CN113402477B - Monofluoroolefin modified heteroatom cyclolactone or lactam derivative and synthetic method and application thereof - Google Patents
Monofluoroolefin modified heteroatom cyclolactone or lactam derivative and synthetic method and application thereof Download PDFInfo
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- CN113402477B CN113402477B CN202110525595.2A CN202110525595A CN113402477B CN 113402477 B CN113402477 B CN 113402477B CN 202110525595 A CN202110525595 A CN 202110525595A CN 113402477 B CN113402477 B CN 113402477B
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- monofluoroolefin
- column chromatography
- heteroatom
- lactam derivative
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- 125000005842 heteroatom Chemical group 0.000 title claims abstract description 31
- 150000003951 lactams Chemical class 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- -1 trifluoromethyl olefin Chemical class 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000004440 column chromatography Methods 0.000 claims abstract description 45
- 238000003756 stirring Methods 0.000 claims abstract description 34
- 238000001308 synthesis method Methods 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000004985 diamines Chemical class 0.000 claims abstract description 7
- 238000000605 extraction Methods 0.000 claims abstract description 7
- 239000012043 crude product Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 150000001414 amino alcohols Chemical class 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 239000012044 organic layer Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- 239000003480 eluent Substances 0.000 claims description 21
- 239000003208 petroleum Substances 0.000 claims description 21
- 238000000746 purification Methods 0.000 claims description 20
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 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 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000002009 diols Chemical class 0.000 claims 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 89
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000575 pesticide Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 238000012360 testing method Methods 0.000 description 19
- 238000000926 separation method Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000004293 19F NMR spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000012512 characterization method Methods 0.000 description 15
- QSUGRMCPSKTJTP-HNNXBMFYSA-N n-[(2s)-1-hydroxy-3-phenylpropan-2-yl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](CO)CC1=CC=CC=C1 QSUGRMCPSKTJTP-HNNXBMFYSA-N 0.000 description 11
- RQXPGOCXZHCXDG-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-en-2-ylbenzene Chemical compound FC(F)(F)C(=C)C1=CC=CC=C1 RQXPGOCXZHCXDG-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- RQOBKAQJZDLRFJ-UHFFFAOYSA-N n-(2-hydroxypropyl)-4-methylbenzenesulfonamide Chemical compound CC(O)CNS(=O)(=O)C1=CC=C(C)C=C1 RQOBKAQJZDLRFJ-UHFFFAOYSA-N 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 241001508003 Mycobacterium abscessus Species 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- VZTZOVQVMFEFOB-UHFFFAOYSA-N 1-(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC(F)(F)C(=C)C1=CC=C(C(F)(F)F)C=C1 VZTZOVQVMFEFOB-UHFFFAOYSA-N 0.000 description 1
- DEAILPKMQOFCRE-UHFFFAOYSA-N 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC(F)(F)C(=C)C1=CC=C(Br)C=C1 DEAILPKMQOFCRE-UHFFFAOYSA-N 0.000 description 1
- VEIIKBNWQPDEAL-UHFFFAOYSA-N 1-chloro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC(F)(F)C(=C)C1=CC=C(Cl)C=C1 VEIIKBNWQPDEAL-UHFFFAOYSA-N 0.000 description 1
- YZAGLIXIDUBVFQ-UHFFFAOYSA-N 1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC1=CC=C(C(=C)C(F)(F)F)C=C1 YZAGLIXIDUBVFQ-UHFFFAOYSA-N 0.000 description 1
- UBJBKRMNBMMMHZ-UHFFFAOYSA-N 1h-indol-7-ylmethanol Chemical compound OCC1=CC=CC2=C1NC=C2 UBJBKRMNBMMMHZ-UHFFFAOYSA-N 0.000 description 1
- XGFCBCOXQYAKDN-UHFFFAOYSA-N 3-(3,3,3-trifluoroprop-1-en-2-yl)quinoline Chemical compound FC(F)(F)C(=C)c1cnc2ccccc2c1 XGFCBCOXQYAKDN-UHFFFAOYSA-N 0.000 description 1
