reactions in the art, preferably the temperature of the methylation reaction is 20 to 30 ℃.
In step (2), the progress of the methylation reaction can be monitored using detection methods conventional in the art (e.g., TLC, HPLC, HNMR). The methylation reaction may take from 1 to 10 hours, preferably from 2 to 6 hours, for example 4 hours or 6 hours.
Preferably, step (1) further comprises the following post-treatment steps: and adding a solvent into the reaction liquid, and concentrating to perform the next reaction. In the post-treatment step of step (1), the solvent is an alcohol solvent (e.g., methanol).
In one embodiment of the present invention, the preparation method of the carboxylic ester compound is the following method a or method B:
method A:
(1) In a solvent, carrying out addition reaction on a compound shown as a formula II-A, a compound shown as a formula III' and carbon monoxide (CO) in the presence of a palladium catalyst, an oxazoline ligand and an oxidant;
(2) In a solvent, carrying out methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -A;
method B:
(1) In a solvent, carrying out addition reaction on a compound shown as a formula II-B, a compound shown as a formula III' and carbon monoxide (CO) in the presence of a palladium catalyst, an oxazoline ligand and an oxidant;
(2) In a solvent, carrying out methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -B;
in either method a or method B, the operation and conditions of the addition reaction are as described in any one of the preceding claims;
*、R 1 、R 2 and R is 8 Is fixed to (1)As defined in any one of the preceding claims.
In one embodiment: the compound shown in the formula I' -A is selected from any one of the following compounds:
in one embodiment: the compound shown in the formula I' -B is selected from any one of the following compounds:
the invention also provides a compound of the formula,
the unit cell parameters are as follows: monoclinic system, P21 space group, unit cell parameters of
α＝γ＝90°，β＝106.762(3)°。
Definition of the definition
In the present invention, "room temperature" means 10 to 30 ℃.
In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.
In the present invention, the term "alkyl" refers to a straight or branched saturated hydrocarbon group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The one or more carbon-carbon double bonds may be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl).
In the present invention, the term "alkynyl" refers to a straight or branched hydrocarbon group of one or more carbon-carbon triple bonds and optionally one or more carbon-carbon double bonds.
In the present invention, the term "cycloalkyl" refers to a saturated monocyclic, or carbocyclic substituent comprising a fused, bridged or spiro polycyclic ring system.
In the present invention, "heterocycloalkyl" means "heterocycloalkyl" of a non-aromatic ring system. The heterocycloalkyl group may be either a monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")) and may be saturated or may be partially unsaturated.
In the present invention, "heterocycloalkenyl" refers to a "heterocyclyl" group containing an ethylenically unsaturated, non-aromatic ring system. The heterocycloalkenyl group may be either a monocyclic ("monocyclic heterocycloalkenyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system ("bicyclic heterocycloalkenyl")) and may be saturated or may be partially unsaturated. In some embodiments, heterocycloalkenyl refers to heterocycloalkenyl having one or more of N, O and S heteroatoms, 1-2 heteroatoms, 5-6 membered.
In the present invention, the term "alkoxy" means a cyclic or acyclic alkyl group linked through an oxygen bridge, and the definition of alkyl and cycloalkyl are as defined above.
In the present invention, "aryl" refers to a group ("C") having 6-14 atoms and zero heteroatoms, a mono-or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared p-electrons in a cyclic array) 6 -C 14 Aryl ").
In the present invention, "heteroaryl" refers to a group ("5-10 membered heteroaryl") of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 shared p-electrons in a cyclic array) having carbon atoms and 1-4 heteroatoms provided in the aromatic ring system (wherein each heteroatom is independently selected from one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, 3, or 4). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation method of the beta-acyloxy carboxylic ester compound has the advantages of high yield, wide substrate universality, good functional group compatibility or better corresponding selectivity control, mild reaction condition and simple operation.
Drawings
FIG. 1 is an X-ray single crystal diffraction pattern of the compound represented by formula I' -46 in example 1.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
EXAMPLE 1 preparation of beta-acyloxycarboxylic acid esters
General operation step 1: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5 mg,0.0375mmol,7.5 mol%), pd (OAc) 2 (5.6 mg,0.05mmol,5 mol%) and benzoquinone (162.1 mg,1.5mmol,3.0 equiv) and Et are added to the reaction tube in this order under the protection of carbon monoxide gas 2 O (0.25 mL), a compound of formula A-2(290.4 mg,2.5mmol,5.0 equiv) and an olefin of formula II' (0.5 mmol,1.0 equiv). The reaction was stirred at room temperature for 72 hours. After the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product obtained was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise 2 (2M n-hexane solution) was stirred for 6 hours. The reaction solution is concentrated and separated by rapid column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General operation step 2: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5 mg,0.0375mmol,7.5 mol%), pd (OAc) 2 (5.6 mg,0.05mmol,5 mol%) and benzoquinone (162.1 mg,1.5mmol,3.0 equiv) and Et are added to the reaction tube in this order under the protection of carbon monoxide gas 2 O (0.25 mL), the compound of formula A-2 (290.4 mg,2.5mmol,5.0 equiv) and the alkene of formula II' (0.5 mmol,1.0 equiv). The reaction was stirred at 0deg.C for 72 hours. After the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product obtained was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise 2 (2M n-hexane solution) was stirred for 6 hours. The reaction solution is concentrated and separated by rapid column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General operation step 3: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5 mg,0.0375mmol,7.5 mol%), pd (OAc) 2 (5.6 mg,0.05mmol,5 mol%) and benzoquinone (162.1 mg,1.5mmol,3.0 equiv) and Et are added to the reaction tube in this order under the protection of carbon monoxide gas 2 O (0.25 mL), the compound of formula A-2 (290.4 mg,2.5mmol,5.0 equiv) and the alkene of formula II' (0.5 mmol,1.0 equiv). The reaction was stirred at-10℃for 72 hours. After the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product obtained was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise 2 (2M n-hexane solution) was stirred for 6 hours. The reaction solution is concentrated and separated by rapid column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General operation step 4: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5 mg,0.0375mmol,7.5 mol%), pd (OAc) 2 (5.6 mg,0.05mmol,5 mol%) and benzoquinone (162.1 mg,1.5mmol,3.0 equiv) under the protection of carbon monoxide gasEt should be added to the tube 2 O (0.25 mL), the compound of formula A-2 (290.4 mg,2.5mmol,5.0 equiv) and the alkene of formula II' (0.5 mmol,1.0 equiv). The reaction was stirred at 0deg.C for 72 hours. After the reaction was completed, 2mL of acetone and 0.2mL of water were added, stirred for 4 hours, and concentrated. Flash column chromatography (petroleum ether/ethyl acetate/methanol) to obtain the target product.
General operation step 5: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5 mg,0.0375mmol,7.5 mol%), pd (OAc) 2 (5.6 mg,0.05mmol,5 mol%) and benzoquinone (324.2 mg,3mmol,6.0 equiv) and Et are added to the reaction tube in this order under the protection of carbon monoxide gas 2 O (0.8 mL), the compound of formula A-2 (380.8 mg,5mmol,10.0 equiv) and the alkene of formula II' (0.5 mmol,1.0 equiv). The reaction was stirred at room temperature for 72 hours. After the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product obtained was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise 2 (2M n-hexane solution) was stirred for 6 hours. The reaction solution is concentrated and separated by rapid column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General operation step 6: in a 10mL reaction tube, pyridine-oxazoline ligand L (S configuration) (9.5 mg,0.0375mmol,7.5 mol%), pd (OAc) 2 (5.6 mg,0.05mmol,5 mol%) and benzoquinone (162.1 mg,1.5mmol,3.0 equiv) and Et are added to the reaction tube in this order under the protection of carbon monoxide gas 2 O (0.25 mL), the compound of formula A-2 (290.4 mg,2.5mmol,5.0 equiv) and the alkene of formula II' (0.5 mmol,1.0 equiv). The reaction was stirred at 0deg.C for 72 hours. After the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product obtained was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise 2 (2M n-hexane solution) was stirred for 6 hours. The reaction solution is concentrated and separated by rapid column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
Compound I' -1:
the reaction is carried out according to general procedure 2, column chromatography separation(petroleum ether: ethyl acetate=20:1) to give an oily liquid product. (89.2 mg,73% yield, 88% ee) [ α] D 29.0 ＝-3.47(c 1.00,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.26-5.19(m,1H),3.64(s,3H),2.59(dd,J＝3.2,15.2Hz,1H),2.52(dd,J＝5.2,15.2Hz,1H),2.18-2.10(m,1H),1.68-1.41(m,6H),1.40-1.25(m,2H),0.91(t,J＝7.2Hz,3H),0.89-0.84(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.49,170.90,69.99,51.64,49.11,39.15,36.12,25.00,24.96,18.35,13.76,11.74,11.67.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 267.1567, found 267.1574.IR (ATR) v (cm) -1 ) 2962,2876,1731,1437,1384,1268,1228,1171,1146,1082,1017,813,742.Chiral GC (CP Chirasil-DEX CB Varian,25m×0.25mm,0.25 μm film thickness, using nitrogen (10.0 psi) as carrier gas: initial temperature=50 ℃, hold for 2min, then heat (2 ℃/min) to 150 ℃, hold for 20min, detect with FID) hold time= 48.99min (minor) and 49.25min (major).
Compound I' -2:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=20:1) gave the product as an oily liquid. (109.6 mg,85% yield, 91% ee) [ α] D 28.9 ＝-2.51(c 0.94,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.26-5.19(m,1H),3.65(s,3H),2.59(dd,J＝7.6,15.2Hz,1H),2.53(dd,J＝5.2,15.2Hz,1H),2.20-2.12(m,1H),1.69-1.53(m,4H),1.52-1.42(m,2H),1.36-1.25(m,4H),0.90-0.85(m,9H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.48,170.91,70.18,51.66,49.12,39.15,33.67,27.18,25.03,24.98,22.35,13.87,11.76,11.69.HRMS: M/z (ESI-TOF) calculation [ M+Na ] + 281.1723, found 281.1728.IR (ATR) v (cm) -1 ) 2961,1875,1731,1459,1437,1383,1267,1170,1146,1082,995,813,740.Chiral GC (CP Chirasil-DEX CB Varian,25m×0.25mm,0.25 μm film thickness, using nitrogen (10.0 psi) as carrier gas: initial temperature=50deg.C, holding for 2min, and heating (2deg.C/min) to165 ℃, detected with FID) retention time = 53.96min (minor) and 54.18min (major).
Compound I' -3:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=20:1) gave the product as an oily liquid. (124.5 mg,83% yield, 87% ee) [ α] D 24.3 ＝0.88(c 0.580,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.25-5.18(m,1H),3.64(s,3H),2.58(dd,J＝7.6,15.6Hz,1H),2.52(dd,J＝6.0,15.6Hz,1H),2.18-2.10(m,1H),1.62-1.41(m,6H),1.28-1.24(m,8H),0.88-0.83(m,9H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.47,170.90,70.18,51.65,49.11,39.13,33.97,31.61,28.92,25.04,24.99,22.47,13.98,11.75,11.69.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 309.2036, found 309.2031.IR (ATR) v (cm) -1 ) =2960, 2930,2860,1731,1459,1437,1383,1268,1227,1170,1146,1082,1014.Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=8.26 min (primary) and 11.41min (secondary).
Compound I' -4:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=20:1) gave the product as an oily liquid. (140.4 mg,82% yield, 85% ee) [ α ] D 24.6 ＝0.60(c 0.73,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.25-5.18(m,1H),3.64(s,3H),2.58(dd,J＝7.2,15.2Hz,1H),2.52(dd,J＝5.6,15.6Hz,1H),2.18-2.11(m,1H),1.62-1.42(m,6H),1.28-1.23(m,16H),0.88-0.84(m,9H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.47,170.90,70.19,51.66,49.12,39.13,33.98,31.85,29.53,29.46,29.42,29.28,29.26,25.04,25.01,22.64,14.07,11.77,11.70.HRMS: m/z (ESI-TOF) meterCalculate [ M+Na ]] + 365.2662, found 365.2662.IR (ATR) v (cm) -1 ) Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=6.75 min (primary) and 9.38min (secondary).
