CN113717092A - 一种含有三氟甲基的3-取代-2-吲哚啉酮类化合物制备方法 - Google Patents
一种含有三氟甲基的3-取代-2-吲哚啉酮类化合物制备方法 Download PDFInfo
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- CN113717092A CN113717092A CN202111183449.2A CN202111183449A CN113717092A CN 113717092 A CN113717092 A CN 113717092A CN 202111183449 A CN202111183449 A CN 202111183449A CN 113717092 A CN113717092 A CN 113717092A
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- -1 3-substituted-2-indolinone compound Chemical class 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000003446 ligand Substances 0.000 claims abstract description 13
- 150000007530 organic bases Chemical class 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 2
- 125000006242 amine protecting group Chemical group 0.000 claims description 2
- 125000005002 aryl methyl group Chemical group 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 72
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- 238000004293 19F NMR spectroscopy Methods 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- 230000014759 maintenance of location Effects 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- WMPHLIJZKDSFFR-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-phenylpropan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC=CC=C1 WMPHLIJZKDSFFR-UHFFFAOYSA-N 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 125000006189 4-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- QQKUNRAHVMQFLS-KRXBUXKQSA-N 1-methyl-4-[(E)-4,4,4-trifluorobut-2-enyl]benzene Chemical compound CC1=CC=C(C\C=C\C(F)(F)F)C=C1 QQKUNRAHVMQFLS-KRXBUXKQSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- CUXBYMYKAIPITO-UHFFFAOYSA-N CC(OC(C(F)(F)F)=CCC(C=CC=C1)=C1OC)=O Chemical compound CC(OC(C(F)(F)F)=CCC(C=CC=C1)=C1OC)=O CUXBYMYKAIPITO-UHFFFAOYSA-N 0.000 description 4
- 238000006717 asymmetric allylation reaction Methods 0.000 description 4
- VDVOPNDZLCYHDQ-UHFFFAOYSA-N CC(OC(C(F)(F)F)=CCC(C=C1)=CC=C1C1=CC=CC=C1)=O Chemical compound CC(OC(C(F)(F)F)=CCC(C=C1)=CC=C1C1=CC=CC=C1)=O VDVOPNDZLCYHDQ-UHFFFAOYSA-N 0.000 description 3
- QCKSTQQVROZGNG-UHFFFAOYSA-N CC(OC(C(F)(F)F)=CCC(C=C1)=CC=C1F)=O Chemical compound CC(OC(C(F)(F)F)=CCC(C=C1)=CC=C1F)=O QCKSTQQVROZGNG-UHFFFAOYSA-N 0.000 description 3
- IEBPTWDNSZUWJH-UHFFFAOYSA-N CC(OC(C(F)(F)F)=CCC1=CC2=CC=CC=C2C=C1)=O Chemical compound CC(OC(C(F)(F)F)=CCC1=CC2=CC=CC=C2C=C1)=O IEBPTWDNSZUWJH-UHFFFAOYSA-N 0.000 description 3
- DVUPXWXITYUBLP-UHFFFAOYSA-N CC(OC(C(F)(F)F)=CCC1=CC=C(C)C=C1)=O Chemical compound CC(OC(C(F)(F)F)=CCC1=CC=C(C)C=C1)=O DVUPXWXITYUBLP-UHFFFAOYSA-N 0.000 description 3
- 229910020323 ClF3 Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 238000005937 allylation reaction Methods 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- RDVVDDHLXATYTJ-UHFFFAOYSA-N CC(OC(C(F)(F)F)=CCC1=C(C)C=CC=C1)=O Chemical compound CC(OC(C(F)(F)F)=CCC1=C(C)C=CC=C1)=O RDVVDDHLXATYTJ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000011875 stereoselective allylation reaction Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- PZFKJRRRYNHHAR-UHFFFAOYSA-N 1,1,1-trifluorobut-2-en-2-yl acetate Chemical compound FC(C(=CC)OC(C)=O)(F)F PZFKJRRRYNHHAR-UHFFFAOYSA-N 0.000 description 1