- HOFGETLODCEHBQ-UHFFFAOYSA-N 4-methyl-n-[2-[(4-methylphenyl)sulfonylamino]ethyl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NCCNS(=O)(=O)C1=CC=C(C)C=C1 HOFGETLODCEHBQ-UHFFFAOYSA-N 0.000 description 1
- 241001019659 Acremonium <Plectosphaerellaceae> Species 0.000 description 1
- 101710145634 Antigen 1 Proteins 0.000 description 1
- VISLTORCGGONMB-UHFFFAOYSA-N C=CC1=C(C(F)(F)F)C2=CC=CC=C2C=C1 Chemical group C=CC1=C(C(F)(F)F)C2=CC=CC=C2C=C1 VISLTORCGGONMB-UHFFFAOYSA-N 0.000 description 1
- FKZPCSAYTIKTJR-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(CO)C1CCCCC1)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(CO)C1CCCCC1)(=O)=O FKZPCSAYTIKTJR-UHFFFAOYSA-N 0.000 description 1
- JKNYGMBZEVNRIV-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NCC1=C2NC=CC2=CC=C1)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NCC1=C2NC=CC2=CC=C1)(=O)=O JKNYGMBZEVNRIV-UHFFFAOYSA-N 0.000 description 1
- BLZQTQWKAGBGEW-UHFFFAOYSA-N CCCCCC(C=C)C#CC(F)(F)F Chemical group CCCCCC(C=C)C#CC(F)(F)F BLZQTQWKAGBGEW-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/62—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms three- or four-membered rings or rings with more than six members
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
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- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Dentistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Agronomy & Crop Science (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a monofluoroolefin modified heteroatom cyclolactone or lactam derivative and a synthetic method and application thereof, wherein the synthetic method comprises the following steps: adding alkali, amino alcohol or diamine and trifluoromethyl olefin into an organic solvent, stirring for reaction, adding an extraction liquid for extraction, and performing reduced pressure rotary evaporation on an extracted organic layer to remove the solvent to obtain a crude product; and purifying the crude product by column chromatography to obtain the monofluoroolefin modified heteroatom cyclic lactone or lactam derivative. The synthesis method does not use a catalyst, and the used raw materials are nontoxic, cheap and easy to obtain; the adaptability to functional groups in the synthesis reaction process is good, the adaptability to substrates is wide, the product yield is high, and the regioselectivity is good; the method is simple and safe to operate, mild in reaction condition, insensitive to water and air and good in industrial application prospect; the product obtained by the invention has wide application in the fields of pesticide, medicine and material.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a monofluoroolefin modified heteroatom cyclic lactone or lactam derivative, and a synthesis method and application thereof.
Background
Cyclolactones and lactams in heteroatoms are structural units of a variety of pharmaceutically active molecules and natural products. For example, compound I is a natural product isolated from the marine fungus Acremonium sp. AWA16-1, is cytotoxic and inhibits the growth of A549 cells (IC50 for A549 cells 27.5. mu.g/mL) (Jang, J. -H.; Kanoh, K.; Adachi, K.; Shizuri, Y.J. Nat. prod.2006,69, 1358-. The compound II has an activity of resisting rapid proliferation mycobacteria, and can inhibit the growth of Mycobacterium abscessus (Mycobacterium abscessus) (Maslivetc, V.; Turner, D.; McNairr, K.; et al, J. org. chem.2018,83, 5650-. Compound iii is an antigen-1 inhibitor associated with lymphocyte function (IC50 ═ 70nM) (watts anasin, s.; Albert, r.; ehhrhardt, c.; et al, bioorg.med. chem.2003,13, 499-. Compound IV is a key intermediate in the synthesis of 8-deoxypiperitoxin 193H, an active molecule that induces convulsions and inhibits neuromuscular activity (Zvejniece, L.; Dambrova, M.; Smits, G.Natural Product research.2021,35, 440-446.). Therefore, the development of a new method for synthesizing cyclolactone and lactam derivatives with simple and efficient heteroatom is a very important topic in the pharmaceutical and chemical fields.