Compound I' -5:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=20:1) gave the product as an oily liquid. (160.0 mg,75% yield, 84% ee) [ α] D 22.5 ＝-0.47(c 1.30,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.26-5.19(m,1H),3.65(s,3H),2.59(dd,J＝7.6,15.2Hz,1H),2.53(dd,J＝5.6,15.6Hz,1H),2.19-2.12(m,1H),1.67-1.42(m,6H),1.29-1.17(m,22H),0.89-0.84(m,9H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.48,170.92,70.21,51.68,49.13,39.16,34.00,31.89,29.65,29.63,29.62,29.59,29.48,29.44,29.33,29.28,25.06,25.02,22.66,14.09,11.79,11.72.hrms: M/z (ESI-TOF) calculation [ m+na] + 407.3132, found 407.3126.IR (ATR) v (cm) -1 ) =2923, 2853,1734,1459,1382,1268,1229,1172,1146,1082,721.Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=5.98 min (primary) and 7.57min (secondary).
Compound I' -6:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=20:1) gave the product as an oily liquid. (160.0 mg,75% yield, 82% ee) [ alpha ] ] D 22.8 ＝0.55(c 1.20,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.26-5.19(m,1H),3.66(s,3H),2.60(dd,J＝7.6,15.2Hz,1H),2.54(dd,J＝5.6,15.6Hz,1H),2.20-2.12(m,1H),1.66-1.53(m,4H),1.53-1.43(m,2H),1.32-1.24(m,28H),0.90-0.85(m,9H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.50,170.94,70.24,51.68,49.14,39.18,34.02,31.91,29.68,29.64,29.60,29.49,29.45,29.34,29.29,25.05,25.00,22.67,14.09,11.79,11.71.HRMS: M/z (ESI-TOF) calculation [ M+Na ]] + 449.3601, found 449.3596.IR (ATR) v (cm) -1 ) =2923, 2853,1734,1460,1437,1383,1268,1228,1172,1146,1082,1013,756.Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=5.54 min (primary) and 6.92min (secondary).
Compound I' -7:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (93.2 mg,69% yield, 91% ee) [ α] D 24.7 ＝-0.98(c 0.54,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.25-5.18(m,1H),4.71(s,1H),4.66(s,1H),3.65(s,3H),2.61(dd,J＝7.6,15.6Hz,1H),2.55(dd,J＝5.6,15.6Hz,1H),2.20-2.12(m,1H),2.08-1.97(m,2H),1.83-1.71(m,2H),1.70(s,3H),1.65-1.42(m,4H),0.87(t,J＝7.6Hz,3H),0.84(t,J＝7.6Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.42,170.74,144.45,110.49,69.86,51.66,49.05,38.97,33.16,31.92,24.99,24.92,22.29,11.76,11.67.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 293.1723, found 193.1722.IR (ATR) v (cm) -1 ) 2965,1935,1734,1459,1438,1269,1228,1174,1147,1083,1019,888.Chiral GC (CP Chirasil-DEX CB Varian,25m×0.25mm,0.25 μm film thickness, using nitrogen (10.0 psi) as carrier gas: initial temperature=50 ℃, hold for 2min, then heat (2 ℃/min) to 160 ℃, hold for 20min, detect with FID) hold time= 58.40min (minor) and 58.63min (major).
Compound I' -8:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (122.0 mg,92% yield, 91% ee) [ α] D 28.9 ＝-5.39(c 0.73,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.39-5.31(m,1H),3.66(s,3H),3.58-3.50(m,2H),2.69-2.58(m,2H),2.22-2.04(m,3H),1.66-1.43(m,4H),0.87(t,J＝7.2Hz,3H),0.86(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.33,170.25,67.64,51.78,48.99,40.30,38.81,36.71,24.98,24.90,11.73,11.65.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 287.1021, measured 287.1028.IR (ATR) v (cm) -1 ) =2964, 1732,1437,1385,1267,1226,1168,1142,1079,1042,947,737,660.Hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=11.68 min (minor) and 12.13min (major).
Compound I' -9:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (85.3 mg,55% yield, 92% ee) [ α] D 28.9 ＝-23.26(c 0.83,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.36-5.29(m,1H),3.66(s,3H),3.43-3.32(m,2H),2.69-2.57(m,2H),2.31-2.12(m,3H),1.66-1.43(m,4H),0.90-0.85(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.32,170.20,68.56,51.80,48.98,38.67,36.92,27.97,24.97,24.90,11.75,11.66.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 331.0515, found 331.0522.IR (ATR) v (cm) -1 ) Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm), retention time=15.57 min (primary) and 16.37min (secondary).
Compound I' -10:
The reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (95.7 mg,75% yield, 91% ee) [ alpha ]] D 28.9 ＝-11.81(c 0.83,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ5.28-5.21(m,1H),3.67(s,3H),2.68(dd,J＝6.4,15.6,Hz,1H),2.57(dd,J＝6.4,16.0,Hz,1H),2.40(t,J＝7.6Hz,2H),2.23-2.15(m,1H),2.12-1.97(m,2H),1.66-1.44(m,4H),0.90-0.84(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.33,169.92,118.73,68.44,51.91,48.79,38.45,29.69,24.91,24.70,13.52,11.79,1.62.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 278.1363, found 278.1368.IR (ATR) v (cm) -1 ) =2964, 1731,1386,1267,1166,1143,1080,1044,948,810,737.Hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=20.24 min (primary) and 22.72min (secondary).
Compound I' -11:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (128.5 mg,84% yield, 96% ee) [ α] D 24.4 ＝2.63(c 0.96,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.30-7.26(m,2H),7.21-7.16(m,3H),5.34-5.28(m,1H),3.66(s,3H),2.74-2.55(m,4H),2.25-2.17(m,1H),2.05-1.89(m,2H),1.70-1.49(m,4H),0.94-0.89(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.40,170.59,141.03,128.39,128.19,125.97,69.77,51.64,49.02,39.03,35.74,31.44,24.98,24.91,11.80,11.68.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 329.1723, found 329.1730.IR (ATR) v (cm) -1 ) =2963, 2934,2876,1730,1496,1455,1436,1384,1310,1267,1170,1144,1081,1030,746,698.Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/1)0, flow rate 0.7mL/min, detection at 214 nm) retention time=14.27 min (minor) and 15.14min (major).
Compound I' -12:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (174.9 mg,81% yield, 97% ee) [ alpha ]] D 29.0 ＝6.35(c 0.8,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,2H),5.29-5.22(m,1H),3.65(s,3H),2.67-2.51(m,4H),2.22-2.14(m,1H),2.00-1.84(m,2H),1.68-1.45(m,4H),0.92-0.87(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.44,170.53,140.67,137.45, 130.35, 91.08, 69.56, 51.74, 49.01, 39.01, 35.49, 31.01, 24.99, 24.90, 11.85, 11.72.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 455.0690, found 455.0692.IR (ATR) v (cm) -1 ) =2961, 2874,1729,1484,1436,1383,1267,1170,1144,1080,1037,1005,829,798,740,508.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=8.61 min (primary) and 10.68min (secondary).
Compound I' -13:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (184.8 mg,80% yield, 93% ee) [ α] D 29.0 ＝6.35(c 0.8,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.73(d,J＝8.4Hz,2H),6.86(d,J＝8.8Hz,2H),5.33-5.28(m,1H),4.00-3.98(m,2H),3.66(s,3H),2.65(dd,J＝7.6,15.6Hz,1H),2.58(dd,J＝5.2,15.2Hz,1H),2.21-2.13(m,1H),1.86-1.79(m,4H),1.63-1.44(m,4H),1.32(s,12H),0.88(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ175.48,170.65,161.41,136.45,113.77,83.47,69.75,66.97,51.70,49.04,39.09,30.64,24.96,24.90,24.79,11.79,11.67.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 485.2681, found 485.2694.IR (ATR) v (cm) -1 ) =2964, 1732,1604,1437,1358,1317,1272,1243,1168,1141,1089,1011,962,859,831,735,670,654,521.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=7.96 min (primary) and 9.31min (secondary).
Compound I' -14:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (160.4 mg,90% yield, 96% ee) [ α] D 29.3 ＝1.34(c 1.00,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.82-7.77(m,3H),7.62(s,1H),7.48-7.41(m,2H),7.34-7.31(m,1H),5.40-5.32(m,1H),3.67(s,3H),2.92-2.76(m,2H),2.70(dd,J＝7.6,15.2Hz,1H),2.62(dd,J＝5.6,15.2Hz,1H),2.27-2.19(m,1H),2.15-1.99(m,2H),1.73-1.50(m,4H),0.96-0.91(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.45,170.62,138.53,133.53,131.99,128.01,127.53,127.35,126.96,126.28,125.92,125.21,69.84,51.68,49.04,39.07,35.63,31.64,24.99,24.91,11.83,11.71.hrms: M/z (ESI-TOF) calculation [ m+na ]] + 379.1880, found 379.1878.IR (ATR) v (cm) -1 ) =2962, 2933,2875,1729,1507,1458,1436,1383,1310,1268,1227,1171,1143,1081,1040,1014,956,890,853,815,745.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=8.05 min (primary) and 10.27min (secondary).
Compound I' -15:
the reaction was carried out according to general procedure 2, column chromatography separation (petroleumEther: ethyl acetate=10:1) to give an oily liquid product. (120.9 mg,72% yield, 91% ee) [ α] D 29.5 ＝9.07(c 0.94,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ8.02-7.99(m,2H),7.57-7.53(m,1H),7.45-7.40(m,2H),5.64-5.57(m,1H),4.50(dd,J＝3.6,12.0Hz,1H),4.44(dd,J＝5.6,12.0Hz,1H),3.67(s,3H),2.81-2.68(m,2H),2.23-2.15(m,1H),1.66-1.42(m,4H),0.87-0.81(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.14,169.99,165.97,133.16,129.62,129.51,128.35,67.66,64.84,51.90,48.86,36.01,24.92,24.88,11.62,11.59.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 359.1465, found 359.1470.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=11.57 min (primary) and 12.74min (secondary).
Compound I' -16:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (168.0 mg,86% yield, 92% ee) [ alpha ]] D 29.6 ＝2.15(c 0.35,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.82-7.78(m,2H),7.71-7.66(m,2H),5.28-5.21(m,1H),3.67(t,J＝6.0Hz,2H),3.62(s,3H),2.59(dd,J＝7.6,15.6Hz,1H),2.51(dd,J＝5.6,15.2Hz,1H),2.17-2.09(m,1H),1.76-1.62(m,4H),1.60-1.39(m,4H),0.83(t,J＝7.2Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.35,170.50,168.20,133.87,131.96,123.13,69.41,51.66,48.90,38.93,37.46,31.22,24.87,24.79,24.26,11.70,11.60.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 412.1731, found 412.1742.IR (ATR) v (cm) -1 ) Hplc (IA, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=23.33 min (primary) and 25.10min (secondary).
Compound I' -17:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (133.7 mg,80% yield, 91% ee) [ α] D 29.5 ＝-6.92(c 0.54,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.93-7.90(m,2H),7.57-7.52(m,1H),7.47-7.42(m,2H),5.38-5.31(m,1H),3.66(s,3H),3.04(t,J＝7.6Hz,2H),2.69(dd,J＝7.6,15.6Hz,1H),2.61(dd,J＝5.6,15.6Hz,1H),2.20-1.00(m,3H),1.66-1.43(m,4H),0.89-0.84(m,6H). 13 CNMR(100MHz,CDCl 3 ) Delta 198.67,175.47,170.49,136.58,133.09,128.55,127.88,69.62,51.71,48.94,39.29,34.26,28.32,24.91,24.77,11.75,11.62.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 357.1673, found 357.1681.IR (ATR) v (cm) -1 ) =2963, 2935,2876,1730,1685,1267,1204,1172,1144,1079,1001,742,690.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=12.99 min (primary) and 21.27min (secondary).