- GRMSIAOXMCYUIV-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-(2-methylphenyl)propan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC=CC=C1C GRMSIAOXMCYUIV-UHFFFAOYSA-N 0.000 description 1
- HTBZRPDJWNUUSD-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)propan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC(OC)=C(OC)C(OC)=C1 HTBZRPDJWNUUSD-UHFFFAOYSA-N 0.000 description 1
- YRMGZGUHCQFKCM-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-(3-methylphenyl)propan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC=CC(C)=C1 YRMGZGUHCQFKCM-UHFFFAOYSA-N 0.000 description 1
- PILCQTXJJGELQA-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-(4-methylphenyl)propan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC=C(C)C=C1 PILCQTXJJGELQA-UHFFFAOYSA-N 0.000 description 1
- FKVQTUFIJGVIHB-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-(4-propan-2-ylphenyl)propan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC=C(C(C)C)C=C1 FKVQTUFIJGVIHB-UHFFFAOYSA-N 0.000 description 1
- WZODSNFGPRTWKR-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC=C(C(F)(F)F)C=C1 WZODSNFGPRTWKR-UHFFFAOYSA-N 0.000 description 1
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- WKGDTBUQSVJZPN-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-thiophen-2-ylpropan-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)CCC1=CC=CS1 WKGDTBUQSVJZPN-UHFFFAOYSA-N 0.000 description 1
- HKMYZRGEJASUJM-UHFFFAOYSA-N 1-(4-methoxyphenyl)nonan-1-one Chemical compound CCCCCCCCC(=O)C1=CC=C(OC)C=C1 HKMYZRGEJASUJM-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D209/34—Oxygen atoms in position 2
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- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract
本发明公开了一种含有三氟甲基的3‑取代‑2‑吲哚啉酮化合物制备方法，式Ⅱ所示1，1，1‑三氟丁‑2‑烯‑2‑基酯化合物和式Ⅲ所示3‑取代‑2‑吲哚啉酮化合物在催化剂、手性配体和有机碱存在下反应得到式Ⅰ所示三氟甲基取代的3‑取代‑2‑吲哚啉酮化合物。本发明为1，1，1‑三氟丁‑2‑烯‑2‑基酯化合物的合成提供了一种方便、低成本的方法。同时1，1，1‑三氟丁‑2‑烯‑2‑基酯化合物可以应用到3‑取代‑2‑吲哚啉酮化合物的不对称三氟甲基烯丙基化反应，并且反应收率和立体选择性较高。
Description
技术领域
本发明涉及化学合成领域，具体涉及一种含有三氟甲基的3-取代-2-吲哚啉酮类化合物制备方法。
背景技术
3-取代-2-吲哚啉酮是一类重要的分子骨架，广泛存在于天然产物和活性分子中。同时，它也是有机功能分子合成中的重要中间体，例如(+)-格列酮C、(-)-烟酰胺等活性分子的合成中都有3-取代-2-吲哚啉酮中间体的身影。因此，针对3-取代-2-吲哚啉酮衍生物的多样性转化，特别是不对称转化一直都是有机化学领域的研究热点
不对称烯丙基化是构筑手性中心的重要手段。目前报道的3-取代-2-吲哚啉酮的不对称烯丙基化主要是利用联烯基酯或者烯丙基酯作为烯丙基供体，在有机小分子催化或者过渡金属/手性配体协同催化条件下实现的。例如，卢一新课题组报道了膦催化3-取代-2-吲哚啉酮和联烯基酯的立体选择性烯丙基化；Trost课题组报道了钯催化3-取代-2-吲哚啉酮和联烯基酯的不对称烯丙基化反应；肖文精课题组报道了有机小分子催化剂和Pd(PPh3)4协同催化的3-取代-2-吲哚啉酮和烯丙基酯的立体选择性烯丙基化反应。除上述方法外，β,γ-烯酮和烯丙基卤代烃也可以作为烯丙基供体参与3-取代-2-吲哚啉酮的不对称烯丙基化反应。
尽管3-取代-2-吲哚啉酮衍生物的不对称烯丙基化已经取得了上述进展，但总体来说针对该反应的报道仍然较少，烯丙基化试剂的类型也亟需扩展。据我们所知，3-取代-2-吲哚啉酮的三氟甲基烯丙基化反应目前仍然没有报道。考虑到在活性分子中引入三氟甲基往往可以正向地改变其性质，因此对3-取代-2-吲哚啉酮衍生物进行不对称三氟甲基烯丙基化转化具有重要意义。
发明内容
本发明通过成本低、原料广泛易得的合成方法提供一种广泛适用的三氟甲基取代的烯基酯反应砌块1，1，1-三氟丁-2-烯-2-基酯化合物。1，1，1-三氟丁-2-烯-2-基酯化合物作为有机合成砌块，可以应用于吡唑啉酮类化合物不对称三氟甲基烯丙基化反应。
一种式Ⅱ所示1，1，1-三氟丁-2-烯-2-基酯化合物：
其中，R选自C2-5烷酰基、苯甲酰基或叔丁氧羰基；R1选自取代或未取代的芳基或杂芳基；
优选的，R1选自
其中X选自O、S或N(CH3)；n＝1、2、3、4、5，波浪线处为连接位置；
R2选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基或氰基；
式Ⅱ所示1，1，1-三氟丁-2-烯-2-基酯化合物，可以按照如下反应制备：