Compound I
Compound II
Compound III
Compound IV
Fluoroolefins are bioisosteres which are non-isomeric in amide, ester and other structural units and are difficult to hydrolyze, and are used in bioactive molecules with various pharmacological activities (anticancer, antibacterial, anti-HIV, anti-diabetic) (Taguchi, T.; Yanai, H. in Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell, Chichester, U.K., 2009; pp 257 and 290.). Thus, the introduction of fluoroolefins into heteroatoms is attractive for cyclic compound molecules in drug design. However, methods for synthesizing cyclic lactone and lactam derivatives in monofluoroolefin-modified heteroatoms have not been reported. Therefore, the development of efficient synthetic methods and strategies to construct these attractive cyclic ring molecules is currently still a challenging research topic.
Disclosure of Invention
To overcome the above disadvantages and drawbacks of the prior art, it is a primary object of the present invention to provide a monofluoroolefin-modified cyclic lactone or lactam derivative in a heteroatom.
The second purpose of the invention is to provide a synthetic method of a cyclic lactone or lactam derivative in a monofluoro olefin modified heteroatom.
The third purpose of the invention is to provide the application of the monofluoroolefin modified heteroatom cyclic lactone or lactam derivative in the fields of pesticides and medicines.
The primary purpose of the invention is realized by the following technical scheme:
a monofluoroolefin-modified heteroatomic cyclolactone or lactam derivative having a structural formula shown in figure 1:
wherein R is1Hydrogen, methyl, isopropyl, benzyl, cyclohexyl; r2Hydrogen, cyclohexyl, 7-indolyl; r3Is phenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-naphthyl, 3-quinolyl, phenylethynyl, triisopropylsilylnyl, octynyl, 3 ', 4' -methylenedioxyphenyl.
The second purpose of the invention is realized by the following technical scheme:
a synthetic method of a monofluoro olefin modified heteroatom cyclic lactone or lactam derivative comprises the following steps:
adding alkali, amino alcohol or diamine and trifluoromethyl olefin into an organic solvent, stirring for reaction, adding an extraction liquid for extraction, and performing reduced pressure rotary evaporation on an extracted organic layer to remove the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain monofluoroolefin modified heteroatom cyclic lactone or lactam derivative;
the specific reaction formula of the synthesis method is shown in figure 2:
preferably, the base is at least one of potassium carbonate, cesium carbonate, lithium tert-butoxide and sodium tert-butoxide.
Preferably, the organic solvent is selected from one of dimethyl sulfoxide or N, N-dimethylformamide.
Preferably, the molar ratio of the amine alcohol or diamine to the trifluoromethyl olefin is 1: 1.5-2.
Preferably, the molar ratio of the base to the amine alcohol or diamine is 3-4: 1.
preferably, the reaction temperature is 25-40 ℃, and the reaction time is 12-24 h.
Preferably, the extract is ethyl acetate and water.
Preferably, the column chromatography purification refers to column chromatography purification of eluent after mixing of petroleum ether and ethyl acetate in a volume ratio of 5-50: 0-1.
The third purpose of the invention is realized by the following technical scheme:
an application of monofluoro olefin modified cyclolactone or lactam derivative in heteroatom in the fields of pesticide and medicine is disclosed.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the synthesis method of the invention does not use a catalyst, and the used raw materials are nontoxic, cheap and easy to obtain; the adaptability to functional groups in the synthesis reaction process is good, the adaptability to substrates is wide, the product yield is high, and the regioselectivity is good;
(2) the synthetic method disclosed by the invention is simple and safe to operate, mild in reaction conditions, insensitive to water and air, and good in industrial application prospect;
(3) the product obtained by the invention has wide application in the fields of pesticide, medicine and material.
Drawings
FIG. 1 is a structural formula of a cyclic lactone or lactam derivative in a monofluoroolefin-modified heteroatom;
FIG. 2 is a reaction scheme of a cyclic lactone or lactam derivative in a monofluoroolefin-modified heteroatom;
FIG. 3 is a hydrogen spectrum of a cyclic lactone or lactam derivative in a monofluoroolefin-modified heteroatom of the products obtained in examples 1-5;
FIG. 4 is a carbon spectrum of a cyclic lactone or lactam derivative in a monofluoroolefin-modified heteroatom of the product obtained in examples 1-5;
FIG. 5 is a fluorine spectrum of a cyclic lactone or lactam derivative in a monofluoroolefin-modified heteroatom of the products obtained in examples 1-5.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.