Compound I' -18:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (151.6 mg,79% yield, 86% ee) [ α] D 29.5 ＝-3.49(c 0.97,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.87-7.84(m,2H),7.65-7.60(m,1H),7.56-7.51(m,2H),5.17-5.10(m,1H),3.61(s,3H),3.17-3.02(m,2H),2.57(dd,J＝7.2,15.6Hz,1H),2.47(dd,J＝5.6,15.6Hz,1H),2.13-2.05(m,1H),1.81-1.63(m,4H),1.55-1.37(m,4H),0.82-0.76(m,6H). 13 C NMR(100MHz,CDCl 3 )δ175.33,170.28,138.76,133.65,129.21,127.91,68.89,55.47,51.69,48.82,38.77,32.35,24.81,24.72,18.66,11.69,11.56.HRMS: M/z (ESI-TOF) calculation [ M+Na ]] + 407.1499, found 407.1498.IR (ATR) v (cm) -1 ) =2963, 2935,2876,1729,1446,1385,1303,1269,1225,1174,1140,1085,1046,999,811,789,752,730,689,594,564,531.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropyl alcohol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time= 49.14min (primary) and 72.02min (secondary). Compound I' -19:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (114.6 mg,71% yield, 89% ee) [ α] D 29.7 ＝-2.97(c 0.5,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ6.62(t,J＝2.0Hz,2H),6.12(J＝2.0Hz,,2H),5.25-5.18(m,1H),3.86(dt,J＝1.2,6.8Hz,2H),3.66(s,3H),2.59(dd,J＝7.2,15.2Hz,1H),2.51(dd,J＝5.6,15.6Hz,1H),2.19-2.11(m,1H),1.83-1.71(m,2H),1.70-1.43(m,6H),1.37-1.24(m,2H),0.87(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.48,170.71,120.36,107.92,69.79,51.70,49.23,49.03,39.01,33.45,31.11,24.97,24.90,22.31,11.79,11.67.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 346.1989, found 346.1996.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=7.76 min (primary) and 11.85min (secondary).
Compound I' -20:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (120.9 mg,76% yield, 94% ee) [ α] D 29.8 ＝-23.35(c 0.54,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝8.0Hz,1H),7.33(d,J＝8.4Hz,1H),7.24-7.19(m,1H),7.14-7.09(m,2H),6.50(dd,J＝0.4,3.2Hz,1H),5.36-5.29(m,1H),4.28-4.12(m,2H),3.63(s,3H),2.64(dd,J＝6.8,15.6Hz,1H),2.53(dd,J＝5.6,15.6Hz,1H),2.29-2.17(m,3H),1.73-1.51(m,4H),0.97-0.91(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.53,170.24,135.62,128.71,127.59,121.56,121.08,119.41,109.05,101.49,68.07,51.77,48.98,42.69,38.98,34.42,24.99,24.84,11.91,11.72.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 368.1832, found 368.1835.IR (ATR) v (cm) -1 ) =2963, 2934,1730,1461,1436,1316,1267,1166,1144,1079,1012,738,716.Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=13.03 min (minor) and 17.50min (major).
Compound I' -21:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (160.2 mg,76% yield, 86% ee) [ α] D 29.9 ＝-3.85(c 0.95,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝7.6Hz,2H),7.48(t,J＝8.0Hz,2H),7.40(d,J＝8.4Hz,2H),7.25(t,J＝7.6Hz,2H),5.26-5.19(m,1H),4.30(t,J＝7.2Hz,2H),3.66(s,3H),2.58(dd,J＝7.6,15.2Hz,1H),2.49(dd,J＝5.6,15.2Hz,1H),2.18-2.10(m,1H),1.99-1.85(m,2H),1.73-1.39(m,8H),0.89-0.82(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.45,170.65,140.29,125.58,122.78,120.28,118.75,108.51,69.73,51.66,48.95,42.67,39.02,33.69,28.62,24.90,24.84,22.89,11.70,11.62.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 446.2302, found 446.2314.IR (ATR) v (cm) -1 ) =2961, 2934,1729,1595,1452,1324,1172,1149,908,749,722.Hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=19.22 min (primary) and 22.09min (secondary).
Compound I' -22:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (140.4 mg,90% yield, 93% ee) [ α] D 29.9 ＝-2.34(c 0.8,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.26-7.22(m,1H),6.96-6.91(m,2H),5.32-5.25(m,1H),3.65(s,3H),2.75-2.53(m,4H),2.23-2.15(m,1H),2.05-1.89(m,2H),1.68-1.45(m,4H),0.92-0.87(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.43,170.60,141.20,127.91,125.51,120.28,69.67,51.68,49.02,39.01,34.74,25.86,24.97,24.91,11.80,11.69.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 335.1288, found 335.1285.IR (ATR) v (cm) -1 ) =2962, 2936,1731,1268,1172,1144,1080,1040,833,777,677.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=8.46 min (primary) and 9.86min (secondary).
Compound I' -23:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (140.6 mg,76% yield, 86% ee) [ α] D 29.9 ＝0.67(c 0.99,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.33-7.30(m,1H),7.02-6.99(m,2H),5.32-5.24(m,1H),4.69(s,2H),3.70(s,3H),3.51(t,J＝6.4Hz,2H),2.65(dd,J＝7.2,15.2Hz,1H),2.59(dd,J＝5.6,15.2Hz,1H),2.25-2.17(m,1H),1.76-1.61(m,6H),1.57-1.38(m,4H),0.92(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.43,170.80,141.30,126.50,126.07,125.56,70.02,69.55,67.26,51.64,49.04,39.03,33.70,29.24,24.97,24.91,21.73,11.75,11.66.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 393.1706, found 393.1712.IR (ATR) v (cm) -1 ) =2961, 2935,2864,1730,1458,1436,1267,1226,1168,1146,1085,1041,1017,993,937,853,830,699.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=8.88 min (primary) and 11.17min (secondary). Compound I' -24:
The reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (170.1 mg,81% yield, 91% ee) [ α] D 30 ＝-3.74(c 0.8,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ8.56(d,J＝8.0Hz,1H),8.37(s,1H),7.85(d,J＝7.6Hz,1H),7.50-7.45(m,1H),7.41-7.37(m,1H),5.36-5.32(m,1H),4.37-4.35(m,2H),3.65(s,3H),2.66(dd,J＝7.2,15.2Hz,1H),2.58(dd,J＝5.6,15.6Hz,1H),2.21-2.14(m,1H),1.89-1.82(m,4H),1.64-1.45(m,4H),0.88(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ175.42,170.51,162.57,139.93,136.59,136.57,127.00,125.33,124.91,124.57,122.41,69.60,63.99,51.69,48.98,38.98,30.64,24.95,24.86,24.55,11.76,11.64.IR(ATR)ν(cm -1 ) =2962, 2875,1730,1709,1503,1461,1436,1423,1385,1363,1262,1212,1169,1145,1065,1016,864,769,746,723.hrms: M/z (ESI-TOF) calculation [ m+na] + 443.1499, found 443.1489.HPLC (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=13.67 min (primary) and 17.02min (secondary).
Compound I' -25:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (139.8 mg,79% yield, 90% ee) [ α] D 24.3 ＝-4.48(c 0.77,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.98-7.97(m,1H),7.39(s,1H),6.70-6.69(m,1H),5.32-5.22(m,1H),4.22(s,2H),3.63(s,3H),2.61(dd,J＝7.2,15.6Hz,1H),2.53(dd,J＝5.6,15.6Hz,1H),2.18-2.10(m,1H),1.77-1.73(m,4H),1.63-1.40(m,4H),0.84(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 174.38,170.51,162.92,147.62,143.63,119.21,109.67,69.54,63.80,51.66,48.96,38.93,30.51,24.93,24.85,24.39,11.72,11.61.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 377.1571, found 377.1577.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=12.28 min (primary) and 15.37min (secondary).
Compound I' -26:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (141.7 mg,80% yield, 86% ee) [ α ] D 24.3 ＝-1.20(c 0.78,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.38-7.36(m,1H),6.32-6.26(m,2H),5.24-5.17(m,1H),4.39(s,2H),3.63(s,3H),3.42(t,J＝6.4Hz,2H),2.57(dd,J＝7.2,15.2Hz,1H),2.51(dd,J＝5.6,15.6Hz,1H),2.17-2.10(m,1H),1.67-1.53(m,6H),1.50-1.29(m,4H),0.85(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.56,170.93,152.07,142.73,110.27,109.08,70.16,69.90,64.79,51.77,49.18,39.15,33.82,29.34,25.11,25.06,21.82,11.87,11.79.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 377.1935, found 377.1941.IR (ATR) v (cm) -1 ) =2962, 2936,2865,1730,1502,1459,1437,1385,1355,1268,1226,1171,1147,1086,1014,994,919,884,812,736,600, hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=9.58 min (primary) and 10.83min (secondary).
Compound I' -27:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (136.5 mg,70% yield, 95% ee) [ α] D 24.3 ＝-23.26(c 0.78,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝8.0Hz,1H),7.59-7.52(m,2H),7.47-7.42(m,1H),7.32-7.28(m,1H),5.47-5.40(m,1H),4.51-4.35(m,2H),3.67(s,3H),2.77-2.65(m,2H),2.23-2.12(m,3H),1.67-1.44(m,4H),0.88(t,J＝6.8Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.36,170.36,159.30,155.75,145.16,127.67,126.87,123.78,122.87,114.13,112.33,67.22,61.31,51.80,48.96,38.96,32.85,24.94,24.84,11.74,11.66.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 413.1571, found 413.1572.IR (ATR) v (cm) -1 ) =2963, 2935,2876,1727,1614,1562,1459,1437,1384,1348,1327,1294,1258,1221,1209,1170,1143,1084,1008,970,950,885,836,813,749,613,429.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=14.88 min (primary) and 15.83min (secondary).
Compound I' -28:
the reaction was carried out according to general procedure 3, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (156.8 mg,78% yield, 91% ee) [ α] D 29.6 ＝-0.37(c 0.77,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.57-7.54(m,2H),7.45-7.40(m,1H),7.37-7.32(m,2H),5.28-5.20(m,1H),4.20(t,J＝6.4Hz,2H),3.64(s,3H),2.61(dd,J＝7.2,15.2Hz,1H),2.54(dd,J＝5.6,15.2Hz,1H),2.19-2.11(m,1H),1.78-1.54(m,6H),1.51-1.38(m,4H),0.89-0.83(m,6H). 13 C NMR(100MHz,CDCl 3 )δ175.45,170.67,154.03,132.89,130.56,128.49,119.52,86.16,80.50,69.74,65.59,51.66,49.02,39.02,33.47,28.05,24.96,24.90,21.49,11.74,11.64.HRMS:m/z(ESI-TOF) calculation [ M+Na] + 425.1935, found 425.1937.IR (ATR) v (cm) -1 ) =2963, 2936,2876,2220,1733,1704,1459,1443,1384,1283,1225,1185,1170,1082,1042,1000,937,757,689,534.Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=70/30, flow rate 0.7mL/min, detection at 214 nm) retention time= 15.46min (primary) and20.12min (secondary).
Compound I' -29:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (148.5 mg,79% yield, 86% ee) [ α] D 24.4 ＝-24.29(c 0.42,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.69(d,J＝16.4Hz,1H),7.55-7.51(m,2H),7.40-7.38(m,3H),6.43(d,J＝16.0Hz,1H),5.44-5.36(m,1H),4.35-4.28(m,1H),4.25-4.18(m,1H),3.68(s,3H),2.71(dd,J＝7.2,15.6Hz,1H),2.65(dd,J＝6.0,15.6Hz,1H),2.24-2.16(m,1H),2.12-2.06(m,2H),1.68-1.45(m,4H),0.89(t,J＝7.2Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.37,170.43,166.73,145.10,134.28,130.32,128.85,128.09,117.70,67.39,60.44,51.78,48.99,38.99,32.91,24.96,24.88,11.75,11.67.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 399.1778, found 399.1776.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=17.23 min (primary) and 22.70min (secondary).