根据上述反应式，为获得1，1，1-三氟丁-2-烯-2-基酯化合物的制备方法，其包括以下步骤：
(1)惰性气体保护下，将式Ⅳ所示3-芳基-1取代-1-丙酮与三氟乙酸乙酯按摩尔比1:1～1:3，在相对于3-芳基-1取代酮1.0～3.0倍当量金属氢化物，比如氢化钠的存在下，于有机溶剂中，在室温至回流条件下，反应1～24小时。
(2)惰性气体保护下，将步骤(1)中反应液降温至0℃～室温，缓慢滴加相对于3-芳基-1取代-1-丙酮1.0～3.0倍当量的式Ⅴ酰氯或式Ⅵ酸酐化合物，反应5分钟～3小时后，加水淬灭，用乙酸乙酯萃取，干燥，过滤，减压条件下旋蒸除去溶剂，硅胶柱层析分离得到目标产物。
所述有机溶剂，选自乙二醇二甲醚、四氢呋喃、正己烷、甲基叔丁基醚或甲苯；优选的，式Ⅳ化合物与有机溶剂的量之比为1mmol:(5～15)mL。
其中，L选自叔丁基、异丙基、
其中n＝1、2、3、4、5，波浪线处为连接位置；
R2选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基或氰基；
一种式Ⅰ化合物的制备方法，其特征在于，式Ⅱ化合物和式Ⅲ化合物在催化剂、手性配体和有机碱存在下反应得到式Ⅰ化合物，
其中，G是胺基保护基；
R选自C2-5烷酰基、苯甲酰基或叔丁氧羰基；
R1选自取代或未取代的芳基或杂芳基；
R3选自芳基、杂芳基或烷基。
优选的，R1选自
其中X选自O、S或N(CH3)；n＝1、2、3、4、5，波浪线处为连接位置；
其中，R2选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基或氰基。
优选的，R3选自芳甲基。
优选的，G选自Boc、Fmoc、COOMe、COOEt、COOPh、COOCH2Ph、Ac或COPh。
其中，催化剂选自钯催化剂，优选醋酸钯或烯丙基氯化钯二聚物。
其中，手性配体选自有机磷手性配体，优选(R)-1,1'-联萘-2,2'-双二苯膦、(S)-2,2'-双[双(4-甲基苯基)膦]-1,1'-联萘或(R)-(+)-4,4'-双(二苯基膦)-3,3'-二(1,2-亚甲基二氧苯)。
其中，有机碱选自1,8-二偶氮杂双螺环[5.4.0]十一-7-烯。
其中，反应溶剂选自选自四氢呋喃、1,4-二氧六环、甲基叔丁基醚或乙腈。
其中，催化剂的用量为式Ⅲ化合物的5mol％～30mol％，手性配体的用量为Ⅲ化合物的5mol％～30mol％。
优选的，催化剂的用量为式Ⅲ化合物的10mol％，手性配体的用量为Ⅲ化合物的22mol％
其中，催化剂和手性配体按摩尔比1:1～1:3。
其中，有机碱的用量为式Ⅲ化合物的1.0～3.0倍当量。
本发明最优的反应条件是：氩气保护下，Pd(OAc)2(10mol％)和(R)-BINAP(22mol％)溶于THF中，在25℃下搅拌五分钟后降温至5℃，随后依次加入1,1,1-三氟丁-2-烯-2-基乙酸酯(1.5eq)、式Ⅲ化合物3-取代-2-吲哚啉酮(1.0eq)、DBU(1.5eq)，上述混合物在5℃下继续搅拌反应60小时。
除另有说明外，本文中使用的术语具有以下含义。
本文中使用的术语“烷基”包括直链烷基和支链烷基。如提及单个烷基如“甲基”，则只特指直链烷基，如提及单个支链烷基如“异丙基”，则只特指支链烷基。例如，“C4以下烷基”包括甲基、乙基、正丙基、异丙基、正丁基和叔丁基等。类似的规则也适用于本说明书中使用的其它基团。
本文中使用术语“卤素”包括氟、氯、溴、碘。
本文中所述C2～C5酯基为具有如下结构的基团：-COOM，其中，M为C1～C4烷基。
本文中所述C1～C4烷氧基为具有如下结构的基团：-O-M1，其中，M1为C1～C4烷基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基。
上述方案中，所述
(n＝1、2、3、4、5)，波浪线处为连接位置，其中，(R2)n中，n＝1、2、3、4、5指R在苯基上的取代可为单取代或多位取代，可为1、2、3、4或5取代。n＝1时为单取代，单取代的取代位可为2、3或4位；n＝2、3、4或5时，为多位取代，其中，n＝2为双取代，双取代的取代位为2，3-、2，4-、2，5-、2，6-、3，4-、3，5-；n＝3为三取代，三取代的取代位为2，3，4-、2，3，5-、2，3，6-、3，4，5-。
本发明为1，1，1-三氟丁-2-烯-2-基酯化合物的合成提供了一种方便、低成本的方法。同时1，1，1-三氟丁-2-烯-2-基酯化合物可以应用到3-取代-2-吲哚啉酮类化合物的不对称三氟甲基烯丙基化反应，并且反应收率和立体选择性较高。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明，但不以任何方式限制本发明。
下述实施例中所述试验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
实施例1
4-苯基-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物1)
(1)室温下，向氩气保护的250mL Schlenk瓶中差量法称取氢化钠480mg(20.0mmol)，加入无水甲基叔丁基醚(100mL)。随后，依次加入1-(4-甲氧基苯基)-3-苯基丙烷-1-酮2.40g(10.0mmol)、1-(4-甲氧基苯基)-3-苯基丙烷-1-酮2.0倍摩尔量的三氟乙酸乙酯2.4mL(20.0mmol)。将上述混合物置于55℃反应12小时。
(2)将上述混合物降温至0℃，在氩气保护下缓慢滴加1-(4-甲氧基苯基)-3-苯基丙烷-1-酮2.0倍摩尔量的乙酰氯1.42mL(20.0mmol)，继续在0℃条件下反应10分钟。加水(10mL)淬灭反应。用乙酸乙酯萃取(3×100mL)，合并有机相用饱和食盐水洗涤(2×50mL)，用无水硫酸镁干燥，通过柱层析获得目标化合物，填充料为硅胶，洗脱剂为石油醚，分离收率86％。
实施例2
4-(2-甲基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物2)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(2-甲基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率83％。
实施例3
4-(2-甲基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物3)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(3-甲基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率84％。
实施例4
4-(4-甲基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物4)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(4-甲基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率86％。