Example 1:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of potassium carbonate, 0.4 mmol of alpha-trifluoromethylstyrene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is carried out for 12 hours at 40 ℃, then stirring is stopped, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, column chromatography separation and purification are carried out to obtain a target product, and the petroleum ether is used as eluent of the column chromatography, so that the yield of the product is 5%.
Example 2:
the synthesis method of the cyclic lactam derivative in the monofluoro olefin modified heteroatom of the embodiment includes the following specific synthesis steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of cesium carbonate, 0.4 mmol of alpha-trifluoromethylstyrene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring is stopped after reaction is carried out for 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, wherein petroleum ether is used as a column chromatography eluent, and the yield of the product is 10%.
Example 3:
the synthesis method of the cyclic lactam derivative in the monofluoro olefin modified heteroatom of the embodiment includes the following specific synthesis steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethylstyrene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours of stirring reaction at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, and the petroleum ether is used as eluent of the column chromatography, so that the yield of the product is 67%.
Example 4:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of sodium tert-butoxide, 0.4 mmol of alpha-trifluoromethylstyrene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours of stirring reaction at 40 ℃, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 52%.
Example 5:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethylstyrene and 2 ml of N, N-dimethylformamide are sequentially added into a 25 ml test tube, stirring is stopped after stirring reaction is carried out for 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by rotary evaporation under reduced pressure, and the target product is obtained by column chromatography separation and purification, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 64%.
The hydrogen, carbon and fluorine spectra of the products obtained in examples 1-5 above are shown in FIGS. 3,4 and 5, respectively. The structural characterization data are as follows:
1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.6Hz,2H),7.57(d,J＝7.2Hz,2H), 7.46(t,J＝7.2Hz,2H),7.37(t,J＝7.2Hz,1H),7.23(d,J＝8.0Hz,2H),7.14–7.15 (m,3H),6.97(d,J＝5.5Hz,2H),4.63(dd,J＝14.0,5.2Hz,1H),4.53(d,J＝13.6 Hz,1H),3.85–4.03(m,3H),2.97(dd,J＝13.6,7.6Hz,1H),2.80(dd,J＝13.6,7.6 Hz,1H),2.46(s,3H)；
13C NMR(101MHz,CDCl3)δ146.9(d,1JF-C＝279.0Hz),144.2,137.2,136.2, 135.0(d,3JF-C＝5.0Hz),129.8,129.3,128.5,128.4(d,3JF-C＝4.1Hz),128.0,127.6 (d,4JF-C＝1.9Hz),126.5,115.8(d,2JF-C＝22.8Hz),73.7,72.5,59.3,36.4,21.7(d, 3JF-C＝4.5Hz)；
19F NMR(471MHz,CDCl3)δ-84.2(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C25H24FNO3S+H,438.1534；found, 438.1528.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 6:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethyl p-chlorostyrene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 89%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.0Hz,2H),7.48(d,J＝8.4Hz,2H), 7.42(d,J＝8.8Hz,2H),7.22(d,J＝8.0Hz,2H),7.09–7.17(m,3H),6.93(d,J＝6.0 Hz,2H),4.57(dd,J＝13.6,4.8Hz,1H),4.51(dd,J＝14.0,2.4Hz,1H),3.93–4.01 (m,2H),3.85(dd,J＝12.4,2.4Hz,1H),2.92(dd,J＝14.0,7.6Hz,1H),2.75(dd,J＝ 13.6,7.6Hz,1H),2.45(s,3H)；
13C NMR(101MHz,CDCl3)δ147.3(d,1JF-C＝279.4Hz),144.3,137.0,136.1, 133.8,133.4(d,3JF-C＝5.2Hz),129.8,129.7(d,3JF-C＝4.3Hz),129.2,128.7,128.6, 127.7(d,4JF-C＝2.1Hz),126.6,114.8(d,2JF-C＝22.7Hz),73.8,72.3,59.3,36.4, 21.7；
19F NMR(471MHz,CDCl3)δ-83.2(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C19H20FNO3S+H,362.1221；found, 362.1217.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 7:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethyl-p-bromostyrene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours of stirring reaction at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, column chromatography separation and purification are carried out to obtain a target product, and petroleum ether is used as eluent of column chromatography, so that the yield of the product is 70%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.0Hz,2H),7.57(d,J＝8.4Hz,2H), 7.41(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.10–7.14(m,3H),6.29(d,J＝6.4 Hz,2H),4.49–4.59(m,2H),3.82–4.00(m,3H),2.91(dd,J＝13.6,7.6Hz,1H),2.74 (dd,J＝13.6,7.6Hz,1H),2.45(s,3H)；