Compound I' -30:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (185.0 mg,92% yield, 87% ee) [ alpha ]] D 24.5 ＝-2.23(c 2.0,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),6.73(dd,J＝10.8,17.6Hz,1H),5.84(dd,J＝0.4,17.6Hz,1H),5.36(dd,J＝0.8,11.2Hz,1H),5.29-5.22(m,1H),4.29(t,J＝6.8Hz,2H),3.64(s,3H),2.61(dd,J＝7.6,15.6Hz,1H),2.54(dd,J＝5.2,15.2Hz,1H),2.18-2.10(m,1H),1.82-1.66(m,4H),1.62-1.41(m,6H),0.87-0.82(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.42,170.66,166.26,141.82,135.94,129.77,129.37,126.00,116.37,69.81,64.51,51.66,49.03,39.06,33.61,28.38,24.96,24.91,21.74,11.75,11.65.HRMS: M/z (ESI-TOF) calculation [ M+Na ]] + 427.2091, found 427.2094.IR (ATR) v (cm) -1 ) =2962, 2876,1714,1607,1459,1437,1403,1385,1311,1270,1229,1175,1146,1103,1015,990,916,860,781,713.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=14.03 min (primary) and 17.64min (secondary).
Compound I' -31:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (158.5 mg,91% yield, 87% ee) [ alpha ]] D 24.5 ＝-17.67(c 0.76,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.32(d,J＝8.4Hz,2H),6.84(d,J＝8.4Hz,2H),6.64(dd,J＝11.2,17.6Hz,1H),5.61(d,J＝18.0Hz,1H),5.48-5.41(m,1H),5.12(d,J＝10.8Hz,1H),4.02(t,J＝6.0Hz,2H),3.66(s,3H),2.71(d,J＝6.4Hz,2H),2.21-2.12(m,3H),1.64-1.44(m,4H),),0.86(t,J＝7.2Hz,3H),0.84(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.37,170.57,158.22,136.06,130.44,127.29,114.29,111.58,67.83,63.82,51.74,48.99,39.10,33.37,25.00,24.94,11.75,11.67.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 371.1829, found 371.1839.IR (ATR) v (cm) -1 ) =2963, 2934,1731,1606,1509,1244,1170,1145,899,833,497.Hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=95/5, flow rate 0.7 mL/min) Detection at 214 nm) retention time = 10.73min (primary) and 11.39min (secondary) ·compound I' -32:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (156.2 mg,72% yield, 93% ee) [ α] D 24.9 ＝-15.80(c 0.98,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝8.8Hz,2H),6.85(d,J＝8.8Hz,2H),5.46-5.39(m,1H),4.80(s,1H),4.78(s,1H),4.37(t,J＝6.8Hz,2H),4.06(t,J＝6.0Hz,2H),3.64(s,3H),2.74-2.64(m,2H),2.44(t,J＝6.8Hz,2H),2.19-2.11(m,3H),1.78(s,3H),1.64-1.40(m,4H),0.87(t,J＝7.6Hz,3H),0.84(t,J＝7.6Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.29,170.42,166.17,162.20,141.73,131.47,122.89,113.92,112.23,67.60,64.04,62.79,51.68,48.93,39.05,36.76,33.28,24.91,24.84,22.43,11.65,11.58.hrms: M/z (ESI-TOF) calculation [ m+na ]] + 457.2197, found 457.2193.IR (ATR) v (cm) -1 ) =2963, 2935,2877,1733,1711,1605,1510,1458,1437,1380,1249,1165,1145,1102,1046,1010,890,847,769,695.Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time= 53.40min (minor) and 57.04min (major).
Compound I' -33:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (200.8 mg,80% yield, 94% ee) [ α] D 24.9 ＝-13.99(c 0.78,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝8.8Hz,2H),6.86(d,J＝8.8Hz,2H),5.46-5.40(m,2H),5.09-5.06(m,1H),4.79(d,J＝7.2Hz,2H),4.06(t,J＝6.0Hz,2H),3.65(s,3H),2.71-2.68(m,2H),2.20-2.05(m,7H),1.74(s,3H),1.66(s,3H),1.59(s,3H),1.62-1.43(m,4H),0.84(t,J＝7.6Hz,3H),0.82(t,J＝7.6Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.29,170.42,166.28,162.15,141.98,131.71,131.52,123.70,123.08,118.54,113.88,67.62,64.05,61.53,51.70,48.96,39.47,39.10,33.32,26.23,25.58,24.94,24.87,17.61,16.46,11.68,11.61.HRMS: M/z (ESI-TOF) calculation [ M+Na ] + 525.2823, measured 525.2825.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=17.36 min (primary) and 19.85min (secondary).
Compound I' -34:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (230.7 mg,71% yield, 92% ee) [ α ]] D 25.3 ＝-3.36(c 1.0,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.97(s,2H),7.49(d,J＝8.0Hz,1H),7.41-7.38(m,1H),7.33-7.27(m,1H),7.26-7.21(m,1H),5.57-5.50(m,1H),4.17(t,J＝6.4Hz,2H),3.69(s,3H),2.92-2.76(m,4H),2.35-2.27(m,2H),2.26-2.16(m,1H),1.69-1.45(m,4H),1.35(t,J＝7.6Hz,3H),0.89(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 ) 187.97,175.36,170.57,166.91,156.60,153.65,137.21,133.54,126.33,124.69,123.85,120.98,118.52,115.28,111.11,69.97,67.88,51.74,48.94,39.16,34.26,24.91,24.84,21.98,12.13,11.84,11.68.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 673.0407, found 673.0410.IR (ATR) v (cm) -1 ) =2963, 2936,1732,1648,1452,1377,1256,1171,1145,983,953,747.Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=9.67 min (minor) and 10.61min (major).
Compound I' -35:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (181.8 mg,90% yield, 91% ee) [ α] D 25.2 ＝-5.04(c 1.2,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝10.0Hz,1H)，7.32(d，J＝8.8Hz，1H)，6.77(dd，J＝2.4，8.4Hz，1H)，6.72(d，J＝2.0Hz，1H)，6.18(d，J＝9.6Hz，1H)5.32-5.25(m,1H),4.00-3.94(m,2H),3.62(s,3H),2.63(dd,J＝7.2,15.2Hz,1H),2.55(dd,J＝5.6,15.2Hz,1H),2.18-2.10(m,1H),1.88-1.78(m,2H),1.62-1.40(m,4H),0.84(t,J＝7.2Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.38,170.50,161.93,161.06,155.68,143.34,128.65,112.86,112.67,112.38,101.21,69.49,67.75,51.65,48.92,38.95,30.48,24.88,24.80,24.65,11.71,11.58.hrms: M/z (ESI-TOF) calculation [ m+na ] + 427.1727, found 427.1735.IR (ATR) v (cm) -1 ) Hplc (IB, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time= 46.130min (primary) and 50.45min (secondary).
Compound I' -36:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (196.7 mg,79% yield, 90% de.) [ alpha ]] D 25.3 ＝83.01(c 0.25,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.17(d,J＝8.4Hz,1H),6.67(dd,J＝2.8,8.8Hz,1H),6.61(d,J＝2.8Hz,1H),5.47-5.39(m,1H),3.99(t,J＝6.0Hz,2H),3.66(s,3H),2.90-2.85(m,2H),2.72-2.69(m,2H),2.49(dd,J＝8.4,18.8Hz,1H),2.41-2.36(m,1H),2.26-1.92(m,8H),1.67-1.54(m,4H),1.54-1.36(m,6H),0.90(s,3H),0.87(t,J＝7.6Hz,3H),0.86(t,J＝7.6Hz,3H). 13 C NMR(100MHz,CDCl 3 )220.85,175.31,170.57,156.52,137.68,132.17,126.25,114.49,111.93,68.01,63.83,51.66,50.32,48.96,47.92,43.89,39.09,38.27,35.78,33.50,31.49,29.54,26.45,25.82,24.92,24.86,21.50,13.76,11.73,11.63.hrms: M/z (ESI-TOF) calculation [ m+na] + 521.2874, found 521.2878.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm), retention time=18.47 min (primary) and20.53min (secondary).
Compound I' -37:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (216.0 mg,85% yield, 84% ee) [ alpha ] ] D 25.5 ＝-1.45(c 1.1,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ8.09(d,J＝2.4Hz,1H),7.88-7.85(m,1H),7.55-7.50(m,1H),7.46-7.38(m,2H),7.33(d,J＝7.2Hz,1H),7.00(d,J＝8.4Hz,1H),5.25-5.21(m,1H),5.16(s,2H),4.11-4.07(m,2H),3.63(s,3H),3.61(s,2H),2.59(dd,J＝7.6,15.2Hz,1H),2.51(dd,J＝5.2,15.2Hz,1H),2.18-2.10(m,1H),1.70-1.41(m,8H),0.85(t,J＝7.6Hz,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 190.65,175.34,171.24,170.50,160.36,140.30,136.22,135.47,132.67,132.31,129.36,129.13,127.71,127.70,125.01,120.95,73.50,69.51,64.32,51.65,48.93,40.08,38.93,30.43,24.90,24.83,24.31,11.73,11.62.hrms: M/z (ESI-TOF) calculation [ m+na] + 533.2146, found 533.2148.IR (ATR) v (cm) -1 ) Hplc (IH-3, 0.46 x 15cm,3 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=24.27 min (primary) and 27.19min (secondary).
Compound I' -38:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (169.4 mg,70% yield, 86% de) [ α] D 24.1 ＝5.02(c 0.66,CHCl 3 ).(m.p.60–61℃). 1 H NMR(400MHz,CDCl 3 )δ7.11(s,4H),5.28-5.21(m,1H),3.68(s,3H),2.62(dd,J＝7.6,15.2Hz,1H),2.56(dd,J＝5.6,15.6Hz,1H),2.47-2.38(m,1H),2.33(s,3H),2.23-2.14(m,1H),1.93-1.89(m,2H),1.85-1.76(m,6H),1.69-1.59(m,4H),1.55-1.38(m,4H),1.28-1.14(m,6H),1.09-0.97(m,3H),0.93-0.88(m,8H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.39,170.84,144.78,135.05,128.86,126.58,70.38,51.60,49.08,44.14,43.23,42.78,39.06,37.49,34.60,33.42,33.32,32.51,31.37,30.30,29.86,25.01,24.97,20.89,11.76,11.69.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 507.3445, found 507.3448.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=6.52 min (primary) and 8.37min (secondary).
Compound I' -39:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (142.1 mg,78% yield, 91% de) [ α] D 25.8 ＝12.08(c 0.84,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ8.05-8.02(m,2H),7.58-7.53(m,1H),7.46-7.41(m,2H),5.41-5.34(m,1H),5.28-5.19(m,1H),3.63(s,3H),2.66(d,J＝6.4Hz,2H),2.26-2.14(m,2H),1.97-1.90(m,1H),1.65-1.44(m,4H),1.39(d,J＝6.4Hz,3H),0.90-0.85(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.40,170.47,165.89,132.93,130.39,129.58,128.35,68.25,67.41,51.73,48.93,39.77,38.80,24.93,24.80,20.03,11.76,11.67.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 387.1778, found 387.1780.IR (ATR) v (cm) -1 ) Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=11.85 min (primary) and 15.57min (secondary).
Compound I' -40:
the reaction was carried out according to general procedure 6, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (136.6 mg,75% yield, 89% de) [ α] D 26.0 ＝40.48(c 0.5，CHCl 3 ). 1 H NMR(400MHz，CDCl 3 )δ8.03-8.00(m，2H)7.57-7.52(m,1H),7.45-7.40(m,2H),5.35-5.28(m,1H),5.22-5.13(m,1H),3.67(s,3H),2.72-2.61(m,2H),2.18-1.97(m,3H),1.60-1.41(m,4H),1.38(d,J＝6.4Hz,3H),0.86-0.81(m,6H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.32,170.51,165.90,132.83,130.48,129.53,128.31,67.89,67.09,51.74,48.82,40.33,39.18,24.84,24.63,20.56,11.68,11.63.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 387.1778, found 387.1786.IR (ATR) v (cm) -1 ) Hplc (IG, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=11.84 min (primary) and15.64min (secondary).