实施例5
4-(4-异丙基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物5)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(4-异丙基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率86％。
实施例6
4-(2-甲氧基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物6)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(2-甲氧基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率80％。
实施例7
4-(2-萘基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物7)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(2-萘基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率85％。
实施例8
4-(4-苯基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物8)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(4-苯基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率86％。
实施例9
4-(4-氟苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物9)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(4-氟苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率89％。
实施例10
4-(3-氯苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物10)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(3-氯苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率87％。
实施例11
4-(4-溴苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物11)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(4-溴苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率85％。
实施例12
4-(4-三氟甲基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物12)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(4-三氟甲基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率90％。
实施例13
4-(3,4,5-三甲氧基苯基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物13)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(3,4,5-三甲氧基苯基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率91％。
实施例14
4-(2-噻吩基)-1,1,1-三氟丁-2-烯-2-基乙酸酯的制备(化合物14)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)-3-(2-噻吩基)丙烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率88％。
实施例15
1,1,1-三氟癸-2-烯-2-基乙酸酯的制备(化合物15)
除了将实施例1中的1-(4-甲氧基苯基)-3-苯基丙烷-1-酮换成同摩尔量的1-(4-甲氧基苯基)壬烷-1-酮外，按与实施例1同样的方法进行，获得目标化合物分离收率84％。
实施例16
4-苯基-1,1,1-三氟丁-2-烯-2-基叔丁基碳酸酯的制备(化合物16)
除了将实施例1中的乙酰氯换成同摩尔量的二碳酸二叔丁酯外，按与实施例1同样的方法进行，获得目标化合物分离收率83％。
实施例17
4-苯基-1,1,1-三氟丁-2-烯-2-基苯甲酸酯的制备(化合物17)
除了将实施例1中的乙酰氯换成同摩尔量的苯甲酰氯外，按与实施例1同样的方法进行，获得目标化合物分离收率81％。
下表列举了合成的具体化合物1～17的结构、物理性质及1H NMR数据，但本发明并不仅限于这些化合物。
实施例18
3-取代-2-吲哚啉酮的不对称三氟甲基烯丙基化反应
氩气保护下，在25mL Schlenk瓶中依次加入Pd(OAc)2(5.6mg,10mol％)、(R)-BINAP(34.2mg，22mol％)、THF(3mL)，上述混合物在25℃条件下搅拌5min后将反应体系降温至5℃，依次加入4-芳基-1,1,1-三氟丁-2-烯-2-基乙酸酯8(0.375mmol,1.5eq)、3-取代-2-吲哚啉酮衍生物(0.25mmol)、DBU(57.0mg，0.375mmol，1.5eq)，上述混合物继续在5℃下搅拌反应36-60h后，减压旋蒸除去溶剂后，将粗产物通过硅胶柱层析纯化得到目标产物。
以下制备得到的部分化合物的结构确证和实验数据：
3-(4-苯基苄基)-3-((E)-1-(4-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
3.44(d,J＝13.2Hz,1H),2.91(d,J＝13.2Hz,1H),2.27(s,3H),1.52(s,9H).13CNMR(101MHz,CDCl3)δ176.8,148.4,140.6,140.1,139.2,137.6,137.5(q,J＝3.7Hz),134.1,133.6,130.4,129.1,129.0,128.7,127.2,127.1,126.8,126.4,124.7,123.6,122.6(q,J＝271.7Hz),121.4(q,J＝33.7Hz),114.9,84.1,58.6,55.6,42.1,28.0,21.1.19F NMR(377MHz,CDCl3)δ-63.85(d,J＝5.4Hz).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝7.44min,tminor＝14.07min.HRMS(ESI)m/z:计算值C37H34F3NNaO3[M+Na]+620.2388,实测值:620.2386.