13C NMR(101MHz,CDCl3)δ147.3(d,1JF-C＝279.5Hz),144.4,137.0,136.1, 133.9(d,3JF-C＝5.1Hz),131.7,130.0(d,3JF-C＝4.4Hz),129.9,129.3,128.6,127.7 (d,4JF-C＝2.1Hz),126.6,122.0,114.9(d,2JF-C＝22.5Hz),73.8,72.2,59.3,36.4, 21.7；
19F NMR(471MHz,CDCl3)δ-83.1(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C25H23BrFNO3S+H,516.0639；found, 516.0634.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 8:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
adding 0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethyl p-fluorostyrene and 2 ml of dimethyl sulfoxide into a 25 ml test tube in sequence, stirring and reacting at 40 ℃ for 12 hours, stopping stirring, adding ethyl acetate and water to extract a reaction solution, carrying out reduced pressure rotary evaporation to remove a solvent, and carrying out column chromatography separation and purification to obtain a target product, wherein petroleum ether is an eluent of the used column chromatography, and the yield of the product is 50%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.0Hz,2H),7.51–7.54(m,2H),7.22 (d,J＝8.0Hz,2H),7.12–7.16(m,5H),6.94(d,J＝6.4Hz,2H),4.50–4.60(m,2H), 3.83–4.01(m,3H),2.93(dd,J＝13.6,7.2Hz,1H),2.76(dd,J＝13.6,7.2Hz,1H), 2.46(s,3H)；
13C NMR(101MHz,CDCl3)δ162.2(d,1JF-C＝248.4Hz),146.9(d,1JF-C＝ 278.4Hz),144.2,137.0,136.1,130.2(d,3JF-C＝4.3Hz),130.1(d,3JF-C＝4.2Hz), 129.7,129.2,128.5,127.6(d,4JF-C＝1.8Hz),126.5,115.4(d,2JF-C＝21.6Hz),115.0 (d,2JF-C＝23.0Hz),73.7,72.4(d,3JF-C＝3.8Hz),59.2,36.4,21.6；
19F NMR(471MHz,CDCl3)δ-84.1(s,1F),-113.4(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C25H23F2NO3S+H,456.1440；found, 456.1435.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 9:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethyl-2-naphthylethylene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring is stopped after stirring reaction is carried out for 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by reduced pressure rotary evaporation, column chromatography separation and purification are carried out to obtain a target product, and petroleum ether is used as eluent of column chromatography, so that the yield of the product is 78%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.90–7.95(m,3H),7.74(d,J＝7.2 Hz,3H),7.56–7.7(m,2H),7.24(d,J＝8.0Hz,2H),7.16(s,3H),6.99(s,2H), 4.76–4.80(m,1H),4.62–4.67(m,1H),3.92–4.08(m,3H),2.99–3.05(m,1H), 2.83–2.90(m,1H),2.47(s,3H)；
13C NMR(101MHz,CDCl3)δ147.2(d,1JF-C＝279.7Hz),144.2,137.1,136.2, 133.2,132.8,132.4,129.8,129.3,128.5,128.2,128.1,127.7,127.7,127.6(d,3JF-C＝ 3.4Hz),126.5,126.1(d,3JF-C＝3.6Hz),115.9(d,2JF-C＝22.4Hz),73.8,72.6(d, 3JF-C＝4.8Hz),59.4,36.5,21.7；
19F NMR(471MHz,CDCl3)δ-83.6(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C29H26FNO3S+H,488.1690；found, 488.1686.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 10:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
adding 0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of 2- (3 ', 4' -methylenedioxyphenyl) -3,3, 3-trifluoro 1-propene and 2 ml of dimethyl sulfoxide into a 25 ml test tube in sequence, stirring and reacting for 12 hours at 40 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, performing reduced pressure rotary evaporation to remove a solvent, and performing column chromatography separation and purification to obtain a target product, wherein petroleum ether is an eluent of the used column chromatography, and the yield of the product is 78%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.0Hz,3H),7.21(d,J＝8.0Hz,2H), 7.11–7.16(m,3H),7.02–7.06(m,2H),6.95(d,J＝6.0Hz,2H),6.89(d,J＝8.0Hz, 1H),6.01(s,2H),4.46–4.58(m,2H),3.82–4.01(m,3H),2.93(dd,J＝14.0,7.6Hz, 1H),2.77(dd,J＝14.0,7.6Hz,1H),2.45(s,3H)；
13C NMR(101MHz,CDCl3)δ147.7,147.3,146.5(d,1JF-C＝277.6Hz),144.2, 137.1,136.2,129.7,129.2,128.6(d,3JF-C＝5.1Hz),128.5,127.6(d,4JF-C＝1.9Hz), 126.5,122.1(d,3JF-C＝3.9Hz),115.8(d,2JF-C＝22.7Hz),108.9(d,3JF-C＝4.7Hz), 108.3,101.3,73.7,72.5,59.3,36.4,21.6(d,J＝2.9Hz)；
19F NMR(471MHz,CDCl3)δ-84.3(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C26H24FNO5S+H,482.1432；found, 482.1427.