Compound I' -41:
the reaction was carried out according to general procedure 2, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (138.2 mg,71% yield, 92% de) [ α] D 26.4 ＝39.80(c 0.8,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.81-7.78(m,2H),7.70-7.67(m,2H),5.26-5.19(m,1H),4.46-4.36(m,1H),3.62(s,3H),2.61(d,J＝6.0Hz,2H),2.34-2.19(m,2H),2.14-1.06(m,1H),1.63-1.52(m,2H),1.49-1.40(m,5H),),0.85(t,J＝7.2Hz,3H),0.84(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.34,170.29,168.10,133.88,131.85,123.10,67.84,51.72,48.76,43.63,38.91,37.92,24.79,24.61,18.14,11.69,11.59.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 412.1731, found 412.1734.IR (ATR) v (cm) -1 ) Hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=13.22 min (primary) and 19.83min (secondary).
Compound I' -42:
the reaction was carried out according to general procedure 6, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (136.3 mg,70% yield, 96% de) [ α] D 25.9 ＝28.02(c 0.1,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.83-7.79(m,2H),7.72-7.67(m,2H),5.10-5.03(m,1H),4.52-4.42(m,1H),3.62(s,3H),2.72-2.65(m,1H),2.63(dd,J＝5.2,14.8Hz,1H),2.57(dd,J＝6.4,15.6Hz,1H),2.11-1.97(m,2H),1.63-1.53(m,2H),1.52-1.39(m,5H),0.91-0.89(t,J＝7.2Hz,3H),0.84(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.27,170.25,168.23,133.85,131.92,123.10,67.33,51.70,48.44,43.39,38.85,37.10,24.54,24.15,19.29,11.70,11.48.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 412.1731, found 412.1742.IR (ATR) v (cm) -1 ) Hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm), retention time=13.21 min (minor) and 19.62min (major).
Compound I' -43:
the reaction is carried out according toBy operating step 5, column chromatography (petroleum ether: ethyl acetate=10:1) gives the product as an oily liquid. (240.3 mg,90% yield, 99% ee.) (2 s, 2's)/meso=94/6. [ α] D 25.5 ＝-1.98(c 0.76,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.08(s,4H),5.31-5.24(m,2H),3.65(s,6H),2.69-2.53(m,8H),2.23-2.15(m,2H),2.01-1.85(m,4H),1.68-1.45(m,8H),0.92-0.87(m,12H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.43,170.64,138.77,128.34,69.78,51.68,49.06,39.06,35.79,31.01,25.00,24.93,11.83,11.71.HRMS: M/z (ESI-TOF) calculation [ M+Na ]] + 557.3085, found 557.3080.IR (ATR) v (cm) -1 ) Hplc (AD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=19.58 min (minor) and 24.31min (major).
Compound I' -44:
the reaction was carried out according to general procedure 5, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (252.1 mg,89% yield, 98% ee), (2 s, 2's)/meso=87/13 ] [ α] D 25.7 ＝-16.94(c 0.63,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ6.77(s,4H),5.47-5.40(m,2H),3.95(t,J＝5.6Hz,4H),3.65(s,6H),2.70(d,J＝6.4Hz,4H),2.20-2.09(m,6H),1.65-1.43(m,8H),0.87-0.81(m,12H). 13 C NMR(100MHz,CDCl 3 ) Delta 175.36,170.60,152.73,115.21,67.89,64.36,51.72,48.98,39.12,33.48,24.99,24.93,11.73,11.66.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 589.2983, found 589.2984.IR (ATR) v (cm) -1 ) Hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=95/5, flow rate 0.7mL/min, detection at 214 nm) retention time=38.86 min (primary) and 46.84min (secondary).
Compound I' -45:
the reaction was carried out according to general procedure 4, and column chromatography (petroleum ether: ethyl acetate=10:1) gave the product as an oily liquid. (2.72 g,93% yield, 96% ee (ee value measured after conversion to I' -11 according to general procedure 2)) [. Alpha. ]] D 26.1 ＝4.62(c 1.0,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.31-7.27(m,2H),7.22-7.17(m,3H),5.34-5.27(m,1H),2.75-2.60(m,4H),2.26-2.18(m,1H),2.06-1.93(m,2H),1.71-1.47(m,4H),0.92(t,J＝7.2Hz,3H),0.91(t,J＝7.2Hz,3H). 13 CNMR(100MHz,CDCl 3 ) 176.45,175.58,140.97,128.46,128.23,126.06,69.51,49.07,38.86,35.68,31.46,24.99,24.97,11.83,11.69.HRMS: M/z (ESI-TOF) calculation [ M+Na] + 315.1567, found 315.1573.IR (coat, cm) -1 ) 2964,2934,2876,1731,1708,1455,1385,1267,1226,1172,1144,1113,1082,1030,939,746,698 Compound I' -46 is obtained after conversion:
LiAlH under nitrogen protection 4 (38 mg,1.0mmol,5 equiv.) is dissolved in dry tetrahydrofuran (2 mL), a tetrahydrofuran solution (1 mL) of I' -45 (0.2 mmol,1 equiv.) is added at 0deg.C, and the mixture is left to react at room temperature for 3 hours after the completion of the dropwise addition. After the reaction was completed, an aqueous solution of NaOH (2 ml,2.5 m) was added, extracted with ethyl acetate, dried and concentrated, and used directly for the next reaction without purification. The crude product obtained above was dissolved in dichloromethane (1 mL) and PPh was added at 0deg.C 3 (52.4 mg,0.2mmol,1 equiv.) and NBS (35.6 mg,0.2mmol,1 equiv.). After 24 hours at room temperature, the mixture was concentrated and separated by column chromatography (petroleum ether: ethyl acetate=5:1) to give the product I' -46 as a white solid.
Compound I' -46:
(35.6 mg,74% yield, 97% ee) [ α] D 26.1 ＝5.16(c 0.41,CHCl 3 ).(m.p.48–49℃). 1 H NMR(400MHz,CDCl 3 )δ7.32-7.28(m,2H),7.22-7.18(m,3H),3.88-3.84(m,1H),3.60-3.50(m,2H),2.85-2.66(m,2H),2.08-1.94(m,2H),1.84-1.78(m,2H),1.60(brs,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 141.60,128.49,128.34,125.98,69.41,39.92,39.03,31.96,30.37.HRMS: M/z (EI-TOF) calculation [ M-H 2 O] + 224.0195, found 224.0195.IR (ATR) v (cm) -1 ) =3338, 2942,2910,2859,1492,1262,1148,1027,896,748,699,607,570,474.hplc (OD-H, 0.46 x 25cm,5 μm, n-hexane/isopropanol=90/10, flow rate 0.7mL/min, detection at 214 nm) retention time=13.08 min (primary) and 14.77min (secondary).
Single crystal preparation of Compound derivative Compound of formula I '-45 formula I' -46
The product with a retention time of 13.08min was single-crystal grown. The product with a retention time of 13.08min was dissolved in dichloromethane and the solvent was evaporated at room temperature to give colorless crystals.
Detection method X-ray single crystal diffraction
The crystal system of the compound shown in the formula I' -46 belongs to monoclinic system, the space group P21 is detected, and the unit cell parameter is
α=γ=90°, β= 106.762 (3) °; the single crystal parameters are shown in the following table; the X-ray single crystal diffraction is shown in figure 1. />
Characterization results from the resulting X-ray single crystal diffractionIt was revealed that the configuration of Compound I' -45 was confirmed to be
Thereby deriving the ligand->
In the presence of the catalyst, the configuration of the obtained main product is S-shaped.
According to the use of chiral ligands in this type of reaction in the art, it is known that, in the enantiomer of the ligand
In the presence, the product is obtained in the opposite configuration.
EXAMPLE 2 Effect of pyridine-oxazoline ligands on the oxycarbonylation reaction
Following procedure 1, procedure 1 was followed using the following ligands, the reaction results are shown below.
EXAMPLE 3 Effect of oxidants on oxycarbonylation reactions
Following the procedure of procedure 1 in example 1, the following oxidizing agents were used, and the reaction results are shown below.
EXAMPLE 4 Effect of solvent on the oxycarbonylation reaction
Following the procedure of procedure 1 in example 1, the following solvents were used, and the reaction results are shown below.
EXAMPLE 5 Effect of temperature on oxycarbonylation reactions
EXAMPLE 6 Effect of acid on oxycarbonylation reactions
Following the procedure of procedure 2 in example 1, the following acids were used and the reaction results are shown below.
Claims (25)
1. The preparation method of the carboxylic ester compound is characterized by comprising the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound containing a fragment II, a compound containing a tablet section III and carbon monoxide to obtain a compound containing a fragment I-1 and/or a compound containing a tablet section I-2;
Wherein the fragment II is
The fragment III is
The fragment I-1 is
Wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
the fragment I-2 is
Wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand
Wherein R is 5 And R is 6 Independently hydrogen, unsubstituted C 1 -C 10 Alkyl, unsubstituted C 3 -C 8 Cycloalkyl or unsubstituted C 6 -C 30 An aryl group;
R 7 is hydrogen, unsubstituted C 1 -C 10 Alkyl, or unsubstituted C 6 -C 30 An aryl group;
when the oxazoline ligand is
When (I)>
Wherein the carbon noted is chiral carbon of the S configuration;
when the oxazoline ligand is
When (I)>
In this, the carbon marked by x is chiral carbon of the R configuration.
2. The method for producing a carboxylic acid ester compound according to claim 1, wherein the solvent is one or more of an alkane solvent, a substituted aromatic hydrocarbon solvent, a nitrile solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, an ester solvent and an amide solvent;
and/or the concentration of the compound of the lozenge section II in the solvent is 0.01-5.00 mol/L;
and/or the palladium catalyst is one or more of palladium acetate, palladium trifluoroacetate, palladium quaternary valerate, palladium dichlorodiacetonitrile, bis (benzonitrile) palladium chloride, palladium bromide, palladium iodide, palladium tetrafluoroborate tetraacetonitrile, palladium hexafluoroacetylacetonate, palladium bis (acetylacetonate), palladium tetrafluoro-mesylate, palladium pivalate, (1E, 4E) -bis (dibenzylideneacetone) palladium, bis (dibenzylideneacetone) dipalladium and tris (dibenzylideneacetone) dipalladium;
And/or the molar ratio of the palladium catalyst to the compound of the buccal tablet segment II is (1-50): 100;
and/or the molar ratio of the oxazoline ligand to the compound of the lozenge segment II is (1-75): 100;
and/or the molar ratio of the palladium catalyst to the oxazoline ligand is 1: (0.5-3);
and/or the oxidant is benzoquinone and/or PhI (OAc) 2 ；
And/or the molar ratio of the oxidant to the compound of the buccal tablet section II is (1.0-5.0): 1;
and/or the molar ratio of the compound of the buccal tablet section III to the compound of the buccal tablet section II is (1.0-100) 1;
and/or the temperature of the addition reaction is-20-30 ℃;
and/or the time of the addition reaction is 1-168 hours;
and/or, the addition reaction further comprises the following post-treatment steps: adding solvent into the reaction solution, concentrating, and purifying;
and/or when R 5 And R is 6 Independently unsubstituted C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 4 An alkyl group;
and/or when R 5 And R is 6 Independently unsubstituted C 3 -C 8 In the case of cycloalkyl, said C 3 -C 8 Cycloalkyl radicals are C 3 -C 6 A monocyclic cycloalkyl group;
and/or when R 5 And R is 6 Independently unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 An aryl group;
and/or when R 7 Is unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 Aryl groups.