3-(4-苯基苄基)-3-((E)-1-(3-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
J＝15.5,6.2Hz,1H),3.98(d,J＝10.4Hz,1H),3.51(d,J＝13.2Hz,1H),2.98(d,J＝13.2Hz,1H),2.32(s,3H),1.59(s,9H).13C NMR(101MHz,CDCl3)(one aromatic carbonmissing)δ176.6,148.4,140.6,140.1,139.2,138.0,137.4(q,J＝3.2Hz),136.5,134.1,130.5,129.9,128.7,128.6,128.2,127.2,127.1,126.8,126.4,126.2,124.8,123.6,122.6(q,J＝270.7Hz),121.50(q,J＝33.7Hz),114.9,84.1,58.6,56.0,41.9,28.0,21.4.19F NMR(377MHz,CDCl3)δ-63.84(d,J＝5.6Hz).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝6.45min,tminor＝14.37min.HRMS(ESI)m/z:计算值C37H34F3NNaO3[M+Na]+620.2388,实测值:620.2378.
3-(4-苯基苄基)-3-((E)-1-(2-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
13.0Hz,1H),2.98(d,J＝13.0Hz,1H),2.45(s,3H),1.61(s,9H).13C NMR(101MHz,CDCl3)δ177.1,148.4,140.5,140.0,139.3,138.3(q,J＝6.0Hz),136.4,135.4,133.9,131.1,130.5,128.7,128.6,127.9,127.5,127.2,127.1,126.8,126.4,126.1,124.8,123.4,122.1(q,J＝278.7Hz),120.81(q,J＝33.6Hz),114.8,84.3,59.0,50.5,41.6,28.0,20.5.19F NMR(376MHz,CDCl3)δ-63.80(d,J＝5.1Hz).HPLC analysis:Daicel CHIRALPAKOD-H,n-hexane/i-PrOH＝7/3,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝5.43min,tminor＝10.62min.HRMS(ESI)m/z:计算值C37H34F3NNaO3[M+Na]+620.2388,实测值:620.2377.
3-(4-苯基苄基)-3-((E)-1-苯基-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
＝12.2,5.8Hz,1H),3.96(d,J＝10.3Hz,1H),3.46(d,J＝13.1Hz,1H),2.92(d,J＝13.2Hz,1H),1.52(s,9H).13C NMR(101MHz,CDCl3)δ176.6,148.3,140.5,140.0,139.3,137.3(q,J＝6.0Hz),136.7,134.0,130.4,129.1,128.7,128.67,128.3,127.8,127.2,127.1,126.8,126.4,124.6,123.7,122.6(q,J＝271.7Hz),121.6(q,J＝33.8Hz),114.9,84.2,58.6,56.0,42.0,28.0.19F NMR(376MHz,CDCl3)δ-63.91(d,J＝5.8Hz).HPLCanalysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝8.05min,tminor＝19.84min.HRMS(ESI)m/z:计算值C36H32F3NNaO3[M+Na]+606.2232,实测值:606.2222.
3-(4-苯基苄基)-3-((E)-1-(4-叔丁基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
3.87(d,J＝10.4Hz,1H),3.36(d,J＝13.2Hz,1H),2.83(d,J＝13.3Hz,1H),2.76(q,J＝7.8Hz,1H),1.45(s,9H),1.13(d,J＝6.9Hz,6H).13C NMR(101MHz,CDCl3)δ176.7,148.5,148.3,140.6,140.1,139.2,137.4(q,J＝6.1Hz),134.1,133.7,130.4,129.1,128.7,127.1,126.8,126.4,126.3,124.8,123.6,122.3(q,J＝271.7Hz),121.5(q,J＝33.8Hz),121.6,121.2,114.9,84.1,58.7,55.7,41.9,33.7,28.0,23.9.19F NMR(377MHz,CDCl3)δ-63.89(d,J＝5.9Hz).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝6.16min,tminor＝12.77min.HRMS(ESI)m/z:计算值C39H38F3NNaO3[M+Na]+648.2701,实测值:648.2694.
3-(4-苯基苄基)-3-((E)-1-(2-甲氧基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
1H),5.90–5.77(m,1H),4.74(d,J＝10.2Hz,1H),3.72(s,3H),3.59(d,J＝13.2Hz,1H),2.93(d,J＝13.2Hz,1H),1.53(s,9H).13C NMR(101MHz,CDCl3)δ176.9,156.6,148.5,140.6,139.9,139.2,137.9(q,J＝6.1Hz),134.3,130.5,128.9,128.7,128.6,128.4,127.3,127.1,126.8,126.4,125.6,125.0,123.1,122.8(q,J＝270.7Hz),121.2(q,J＝33.6Hz),120.3,114.4,110.6,84.0,58.8,55.1,46.5,41.8,28.0.19F NMR(376MHz,CDCl3)δ-63.75(d,J＝6.0Hz).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝7.30min,tminor＝12.81min.HRMS(ESI)m/z:计算值C37H34F3NNaO4[M+Na]+636.2338,实测值:636.2328.