from the above data, it is concluded that the structure of the product obtained in this example is shown in the following formula:
example 11:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-phenylethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of 2- (3-quinolyl) -3,3, 3-trifluoropropene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring is stopped after stirring reaction is carried out for 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, a solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by separation and purification through column chromatography, and petroleum ether is used as eluent of the column chromatography, so that the yield of the product is 75%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.29(s,1H),8.16(d,J＝8.8Hz, 1H),7.89(d,J＝8.4Hz,1H),7.77(t,J＝7.6Hz,1H),7.69(d,J＝8.0Hz,2H),7.61 (t,J＝7.6Hz,1H),7.22(d,J＝8.0Hz,2H),7.09–7.16(m,3H),6.92(d,J＝6.8Hz, 2H),4.74(dd,J＝13.6,5.2Hz,1H),4.64(d,J＝14.0Hz,1H),3.99–4.05(m,2H), 3.91(d,J＝12.4Hz,1H),2.96(dd,J＝14.0,7.2Hz,1H),2.80(dd,J＝14.0,7.6Hz, 1H),2.46(s,3H)；
13C NMR(101MHz,CDCl3)δ150.2(d,3JF-C＝5.4Hz),148.3(d,1JF-C＝280.6 Hz),147.4,144.5,136.9,135.9,135.0(d,3JF-C＝4.4Hz),130.0,129.9,129.4,129.2, 128.6,128.2(d,3JF-C＝5.7Hz),128.1,127.7(d,4JF-C＝1.9Hz),127.7,127.3,126.7, 112.8(d,2JF-C＝23.2Hz),73.9(d,4JF-C＝2.6Hz),72.1(d,3JF-C＝4.7Hz),59.4,36.4, 21.7；
19F NMR(471MHz,CDCl3)δ-82.0(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C28H25FN2O3S+H,489.1643；found, 489.1640.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 12:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of (S) -N- [1- (hydroxymethyl) -2-ethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha- (trifluoromethyl) -phenylethynyl ethylene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, wherein petroleum ether is used as eluent of the column chromatography, and the yield of the product is 80%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.0Hz,2H),7.44–7.45(m,2H), 7.30–7.34(m,5H),4.41–4.45(m,2H),4.13–4.18(m,2H),4.03(t,J＝12.0Hz,1H), 2.43(s,3H),1.25(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl3)δ163.6(d,1JF-C＝268.8Hz),143.7,137.1,131.3, 129.5,128.4,128.2,127.4,123.4,93.4(d,3JF-C＝5.5Hz),82.1(d,4JF-C＝3.0Hz), 75.4(d,2JF-C＝25.7Hz),74.7,52.8,40.6(d,4JF-C＝2.2Hz),21.6,15.8；
19F NMR(471MHz,CDCl3)δ-70.0(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C21H20FNO3S+H,386.1221；found, 386.1214.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 13:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
adding 0.2 mmol of 7-hydroxymethyl-1H-indole, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethylstyrene and 2 ml of dimethyl sulfoxide into a 25 ml test tube in sequence, stirring and reacting for 12 hours at 40 ℃, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, separating and purifying by column chromatography to obtain a target product, wherein the petroleum ether is used as eluent of the column chromatography, and the yield of the product is 55%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.63–7.66(m,1H),7.16–7.27(m,3H),7.03–7.08 (m,5H),6.46(d,J＝3.2Hz,1H),5.73(s,2H),5.14(s,2H)；
13C NMR(101MHz,CDCl3)δ159.2(d,1JF-C＝262.9Hz),137.1(d,3JF-C＝2.4 Hz),135.0,130.9,130.2(d,3JF-C＝3.7Hz),128.5,126.9,124.6,123.0,119.9, 119.2,101.8(d,3JF-C＝2.7Hz),93.2(d,2JF-C＝29.7Hz),73.7,49.7(d,3JF-C＝6.0 Hz)；
19F NMR(471MHz,CDCl3)δ-80.6(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C18H14FNO+H,280.1132；found, 280.1128.