3. The process for producing a carboxylic acid ester compound according to claim 2, characterized in that,
the alkane solvent is n-hexane; the substituted aromatic hydrocarbon solvent is one or more of chlorobenzene, toluene and trifluoromethyl benzene; the nitrile solvent is acetonitrile; the halogenated hydrocarbon solvent is dichloromethane and chloroform; the ether solvent is one or more of tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, ethyl tertiary butyl ether, anisole, ethylene glycol dimethyl ether and 1, 4-dioxane; the ketone solvent is acetone; the ester solvent is ethyl acetate and/or ethylene glycol diacetate; the amide solvent is N, N-dimethylformamide;
and/or the concentration of the compound of the tablet section II in the solvent is 0.625 or 2.00mol/L;
and/or the palladium catalyst is palladium acetate;
and/or the molar ratio of the palladium catalyst to the compound of the buccal tablet segment II is (1-10): 100;
and/or the molar ratio of the oxazoline ligand to the compound of the lozenge segment II is 7.5:100 or 15:100;
And/or the molar ratio of the palladium catalyst to the oxazoline ligand is 1:1.5;
and/or the molar ratio of the oxidant to the compound of the buccal tablet section II is (1.0-3.0): 1;
and/or the molar ratio of the compound of the buccal tablet section III to the compound of the buccal tablet section II is (2.5-10) 1;
and/or the temperature of the addition reaction is 0-20 ℃;
and/or the time of the addition reaction is 10-72 hours;
and/or, in the post-treatment step, the solvent is an alcohol solvent or a ketone solvent and water;
and/or when R 5 And R is 6 Independently unsubstituted C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl or ethyl;
and/or when R 5 And R is 6 Independently unsubstituted C 3 -C 8 In the case of cycloalkyl, said C 3 -C 8 Cycloalkyl is cyclopentyl or cyclohexyl;
and/or when R 5 And R is 6 Independently unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is phenyl;
and/or when R 7 Is unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is phenyl.
4. The process for producing a carboxylic acid ester compound according to claim 2, characterized in that,
the solvent is an ether solvent and/or a halogenated hydrocarbon solvent;
and/or the concentration of the compound of the lozenge section II in the solvent is 0.01-0.20 mol/L;
And/or the molar ratio of the palladium catalyst to the compound of the lozenge section II is 5:100 or 10:100;
and/or the molar ratio of the oxidizing agent to the compound of the buccal tablet segment II is 1.2:1 or 3:1;
and/or the molar ratio of the compound of the buccal tablet section III to the compound of the buccal tablet section II is 5:1 or 10:1;
and/or the time of the addition reaction is 16 hours, 24 hours, 36 hours, 48 hours or 72 hours;
and/or in the post-treatment step, the solvent is an alcohol solvent, or a ketone solvent and water, wherein the alcohol solvent is methanol, and the ketone solvent is acetone.
5. The process for producing a carboxylic acid ester compound according to claim 4, wherein,
the solvent is diethyl ether and/or dichloromethane.
6. The process for producing a carboxylic acid ester compound according to claim 1, characterized in that,
R 5 and R is 6 Independently hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, or phenyl;
and/or R 7 Is unsubstituted C 6 -C 30 An aryl group;
and/or R 5 And R is 6 Identical, or R 5 And R is 6 Different, and one is H.
7. The process for producing a carboxylic acid ester compound according to claim 6, characterized in that,
R 7 Is phenyl.
8. The process for producing a carboxylic acid ester compound according to claim 1, wherein the oxazoline ligand is any one of the following compounds,
9. the method for producing a carboxylic acid ester compound according to claim 1, wherein the method for producing a carboxylic acid ester compound is one or two of the following methods;
the method comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound shown in a formula II-A, a compound shown in a formula III' and carbon monoxide to obtain a compound shown in a formula I-1-A and/or a compound shown in a formula I-2-A;
the second method is as follows: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound shown in a formula II-B, a compound shown in a formula III' and carbon monoxide to obtain a compound shown in a formula I-1-B and/or a compound shown in a formula I-2-B;
in the first and second methods, the operation and conditions of the addition reaction are as defined in any one of claims 1 to 8;
wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
R 1 is hydrogen, or R 1-1 Substituted or unsubstituted C 1 -C 30 An alkyl group;
R 1-1 cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl, R 1-1a Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, C, wherein the hetero atoms are one or more selected from N, O and S 2 -C 10 Alkenyl, -O (CH) 2 ) n R 1-1b 、-S(＝O) 2 R 1-1c 、-OC(＝O)R 1-1d 、-C(＝O)OR 1-1e 、
-C(＝O)R 1-1h Or->
n is an integer of 0 to 10;
R 1-1a is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, cyano, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group;
R 1-1b is R 1-1b-1 Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, wherein the hetero atoms are one or more selected from N, O and S,
R 1-1b-1 Is nitro, aldehyde, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, -S (=o) 2 R 1-1b-1a 、
-C(＝O)OR 1-1b-1f or-C (=O) R 1-1b-1g ；
R 1-1b-1a 、R 1-1b-1b 、R 1-1b-1c 、R 1-1b-1d And R is 1-1b-1e Independently C 1 -C 10 An alkyl group;
R 1-1b-1f and R is 1-1b-1g Independently C 2 -C 10 Alkenyl, or by one or more C 1 -C 10 An alkyl substituted or unsubstituted "heteroatom selected from one or more of N, O and S, a 5-to 15-membered heteroaryl having 1-4 heteroatoms;
R 1-1c 、R 1-1f and R is 1-1g Independently hydrogen, C 6 -C 30 Aryl or p-toluenesulfonyl;
R 1-1d is R 1-1d-1 Substituted or unsubstituted C 1-10 Alkyl, R 1-1d-2 Substituted or unsubstituted C 2-10 Alkenyl, R 1-1d-3 Substituted or unsubstituted C 2-10 Alkynyl, R 1-1d-4 Substituted or unsubstituted C 6-30 Aryl, R 1-1d-5 A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R 1-1d-1 is-OR 1-1d-1a Or (b)
R 1-1d-1a Is R 1-1d - 1a-1 Substituted or unsubstituted C 6 -C 30 An aryl group; r is R 1 -1d-1a-1 For C substituted by one or more halogens 3 -C 15 Cycloalkyl;
R 1-1d-2 and R is 1-1d-3 Independently C 6 -C 30 An aryl group;
R 1-1d-4 is-C (=O) OR 1-1d-4a ；R 1-1d-4a Is C 2 -C 10 Alkenyl, or by one or more-OC (=o) R 1-1d-4a-1 Substituted C 1 -C 10 An alkyl group; r is R 1-1d-4a-1 Is C 1 -C 10 An alkyl group;
R 1-1d-5 is p-toluenesulfonyl;
R 1-1e is hydrogen, C 1 -C 10 Alkyl or
R 1-1h Is C 2 -C 10 Alkenyl, or by one or more-OC (=o) R 1-1h-1 Substituted C 1 -C 10 An alkyl group; r is R 1-1h-1 Is C 1 -C 10 An alkyl group;
R 2 is hydrogen, R 2-1 Substituted or unsubstituted C 1 -C 30 Alkyl, R 2-2 Substituted or unsubstituted C 6 -C 30 Aryl, or C 2 -C 10 Alkenyl groups;
R 2-1 cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl, R 2-1a Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, C, wherein the hetero atoms are one or more selected from N, O and S 2 -C 10 Alkenyl, -O (CH) 2 ) n R 2-1b 、-S(＝O) 2 R 2-1c 、-OC(＝O)R 2-1d 、-C(＝O)OR 2-1e 、
-C(＝O)R 2-1h Or->
R 2-2 Is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, cyano, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group;
R 2-1a is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, cyano, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group;
R 2-1b is R 2-1b-1 Substituted or unsubstituted C 6 -C 30 Aryl, 5-15 membered heteroaryl with 1-4 hetero atoms, wherein the hetero atoms are one or more selected from N, O and S,
R 2-1b-1 Is nitro, aldehyde, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, -S (=o) 2 R 2-1b-1a 、
-C(＝O)OR 2-1b-1f or-C (=O) R 2-1b-1g ；
R 2-1b-1a 、R 2-1b-1b 、R 2-1b-1c 、R 2-1b-1d And R is 2-1b-1e Independently C 1 -C 10 An alkyl group;
R 2-1b-1f and R is 2-1b-1g Independently C 2 -C 10 Alkenyl, or C 1 -C 10 An alkyl substituted or unsubstituted "heteroatom selected from one or more of N, O and S, a 5-to 15-membered heteroaryl having 1-4 heteroatoms;
R 2-1c 、R 2-1f and R is 2-1g Independently hydrogen, C 6 -C 30 Aryl or p-toluenesulfonyl;
R 2-1d is R 2-1d-1 Substituted or unsubstituted C 1-10 Alkyl, R 2-1d-2 Substituted or unsubstituted C 2-10 Alkenyl, R 2-1d-3 Substituted or unsubstituted C 2-10 Alkynyl, R 2-1d-4 Substituted or unsubstituted C 6-30 Aryl, R 2-1d-5 A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R 2-1d-1 is-OR 2-1d-1a Or (b)
R 2-1d-1a Is R 2-1d-1a-1 Substituted or unsubstituted C 6 -C 30 An aryl group; r is R 2 -1d-1a-1 For C substituted by one or more halogens 3 -C 15 Cycloalkyl;
R 2-1d-2 and R is 2-1d-3 Independently C 6 -C 30 An aryl group;
R 2-1d-4 is-C (=O) OR 2-1d-4a ；R 2-1d-4a Is C 2 -C 10 Alkenyl groups;
R 2-1d-5 is p-toluenesulfonyl;
R 2-1e is hydrogen or C 1 -C 10 An alkyl group;
R 2-1h is C 2 -C 10 Alkenyl groups;
R 8 is C 1 -C 10 Alkylene group,
Or- (CH) 2 ) m3 -O(C＝O)-(C 6 -C 10 Arylene) - (c=o) O- (CH 2 ) m4 -；
m1, m2, m3 and m4 are independently 0, 1, 2, 3, 4, 5 or 6;
or a compound represented by the formula II-B is selected from any one of the following compounds:
10. the method for producing carboxylic acid ester compound according to claim 9, wherein R 1-1 、R 1-1a 、R 1-1b-1 、R 1 -1d-1 、R 1-1d-2 、R 1-1d-3 、R 1-1d-4 、R 1-1d-5 、R 1-1d-1a-1 、R 8-1 And R is 8-1a-1 Independently 1 or more, and when plural, the same or different;
and/or when R 1 Is R 1-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is C 1 -C 10 An alkyl group;
and/or, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R 1-1 Is C 3 -C 15 When cycloalkyl is a cycloalkyl group, C 3 -C 15 Cycloalkyl of (2) is monocyclic C 3 -C 15 Cycloalkyl, condensed ring C 3 -C 15 Cycloalkyl, spiro C 3 -C 15 Cycloalkyl or bridged ring C of (C) 3 -C 15 Cycloalkyl of (c);
and/or when R 1-1 Is R 1-1a Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 An aryl group;
and/or when R 1-1 Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 6 Alkenyl groups;
and/or when R 1-1a When halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R 1-1a Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 1-1a Is C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 An aryl group;
and/or when R 1-1b Is R 1-1b-1 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 An aryl group;
and/or when R 1-1b When the hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 ", the hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4, and the hetero atom of the 5-15 membered hetero aryl is selected from one or more of N, O and S and the hetero atom number is 1-4, and is a 5-15 membered monocyclic hetero aryl or a 5-15 membered bicyclic hetero aryl;
And/or n is 0, 1, 2, 3, 4, 5 or 6;
and/or when R 1-1b-1 Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 1-1b-1 Is C 2 -C 10 In the case of alkenyl, the alkenyl is C 2 -C 4 Alkenyl groups;
and/or when R 1-1b-1a 、R 1-1b-1b 、R 1-1b-1c 、R 1-1b-1d And R is 1-1b-1e Independently C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is independently C 1 -C 6 An alkyl group;
and/or when R 1-1b-1f Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl groups being
And/or when R 1-1b-1g Is one or more C 1 -C 10 When the alkyl substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4' 5-15 membered heteroaryl, C 1 -C 10 The number of the alkyl groups is 1, 2 or 3;
and/or when R 1-1b-1g Is C 1 -C 10 When the heteroatom of the alkyl substituted or unsubstituted 'heteroatom is selected from one or more of N, O and S and the heteroatom number is 1-4' and is a 5-15 membered heteroaryl, the 'heteroatom is selected from one or more of N, O and S, the 5-15 membered heteroaryl with the heteroatom number of 1-4' is 'heteroatom is selected from one or more of N, O and S, and the 5-15 membered monocyclic heteroaryl or the 5-15 membered bicyclic heteroaryl with the heteroatom number of 1-4';
and/or when R 1-1b-1g Is one or more C 1 -C 10 When the alkyl substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4, the C is 5-15 membered heteroaryl 1 -C 10 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 1-1c 、R 1-1f And R is 1-1g Independently C 6 -C 30 Aryl, the C 6 -C 30 Aryl is independently C 6 -C 10 An aryl group;
and/or when R 1-1d Is R 1-1d-1 Substituted or unsubstituted C 1-10 In the case of alkyl, said C 1-10 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 1-1d Is R 1-1d-2 Substituted or unsubstituted C 2-10 In the case of alkenyl, said C 2-10 Alkenyl group is C 2-4 Alkenyl groups;
and/or when R 1-1d Is R 1-1d-3 Substituted or unsubstituted C 2-10 In the case of alkynyl, said C 2-10 Alkynyl is C 2-4 Alkynyl;
and/or when R 1-1d Is R 1-1d-4 Substituted or unsubstituted C 6-30 Aryl, the C 6-30 Aryl is C 6-10 An aryl group;