3-(4-苯基苄基)-3-((E)-1-(4-苯基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
J＝10.3Hz,1H),3.48(d,J＝13.2Hz,1H),2.96(d,J＝13.2Hz,1H),1.52(s,9H).13CNMR(101MHz,CDCl3)δ176.6,148.3,140.6,140.5,140.2,140.1,139.3,137.2(q,J＝6.1Hz),135.6,133.9,130.4,129.6,128.8,128.78,128.7,127.5,127.2,127.1,127.0,126.9,126.8,126.4,124.7,123.7,122.5(q,J＝270.7Hz),121.7(q,J＝33.6Hz),115.0,84.2,58.6,55.6,42.1,28.0.19F NMR(377MHz,CDCl3)δ-63.93(d,J＝5.8Hz).HPLCanalysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝12.48min,tminor＝22.29min.HRMS(ESI)m/z:计算值C42H36F3NNaO3[M+Na]+682.2545,实测值:682.2537.
3-(4-苯基苄基)-3-((E)-1-(2-萘基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
5.93–5.83(m,1H),4.14(d,J＝10.2Hz,1H),3.53(d,J＝13.2Hz,1H),2.96(d,J＝13.2Hz,1H),1.48(s,9H).13C NMR(101MHz,CDCl3)δ176.7,148.2,140.5,140.1,139.3,137.3(q,J＝6.1Hz),134.2,133.9,133.0,132.7,130.4,128.8,128.7,128.3,128.0,127.9,127.6,127.2,127.1,127.0,126.8,126.4,126.38,126.3,124.7,123.7,122.6(q,J＝270.7Hz),121.8(q,J＝33.9Hz),115.0,84.2,58.7,56.0,42.1,27.9.19F NMR(376MHz,CDCl3)δ-63.90(d,J＝4.6Hz).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝12.80min,tminor＝31.70min.HRMS(ESI)m/z:计算值C40H34F3NNaO3[M+Na]+656.2388,实测值:656.2388.
3-(4-苯基苄基)-3-((E)-1-(3-氯苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
J＝13.2Hz,1H),2.93(d,J＝13.2Hz,1H),1.53(s,9H).13C NMR(101MHz,CDCl3)δ176.2,148.2,140.5,140.0,139.4,138.7,136.6(q,J＝6.1Hz),134.2,133.7,130.4,129.5,129.1,128.9,128.7,128.0,127.2,127.1,126.9,126.8,126.5,124.3,123.8,122.4(q,J＝270.7Hz),122.1(q,J＝34.3Hz),115.0,84.4,58.3,55.6,41.9,28.0.19F NMR(376MHz,CDCl3)δ-63.99(d,J＝5.9Hz).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝8.67min,tminor＝28.00min.HRMS(ESI)m/z:计算值C36H31ClF3NNaO3[M+Na]+640.1842,实测值:640.1836.
3-(4-苯基苄基)-3-((E)-1-(2-氯苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
13.0Hz,1H),3.00(d,J＝13.0Hz,1H),1.54(s,9H).13C NMR(101MHz,CDCl3)(twoaromatic carbons missing)δ176.7,148.4,140.5,139.6,139.4,137.2(q,J＝7.1Hz),135.3,134.1,133.6,130.5,130.1,128.8,128.7,128.68,127.2,127.0,126.8,126.4,124.6,123.6,122.6(q,J＝270.7Hz),121.80(q,J＝33.7Hz),114.6,84.3,58.5,50.0,42.4,28.0.19F NMR(376MHz,CDCl3)δ-63.90(d,J＝5.3Hz).HPLC analysis:DaicelCHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝6.85min,tminor＝13.13min.HRMS(ESI)m/z:计算值C36H31ClF3NNaO3[M+Na]+640.1842,实测值:640.1835.
3-(4-苯基苄基)-3-((E)-1-(4-三氟甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
13.2Hz,1H),2.95(d,J＝13.2Hz,1H),1.52(s,9H).13C NMR(101MHz,CDCl3)δ176.1,148.2,140.5,139.9,139.5,137.8,136.5(q,J＝6.5Hz),133.6,132.0,130.4,129.0,128.8,128.7,127.2,126.9,126.8,126.5,125.8(q,J＝3.7Hz),124.6(q,J＝3.7Hz),124.0(q,J＝28.3Hz),123.7(q,J＝273.7Hz),122.5(q,J＝34.3Hz),122.4(q,J＝270.7Hz),115.0,84.4,58.4,55.8,41.8,27.9.19F NMR(376MHz,CDCl3)δ-62.71(s,3F),-64.00(d,J＝6.0Hz,3F).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝8.19min,tminor＝30.42min.HRMS(ESI)m/z:计算值C37H31F6NNaO3[M+Na]+674.2106,实测值:674.2104.