from the above data, it is concluded that the structure of the product obtained in this example is shown in the following formula:
example 14:
the synthesis method of the cyclic lactam derivative in the monofluoro olefin modified heteroatom of the embodiment includes the following specific synthesis steps:
0.2 mmol of N- [ 1-cyclohexyl-2-hydroxyethyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha- (trifluoromethyl) -phenylethynyl ethylene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification through the used column chromatography eluent petroleum ether, so that the yield of the product is 60%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.0Hz,2H),7.43–7.45(m,2H), 7.34–7.36(m,3H),7.29(d,J＝8.0Hz,2H),4.43(dd,J＝18.0,4.8Hz,1H),4.28(dd, J＝12.0,4.8Hz,1H),4.02–4.15(m,3H),2.42(s,3H),1.79–1.96(m,3H),1.59–1.71 (m,3H),1.09–1.29(m,5H)；
13C NMR(101MHz,CDCl3)δ163.6(d,1JF-C＝270.3Hz),143.6,137.3,131.3, 129.4,128.4,128.2,127.6,123.4,93.3(d,3JF-C＝5.1Hz),82.1(d,4JF-C＝3.3Hz), 75.4(d,2JF-C＝25.8Hz),73.6,61.5(d,4JF-C＝1.6Hz),41.9(d,4JF-C＝2.1Hz),38.5, 29.9,29.8,26.1,26.0,21.6；
19F NMR(471MHz,CDCl3)δ-77.7(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C26H28FNO3S+H,454.1847；found, 454.1839.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 15:
the synthesis method of the monofluoroolefin modified cyclolactone derivative in heteroatom of this embodiment includes the following specific synthesis steps:
0.2 mmol of N- [ 2-hydroxypropyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha- (trifluoromethyl) -triisopropylsilylvinylene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, wherein the petroleum ether is used as a column chromatography eluent, and the yield of the product is 70%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H), 4.12–4.21(m,2H),3.89(dd,J＝15.6,3.2Hz,1H),3.74(d,J＝14.8Hz,1H),3.29 (dd,J＝14.4,9.6Hz,1H),2.44(s,3H),1.31(d,J＝6.0Hz,3H),1.11(s,21H)；
13C NMR(101MHz,CDCl3)δ164.6(d,1JF-C＝278.2Hz),143.8,136.4,129.9, 127.4,99.7(d,3JF-C＝4.5Hz),95.7(d,4JF-C＝5.6Hz),80.2(d,2JF-C＝29.6Hz),79.0 (d,3JF-C＝1.7Hz),54.9(d,4JF-C＝2.2Hz),47.2(d,4JF-C＝2.9Hz),21.6,18.7,18.5, 11.3；
19F NMR(471MHz,CDCl3)δ-64.7(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C24H36FNO3SSi+H,466.2242；found, 466.2239.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 16:
the synthesis method of the monofluoroolefin modified cyclolactone derivative in heteroatom of this embodiment includes the following specific synthesis steps:
0.2 mmol of N- [ 2-hydroxypropyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha- (trifluoromethyl) -octynyl ethylene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours of stirring reaction at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, wherein the petroleum ether is used as a column chromatography eluent, and the yield of the product is 60%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H), 4.16(q,J＝6.4Hz,1H),4.06(dd,J＝15.6,4.4Hz,1H),3.78(dd,J＝15.6,3.2Hz, 1H),3.71(d,J＝14.4Hz,1H),3.17(dd,J＝14.4,9.6Hz,1H),2.43(s,3H),2.34(t,J ＝7.2Hz,2H),1.54(q,J＝7.2Hz,2H),1.29–1.45(m,9H),0.91(t,J＝7.2Hz,3H)；