and/or when R 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 '5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4' 5-15 membered heteroaryl is 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4' 5-15 membered monocyclic heteroaryl or 5-15 membered bicyclic heteroaryl;
and/or when R 1-1d-1a Is R 1-1d-1a-1 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 An aryl group;
and/or when R 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 In the case of cycloalkyl, the number of the halogen is 1, 2 or 3;
And/or when R 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 When cycloalkyl, halogen is fluorine, chlorine, bromine or iodine;
and/or when R 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 In the case of cycloalkyl, said C 3 -C 15 Cycloalkyl radicals are C 3 -C 15 Monocyclic cycloalkyl, C 3 -C 15 Condensed ring cycloalkyl, C 3 -C 15 Spiro cycloalkyl or C 3 -C 15 Bridged cycloalkyl;
and/or when R 1-1d-2 And R is 1-1d-3 Independently C 6 -C 30 Aryl, the C 6 -C 30 Aryl is independently C 6 -C 10 An aryl group;
and/or when R 1-1d-4a Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 4 Alkenyl groups;
and/or when R 1-1e Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 1-1h Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 6 Alkenyl groups;
and/or R 2-1 、R 2-2 、R 2-1a 、R 2-1b-1 、R 2-1d-1 、R 2-1d-2 、R 2-1d-3 、R 2-1d-4 、R 2-1d-5 And R is 2-1d-1a-1 Independently 1 or more, and when plural, the same or different;
and/or when R 2 Is R 2-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is C 1 -C 10 An alkyl group;
and/or when R 2 Is R 2-2 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 An aryl group;
and/or when R 2 Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl group is C 2 -C 4 Alkenyl groups;
and/or when R 2-2 In the case of halogen, the halogen is fluorineChlorine, bromine or iodine;
and/or when R 2-2 Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 2-2 Is C 1 -C 10 In the case of alkoxy, said C 1 -C 10 Alkoxy is C 1 -C 4 An alkoxy group;
and/or when R 2-2 Is C 6 -C 30 Aryl, the C 6 -C 30 Aryl is C 6 -C 10 An aryl group;
and/or when R 2-2 For C substituted by one or more halogens 1 -C 10 When alkyl is used, the number of the halogen is 1, 2 or 3;
and/or when R 2-2 For C substituted by one or more halogens 1 -C 10 When alkyl, halogen is fluorine, chlorine, bromine or iodine;
and/or when R 2-2 For C substituted by one or more halogens 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 8 Is R 8-1 Substituted or unsubstituted C 1 -C 10 R in the case of alkylene 8-1 The number of (2) is 1, 2 or 3;
and/or when R 8 Is R 8-1 Substituted or unsubstituted C 1 -C 10 In the case of alkylene, said C 1 -C 10 Alkylene is C 1 -C 6 An alkylene group;
and/or when R 8 Is- (CH) 2 ) m3 -O(C＝O)-(C 6 -C 10 Arylene) - (c=o) O- (CH 2 ) m4 -wherein C 6 -C 10 Arylene is phenylene;
and/or, m1, m2, m3, and m4 are independently 1, 2, or 3.
11. The process for producing a carboxylic acid ester compound according to claim 10, characterized in that,
R 1-1 、R 1-1a 、R 1-1b-1 、R 1-1d-1 、R 1-1d-2 、R 1-1d-3 、R 1-1d-4 、R 1-1d-5 、R 1-1d-1a-1 、R 8-1 and R is 8-1a-1 Independently 1 or more, when a plurality, said plurality is 2, 3 or 4;
and/or when R 1 Is R 1-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is C 1 -C 8 An alkyl group;
and/or, the halogen is chlorine or bromine;
And/or when R 1-1 Is C 3 -C 15 When cycloalkyl is a cycloalkyl group, C 3 -C 15 Cycloalkyl of (2) is monocyclic C 3 -C 15 Cycloalkyl of (c);
and/or when R 1-1 Is R 1-1a Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is phenyl or naphthyl;
and/or when R 1-1 Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl groups being
And/or when R 1-1a When halogen, the halogen is fluorine or iodine;
and/or when R 1-1a Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 1-1a Is C 6 -C 30 Aryl, the C 6 -C 30 Aryl is phenyl;
and/or when R 1-1b Is R 1-1b-1 Substituted or unsubstituted C 6 -C 30 Aryl radicals, as describedC 6 -C 30 Aryl is phenyl or naphthyl;
and/or when R 1-1b When the hetero atom is one or more of N, O and S and is 5-15 membered heteroaryl with 1-4 hetero atoms, the hetero atom is one or more of N, O and S, and the 5-15 membered heteroaryl with 1-4 hetero atoms is a 5-15 membered monocyclic heteroaryl with 1-4 hetero atoms, wherein the hetero atom is one or more of N, O and S;
and/or n is 0 or 1;
and/or when R 1-1b-1 Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
And/or when R 1-1b-1 Is C 2 -C 10 In the case of alkenyl, the alkenyl is
And/or when R 1-1b-1a 、R 1-1b-1b 、R 1-1b-1c 、R 1-1b-1d And R is 1-1b-1e Independently C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 1-1b-1g Is C 1 -C 10 When the heteroatom of the alkyl substituted or unsubstituted 'heteroatom is selected from one or more of N, O and S and is 5-15 membered heteroaryl with 1-4 heteroatoms', the 'heteroatom is selected from one or more of N, O and S, and the 5-15 membered heteroaryl with 1-4 heteroatoms' is '5-15 membered bicyclic heteroaryl with 1-4 heteroatoms' selected from one or more of N, O and S;
and/or when R 1-1b-1g Is one or more C 1 -C 10 The "heteroatom substituted or unsubstituted by alkyl" is selected from one or more of N, O and S, and the number of the heteroatom is 1-4 "5-15 memberedHeteroaryl, C 1 -C 10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 1-1c 、R 1-1f And R is 1-1g Independently C 6 -C 30 Aryl, the C 6 -C 30 Aryl is independently phenyl;
and/or when R 1-1d Is R 1-1d-1 Substituted or unsubstituted C 1-10 In the case of alkyl, said C 1-10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
And/or when R 1-1d Is R 1-1d-2 Substituted or unsubstituted C 2-10 In the case of alkenyl, said C 2-10 Alkenyl groups being
And/or when R 1-1d Is R 1-1d-3 Substituted or unsubstituted C 2-10 In the case of alkynyl, said C 2-10 Alkynyl is
And/or when R 1-1d Is R 1-1d-4 Substituted or unsubstituted C 6-30 Aryl, the C 6-30 Aryl is phenyl;
and/or when R 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 'and the hetero atom is 5-15 membered hetero aryl, the hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4' and the hetero atom is 5-15 membered hetero arylN, O and S, a 5-to 15-membered monocyclic heteroaryl group or a 5-to 15-membered bicyclic heteroaryl group having 1-4 "heteroatoms; wherein the 'hetero atom is selected from one or more of N, O and S, the 5-15 membered monocyclic heteroaryl with 1-4 hetero atoms' is '5-6 membered monocyclic heteroaryl with 1 or 2 hetero atoms' selected from one or more of N, O and S; when R is 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 '5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4' 5-15 membered heteroaryl is 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4' 5-15 membered monocyclic heteroaryl or 5-15 membered bicyclic heteroaryl; wherein the 'hetero atom is selected from one or more of N, O and S, the 5-15 membered bicyclic heteroaryl with 1-4 hetero atoms' is '8-10 membered bicyclic heteroaryl with 1 or 2 hetero atoms' selected from one or more of N, O and S;
And/or when R 1-1d-1a Is R 1-1d-1a-1 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is phenyl;
and/or when R 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 When cycloalkyl, halogen is chlorine;
and/or when R 1-1d-1a-1 For C substituted by one or more halogens 3 -C 15 In the case of cycloalkyl, said C 3 -C 15 Cycloalkyl radicals are C 3 -C 15 A monocyclic cycloalkyl group;
and/or when R 1-1d-2 And R is 1-1d-3 Independently C 6 -C 30 Aryl, the C 6 -C 30 Aryl is independently phenyl;
and/or when R 1-1d-4a Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl groups being
And/or when R 1-1e Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 1-1h Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl groups being
And/or R 2-1 、R 2-2 、R 2-1a 、R 2-1b-1 、R 2-1d-1 、R 2-1d-2 、R 2-1d-3 、R 2-1d-4 、R 2-1d-5 And R is 2-1d-1a-1 Independently 1 or more, when a plurality, said plurality is 2, 3 or 4;
and/or when R 2 Is R 2-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is C 1 -C 6 An alkyl group;
and/or when R 2 Is R 2-2 Substituted or unsubstituted C 6 -C 30 Aryl, the C 6 -C 30 Aryl is phenyl or naphthyl;
and/or when R 2 Is C 2 -C 10 In the case of alkenyl, said C 2 -C 10 Alkenyl is vinyl;
and/or when R 2-2 When halogen, the halogen is fluorine or chlorine;
And/or when R 2-2 Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 2-2 Is C 1 -C 10 In the case of alkoxy, said C 1 -C 10 Alkoxy is methoxy;
and/or when R 2-2 Is C 6 -C 30 Aryl, the C 6 -C 30 Aryl is phenyl;
and/or when R 2-2 For C substituted by one or more halogens 1 -C 10 When alkyl, halogen is fluorine;
and/or when R 2-2 For C substituted by one or more halogens 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 8 Is R 8-1 Substituted or unsubstituted C 1 -C 10 In the case of alkylene, said C 1 -C 10 Alkylene is methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, sec-butylene or tert-butylene;
and/or when R 8 Is- (CH) 2 ) m3 -O(C＝O)-(C 6 -C 10 Arylene) - (c=o) O- (CH 2 ) m4 -wherein C 6 -C 10 Arylene group is
12. The process for producing a carboxylic acid ester compound according to claim 10, characterized in that,
when R is 1 Is R 1-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is methyl,
And/or when R 1-1 Is C 3 -C 15 When cycloalkyl is a cycloalkyl group, C 3 -C 15 Cycloalkyl of (2) is monocyclic C 3 -C 15 Cycloalkyl, condensed ring C 3 -C 15 Cycloalkyl, spiro C 3 -C 15 Cycloalkyl or bridged ring C of (C) 3 -C 15 Wherein, the monocyclic C 3 -C 15 Cycloalkyl of (C) 3 -C 6 Cycloalkyl of (c);
and/or when R 1-1a Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is tert-butyl;
and/or when R 1-1b When the hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 ", the hetero atom is selected from one or more of N, O and S, the hetero atom of the 5-15 membered hetero aryl group with the hetero atom number of 1-4 is selected from one or more of N, O and S, the hetero atom number of the 5-15 membered monocyclic hetero aryl group with the hetero atom number of 1-4 or the 5-15 membered bicyclic hetero aryl group, wherein the hetero atom is selected from one or more of N, O and S, the 5-15 membered monocyclic hetero aryl group with the hetero atom number of 1-4 is selected from one or more of N, O and S, and the 5-6 membered monocyclic hetero aryl group with the hetero atom number of 1 or 2';
and/or when R 1-1b-1 Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is tert-butyl;
and/or when R 1-1b-1a 、R 1-1b-1b 、R 1-1b-1c 、R 1-1b-1d And R is 1-1b-1e Independently C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is independently methyl;
and/or when R 1-1b-1g Is C 1 -C 10 When the alkyl substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 ' 5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4 ' 5-15 membered heteroaryl is selected from one or more of N, O and S, and the hetero atom number is 1-4 ' 5-15 membered monocyclic heteroaryl A group or 5-15 membered bicyclic heteroaryl, wherein the "heteroatom is selected from one or more of N, O and S, the 5-15 membered bicyclic heteroaryl having 1-4 heteroatoms" is an 8-10 membered bicyclic heteroaryl having "heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1 or 2";
and/or when R 1-1b-1g Is one or more C 1 -C 10 When the alkyl substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4, the C is 5-15 membered heteroaryl 1 -C 10 Alkyl is ethyl;
and/or when R 1-1d Is R 1-1d-1 Substituted or unsubstituted C 1-10 In the case of alkyl, said C 1-10 Alkyl is methyl or isopropyl;
and/or when R 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 '5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4' 5-15 membered heteroaryl is 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4' 5-15 membered monocyclic heteroaryl or 5-15 membered bicyclic heteroaryl; wherein the heteroatom is one or more of N, O and S, and the 5-15 membered monocyclic heteroaryl with 1-4 heteroatoms is furyl;
When R is 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 '5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4' 5-15 membered heteroaryl is 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4' 5-15 membered monocyclic heteroaryl or 5-15 membered bicyclic heteroaryl; wherein the heteroatom is selected from one or more of N, O and S, and the 5-15 membered bicyclic heteroaryl with the heteroatom number of 1-4 is benzofuranyl, benzothienyl or indolyl;
and/or, the C 3 -C 15 Monocyclic cycloalkyl of C 3 -C 6 A monocyclic cycloalkyl group;
and/or when R 1-1e Is C 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl or ethyl;
and/or when R 2 Is R 2-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 2-2 For C substituted by one or more halogens 1 -C 10 In the case of alkyl, said C 1 -C 10 Alkyl is methyl;
and/or when R 8 Is R 8-1 Substituted or unsubstituted C 1 -C 10 In the case of alkylene, said C 1 -C 10 The alkylene group is methylene or ethylene.