3-(4-苯基苄基)-3-((E)-1-(2-噻吩)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
(m,1H),5.95–5.82(m,1H),4.31(d,J＝10.1Hz,1H),3.46(d,J＝13.0Hz,1H),3.07(d,J＝13.0Hz,1H),1.55(s,9H).13C NMR(101MHz,CDCl3)δ176.4,148.3,140.5,140.3,139.4,138.5,136.9(q,J＝6.7Hz),133.7,130.3,128.9,128.7,127.2,127.1,126.9,126.8,126.6,126.4,125.0,124.4,123.9,122.4(q,J＝270.7Hz),121.6(d,J＝34.0Hz),115.0,84.2,58.6,50.9,42.4,28.0.19F NMR(376MHz,CDCl3)δ-64.07(d,J＝5.9Hz).HPLCanalysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝8.75min,tminor＝19.80min.HRMS(ESI)m/z:计算值C34H30F3NNaO3S[M+Na]+612.1796,实测值:612.1796.
3-(4-甲基苄基)-3-((E)-1-(4-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
＝10.3Hz,1H),3.40(d,J＝13.2Hz,1H),2.87(d,J＝13.2Hz,1H),2.31(s,3H),2.17(s,3H),1.57(s,9H).13C NMR(101MHz,CDCl3)(three aromatic carbons missing)δ176.7,148.4,140.1,137.6(q,J＝6.5Hz),137.5,136.0,133.7,131.8,129.8,129.0,128.5,127.4,124.7,123.5,122.6(q,J＝270.7Hz),121.3(q,J＝34.3Hz),114.8,84.0,58.6,55.5,42.1,28.0,21.0.19F NMR(376MHz,CDCl3)δ-63.90(d,J＝5.0Hz).HPLCanalysis:Daicel CHIRALPAK AD-H,n-hexane/i-PrOH＝50/1,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝15.20min,tminor＝26.26min.HRMS(ESI)m/z:计算值C32H32F3NNaO3[M+Na]+558.2232,实测值:558.2226.
3-(4-甲氧基苄基)-3-((E)-1-(4-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
1H),3.91(d,J＝10.3Hz,1H),3.64(s,3H),3.35(d,J＝13.3Hz,1H),2.82(d,J＝13.3Hz,1H),2.28(s,3H),1.54(s,9H).13C NMR(101MHz,CDCl3)δ176.8,158.2,148.4,140.1,137.7(q,J＝6.5Hz),137.5,133.7,131.0,129.0,128.98,128.5,127.4,126.9,124.6,123.6,122.6(q,J＝270.7Hz),121.2(q,J＝34.3Hz),114.8,113.2,84.0,58.7,55.4,54.9,41.7,28.0,21.0.19F NMR(377MHz,CDCl3)δ-63.85(d,J＝5.9Hz).HPLCanalysis:Daicel CHIRALPAK AD-H,n-hexane/i-PrOH＝9/1,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝7.33min,tminor＝8.11min.HRMS(ESI)m/z:计算值C32H32F3NNaO4[M+Na]+574.2181,实测值:574.2173.
3-(2-萘甲基)-3-((E)-1-(4-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
＝8.2Hz,2H),6.90–6.80(m,2H),5.84(dq,J＝15.6,6.2Hz,1H),3.98(d,J＝10.3Hz,1H),3.58(d,J＝13.2Hz,1H),3.04(d,J＝13.2Hz,1H),2.30(s,3H),1.45(s,9H).13CNMR(101MHz,CDCl3)(one aromatic carbon missing)δ176.7,148.2,140.1,137.6(q,J＝6.5Hz),137.5,133.6,133.1,132.6,132.2,129.1,129.06,129.03,128.7,128.1,127.7,127.4,127.2,125.7,125.5,124.7,123.6,122.6(q,J＝270.7Hz),121.5(q,J＝33.3Hz),114.9,84.0,58.7,55.6,42.6,27.9,21.0.19F NMR(377MHz,CDCl3)δ-63.84(d,J＝5.7Hz).HPLC analysis:Daicel CHIRALPAK OD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝8.52min,tminor＝10.88min.HRMS(ESI)m/z:计算值C35H32F3NNaO3[M+Na]+594.2232,实测值:594.2231.
3-(4-氯苄基)-3-((E)-1-(4-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
3.37(d,J＝13.2Hz,1H),2.82(d,J＝13.2Hz,1H),2.29(s,3H),1.54(s,9H).13CNMR(101MHz,CDCl3)δ176.5,148.2,140.0,137.6,137.3(q,J＝6.3Hz),133.5,133.3,132.6,131.3,129.1,129.0,128.8,128.0,126.8,124.6,123.7,122.5(q,J＝270.7Hz),121.5(q,J＝33.9Hz),114.9,84.3,58.5,55.5,41.7,27.9,21.0.19F NMR(376MHz,CDCl3)δ-63.97(d,J＝5.8Hz).HPLC analysis:Daicel CHIRALPAK AD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝9.51min,tminor＝13.13min.HRMS(ESI)m/z:计算值C31H29ClF3NNaO3[M+Na]+578.1686,实测值:578.1676.