13. The process for producing a carboxylic acid ester compound according to claim 12, characterized in that,
when R is 1-1 Is C 3 -C 15 When cycloalkyl is a cycloalkyl group, C 3 -C 15 Cycloalkyl of (2) is monocyclic C 3 -C 15 Cycloalkyl, condensed ring C 3 -C 15 Cycloalkyl, spiro C 3 -C 15 Cycloalkyl or bridged ring C of (C) 3 -C 15 Wherein, the monocyclic C 3 -C 15 Cycloalkyl of (2) is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or when R 1-1b In the case of a 5-15 membered heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and S, the 5-15 membered heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and S is a 5-15 membered monocyclic heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and S, or a 5-15 membered bicyclic heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and SA plurality of 5-15 membered monocyclic heteroaryl groups with 1-4 heteroatoms are thienyl;
and/or when R 1-1b-1g Is C 1 -C 10 When the heteroatom of the alkyl substituted or unsubstituted 'heteroatom is selected from one or more of N, O and S and is 5-15 membered heteroaryl with 1-4 heteroatoms', the 'heteroatom is selected from one or more of N, O and S, the 5-15 membered heteroaryl with 1-4 heteroatoms' is 'heteroatom is selected from one or more of N, O and S, the 5-15 membered monocyclic heteroaryl with 1-4 heteroatoms' or the 5-15 membered bicyclic heteroaryl, wherein the 'heteroatom is selected from one or more of N, O and S, and the 5-15 membered bicyclic heteroaryl with 1-4 heteroatoms' is benzofuranyl;
And/or when R 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 '5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4' 5-15 membered heteroaryl is 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4' 5-15 membered monocyclic heteroaryl or 5-15 membered bicyclic heteroaryl; wherein the hetero atom is one or more of N, O and S, and the 5-15 membered monocyclic heteroaryl with 1-4 hetero atoms is
When R is 1-1d Is R 1-1d-5 When the substituted or unsubstituted hetero atom is selected from one or more of N, O and S and the hetero atom number is 1-4 '5-15 membered heteroaryl, the hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-4' 5-15 membered heteroaryl is 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-4' 5-15 membered monocyclic heteroaryl or 5-15 membered bicyclic heteroaryl; wherein the hetero atom is one or more of N, O and S, and the 5-15 membered bicyclic heteroaryl with 1-4 hetero atoms is 
And/or, the C 3 -C 15 The monocyclic cycloalkyl is cyclopropyl;
and/or when R 2 Is R 2-1 Substituted or unsubstituted C 1 -C 30 In the case of alkyl, said C 1 -C 30 Alkyl is methyl.
14. The process for producing a carboxylic acid ester compound according to claim 13, characterized in that,
said single ring C 3 -C 15 Cycloalkyl of (2) is cyclohexyl;
and/or when R 1-1b In the case of a 5-15 membered heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and S, the 5-15 membered heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and S is a 5-15 membered monocyclic heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and S, or a 5-15 membered bicyclic heteroaryl group having 1-4 hetero atoms selected from one or more of N, O and S, and a 5-15 membered monocyclic heteroaryl group having 1-4 hetero atoms is
And/or when R 1-1b-1g Is C 1 -C 10 When the heteroatom of the alkyl substituted or unsubstituted 'heteroatom is selected from one or more of N, O and S and 5-15 membered heteroaryl with 1-4 heteroatoms', the 'heteroatom is selected from one or more of N, O and S, the 5-15 membered heteroaryl with 1-4 heteroatoms' is 'heteroatom is selected from one or more of N, O and S, the 5-15 membered monocyclic heteroaryl with 1-4 heteroatoms' or 5-15 membered bicyclic heteroaryl, wherein the 'heteroatom is selected from one or more of N, O and S, and the 5-15 membered bicyclic heteroaryl with 1-4 heteroatoms' is 
15. The method for producing carboxylic acid ester compound according to claim 9, wherein when R 1-1 Is R 1-1a Substituted or unsubstituted C 6 -C 30 In the case of aryl radicals, R 1-1 In any one of the structures described in the following,
and/or when R 1-1 is-O (CH) 2 ) n R 1-1b When R is 1-1 In any one of the structures described in the following,
and/or when R 1-1 is-OC (=O) R 1-1d When R is 1-1 In any one of the structures described in the following,
and/or when R 1-1 is-C (=O) OR 1-1e When R is 1-1 In any one of the structures described in the following,
16. the method for producing carboxylic acid ester compound according to claim 9, wherein R 1 Is R 1-1 Substituted or unsubstituted C 1 -C 30 An alkyl group;
and/or R 1-1 Cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl of (c)、R 1-1a Substituted or unsubstituted C 6 -C 30 Aryl, C 2 -C 10 Alkenyl, -O (CH) 2 ) n R 1-1b 、-S(＝O) 2 R 1-1c 、-OC(＝O)R 1-1d 、-C(＝O)OR 1-1e 、
-C(＝O)R 1-1h Or->
And/or R 1-1a Is halogen, C 1 -C 10 Alkyl or C 6 -C 30 An aryl group;
and/or R 1-1d Is R 1-1d-1 Substituted or unsubstituted C 1-10 Alkyl, R 1-1d-2 Substituted or unsubstituted C 2-10 Alkenyl, R 1-1d-3 Substituted or unsubstituted C 2-10 Alkynyl, unsubstituted C 6-30 Aryl, R 1-1d-5 A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
and/or R 1-1h Is C 2 -C 10 Alkenyl groups;
and/or R 2 Is hydrogen, unsubstituted C 1 -C 30 Alkyl, or R 2-2 Substituted or unsubstituted C 6 -C 30 An aryl group;
and/or R 2-2 Is halogen, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 6 -C 30 Aryl or C substituted by one or more halogens 1 -C 10 An alkyl group.
17. The process for producing a carboxylic acid ester compound according to claim 16, characterized in that,
R 1-1 cyano, hydroxy, nitro, halogen, C 3 -C 15 Cycloalkyl, C 2 -C 10 Alkenyl group,-O(CH 2 ) n R 1-1b 、-S(＝O) 2 R 1 -1c 、-OC(＝O)R 1-1d 、-C(＝O)OR 1-1e 、
C(＝O)R 1-1h Or->
18. The method for producing carboxylic acid ester compound according to claim 9, wherein R 1-1 In any one of the structures described in the following,
19. the method for producing carboxylic acid ester compound according to claim 9, wherein the compound represented by the formula II-a is selected from any one of the following compounds:
the compound shown in the formula III' is selected from any one of the following compounds:
the compound shown in the formula I-2-A is:
20. the preparation method of the chiral beta-acyloxy carboxylic ester compound is characterized by comprising the following steps:
(1) In a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out an addition reaction on a compound containing a fragment II, a compound containing a fragment III and carbon monoxide;
(2) In a solvent, carrying out methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound containing a fragment I;
Wherein the fragment II is
The fragment III is
/>
The fragment I is
Wherein, the carbon marked by x refers to S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand
Wherein R is 5 、R 6 And R is 7 Is as defined in any one of claims 1 to 19;
when the oxazoline ligand is
In the time-course of which the first and second contact surfaces,
wherein the carbon noted is chiral carbon of the S configuration;
when the oxazoline ligand is
In the time-course of which the first and second contact surfaces,
wherein the carbon noted is chiral carbon of the R configuration;
the reaction operations and conditions of step (1) are as defined in any one of claims 1 to 8.
21. The method for producing chiral β -acyloxycarboxylic acid ester compounds according to claim 20, wherein in step (2), the solvent is an alcohol solvent and/or a substituted aromatic hydrocarbon solvent;
and/or, in the step (2), the methylation reagent is TMSCHN 2 ；
And/or, in step (2), the molar ratio of the methylating agent to the compound of the lozenge segment II in step (1) is (2-10): 1, a step of;
and/or the temperature of the methylation reaction is 20-30 ℃;
and/or the methylation reaction time is 1-10 hours;
and/or, the step (1) further comprises the following post-treatment steps: and adding a solvent into the reaction liquid, and concentrating to perform the next reaction.
22. The method for preparing chiral β -acyloxycarboxylic acid ester compounds according to claim 21, wherein in step (2), the alcohol solvent is methanol and/or ethanol; the substituted aromatic hydrocarbon solvent is one or more of chlorobenzene, toluene and trifluoromethyl benzene;
and/or, in step (2), the molar ratio of the methylating agent to the compound of the lozenge segment II in step (1) is 4:1;
and/or the methylation reaction time is 2-6 hours;
and/or, in the post-treatment step of the step (1), the solvent is an alcohol solvent.
23. The method for producing chiral β -acyloxycarboxylic acid ester compounds according to claim 22, wherein in step (2), the solvent is a mixed solvent of methanol and/or toluene;
and/or, the methylation reaction time is 4 hours or 6 hours;
and/or, in the post-treatment step of the step (1), the solvent is methanol.
24. The method for preparing chiral beta-acyloxy carboxylic acid ester compound according to claim 20, wherein the preparation method of the carboxylic acid ester compound is the following method a or method B:
method A:
(1) In a solvent, carrying out addition reaction on a compound shown as a formula II-A, a compound shown as a formula III' and carbon monoxide in the presence of a palladium catalyst, an oxazoline ligand and an oxidant;
(2) In a solvent, carrying out methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -A;
method B:
(1) In a solvent, carrying out addition reaction on a compound shown as a formula II-B, a compound shown as a formula III' and carbon monoxide in the presence of a palladium catalyst, an oxazoline ligand and an oxidant;
(2) In a solvent, carrying out methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -B;
process a or process B wherein the operation and conditions of the addition reaction are as defined in any one of the preceding claims 1 to 8;
*、R 1 、R 2 and R is 8 Is as defined in any one of claims 1 to 19.
25. The method for preparing chiral β -acyloxycarboxylic acid ester compounds according to claim 24, wherein the compound of formula I' -a is selected from any one of the following:
the compound shown in the formula I' -B is selected from any one of the following compounds:
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