3-苄基-3-((E)-1-(2-噻吩基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
6.83(d,J＝3.6Hz,1H),6.78–6.69(m,2H),5.84(dq,J＝15.5,6.2Hz,1H),4.26(d,J＝10.2Hz,1H),3.39(d,J＝13.0Hz,0H),2.99(d,J＝13.0Hz,0H),1.53(s,9H).13CNMR(101MHz,CDCl3)δ176.3,148.3,140.2,138.6,137.0(q,J＝6.6Hz),134.6,130.0,128.9,127.8,127.1,126.8,126.7,126.6,125.0,124.3,123.9,122.4(q,J＝270.7Hz),121.5(q,J＝34.0Hz),114.9,84.1,58.6,50.8,42.9,28.0.19F NMR(376MHz,CDCl3)δ-64.06(d,J＝5.7Hz).HPLC analysis:Daicel CHIRALPAK AD-H,n-hexane/i-PrOH＝95/5,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝8.40min,tminor＝14.22min.HRMS(ESI)m/z:计算值C28H25F3NNaO3S[M+Na]536.1483,实测值:536.1478.
3-苯基-3-((E)-1-(4-甲基苯基)-4,4,4-三氟丁-2-烯)基-2-氧代二氢吲哚-1-甲酸叔丁酯
NMR(101MHz,CDCl3)(three aromatic carbons missing)δ175.4,148.8,139.6,137.6(q,J＝6.8Hz),137.3,137.0,133.3,129.1,128.8,128.6,128.1,127.8,127.6,125.1(q,J＝269.3Hz),122.1(q,J＝33.7Hz),115.0,84.5,60.8,55.0,28.0,21.0.19F NMR(377MHz,CDCl3)δ-64.20(d,J＝6.3Hz).HPLC analysis:Daicel CHIRALPAK AD-H,n-hexane/i-PrOH＝50/1,流速＝0.8mL/min,λ＝254nm,保留时间：tmajor＝9.10min,tminor＝9.92min.HRMS(ESI)m/z:计算值C30H28F3NNaO3[M+Na]530.1919,实测值:530.1911.。
Claims (10)
1.一种式Ⅰ化合物的制备方法，其特征在于，式Ⅱ化合物和式Ⅲ化合物在催化剂、手性配体和有机碱存在下反应得到式Ⅰ化合物，
其中，G是胺基保护基；
R选自C2-5烷酰基、苯甲酰基或叔丁氧羰基；
R1选自取代或未取代的芳基或杂芳基；
R3选自芳基、杂芳基或烷基。
2.根据权利要求1所述的方法，其特征在于，R1选自
其中X选自O、S或N(CH3)；n＝1、2、3、4、5，波浪线处为连接位置；R2选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基或氰基。
3.根据权利要求1所述的方法，其特征在于，R3选自芳甲基。
4.根据权利要求1所述的方法，其特征在于，G选自Boc、Fmoc、COOMe、COOEt、COOPh、COOCH2Ph、Ac或COPh。
5.根据权利要求1所述的方法，其特征在于，催化剂选自钯催化剂，优选醋酸钯或烯丙基氯化钯二聚物。
6.根据权利要求1所述的方法，其特征在于，手性配体选自有机磷手性配体，优选(R)-1,1'-联萘-2,2'-双二苯膦、(S)-2,2'-双[双(4-甲基苯基)膦]-1,1'-联萘或(R)-(+)-4,4'-双(二苯基膦)-3,3'-二(1,2-亚甲基二氧苯)。
7.根据权利要求1所述的方法，其特征在于，有机碱选自1,8-二偶氮杂双螺环[5.4.0]十一-7-烯。
8.根据权利要求1所述的方法，其特征在于，反应溶剂选自四氢呋喃、1,4-二氧六环、甲基叔丁基醚或乙腈。
9.根据权利要求1所述的方法，其特征在于，催化剂的用量为式Ⅲ化合物的5mol％～30mol％，手性配体的用量为Ⅲ化合物的5mol％～30mol％。
10.根据权利要求1所述的方法，其特征在于，催化剂的用量为式Ⅲ化合物的10mol％，手性配体的用量为Ⅲ化合物的22mol％。
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| CN1070647A (zh) * | 1992-09-30 | 1993-04-07 | 孙伟燕 | 制备具有光学活性的假蟾毒胺醇的方法 |
| CN113354586A (zh) * | 2021-07-08 | 2021-09-07 | 大连理工大学 | 一种含有三氟甲基的吡唑啉酮类化合物制备方法 |
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| CN1070647A (zh) * | 1992-09-30 | 1993-04-07 | 孙伟燕 | 制备具有光学活性的假蟾毒胺醇的方法 |
| CN113354586A (zh) * | 2021-07-08 | 2021-09-07 | 大连理工大学 | 一种含有三氟甲基的吡唑啉酮类化合物制备方法 |
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