13C NMR(101MHz,CDCl3)δ163.5(d,1JF-C＝277.2Hz),143.7,136.1,129.8, 127.3,95.3(d,3JF-C＝5.5Hz),80.7(d,2JF-C＝30.1Hz),78.9(d,4JF-C＝2.1Hz),73.2 (d,4JF-C＝4.7Hz),55.2(d,4JF-C＝2.3Hz),47.8(d,4JF-C＝3.3Hz),31.3,28.7,28.5, 22.6,21.5,19.6,18.4,14.1；
19F NMR(471MHz,CDCl3)δ-68.1(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C21H28FNO3SSi+H,394.1847；found, 394.1844.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 17:
the synthesis method of the monofluoroolefin modified cyclolactone derivative in heteroatom of this embodiment includes the following specific synthesis steps:
0.2 mmol of N- [ 2-hydroxypropyl ] -4-methylbenzenesulfonamide, 0.8 mmol of lithium tert-butoxide, 0.4 mmol of alpha-trifluoromethyl-p-trifluoromethylstyrene and 2 ml of dimethyl sulfoxide are sequentially added into a 25 ml test tube, stirring reaction is stopped after 12 hours at 40 ℃, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the target product is obtained by column chromatography separation and purification, wherein the petroleum ether is used as a column chromatography eluent, and the yield of the product is 67%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.6Hz,2H),7.59–7.64(m,4H),7.33 (d,J＝8.0Hz,2H),4.34–4.41(m,2H),3.87(t,J＝14.4Hz,2H),3.10(dd,J＝13.6, 8.8Hz,1H),2.45(s,3H),1.42(d,J＝6.4Hz,3H)；
13C NMR(101MHz,CDCl3)δ159.1(d,1JF-C＝281.2Hz),144.1,139.0(d,3JF-C＝5.5Hz),135.3,130.1,128.9(q,2JF-C＝32.3Hz),128.4(d,3JF-C＝4.6Hz),127.3, 125.4(q,3JF-C＝3.6Hz),124.3(q,1JF-C＝271.9Hz),96.8(d,2JF-C＝26.4Hz),79.5 (d,3JF-C＝2.8Hz),56.0(d,4JF-C＝2.6Hz),49.1(d,3JF-C＝4.9Hz),21.6,18.6；
19F NMR(471MHz,CDCl3)δ-62.5(s,3F),-74.9(s,1F)；
HRMS(APCI,m/z):[M+H]+Calcd.for C20H19F4NO3S+H,430.1095；found, 430.1090.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 18:
the synthesis method of the cyclic lactam derivative in the monofluoroolefin-modified heteroatom of the embodiment specifically comprises the following steps:
0.2 mmol of N- [ 2-p-toluenesulfonamidoethyl ] -4-methylbenzenesulfonamide, 0.6 mmol of cesium carbonate, 0.3 mmol of alpha-trifluoromethylstyrene and 2 ml of N, N-dimethylformamide are sequentially added into a 25 ml test tube, stirring is stopped after the mixture is stirred and reacts for 24 hours at room temperature, ethyl acetate and water are added to extract a reaction solution, the solvent is removed by reduced pressure rotary evaporation, and the mixture is separated and purified by column chromatography to obtain a target product, and the eluent of the column chromatography, petroleum ether, is used to obtain the product with the yield of 80 percent.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,DMSO-d6)δ7.79(d,J＝8.4Hz,2H),7.65(d,J＝8.4Hz, 2H),7.53(d,J＝6.8Hz,2H),7.34–7.46(m,7H),3.88(s,2H),3.73(s,2H),3.24(s, 2H),2.43(s,3H),2.39(s,3H)；
13C NMR(101MHz,DMSO-d6)δ149.9(d,1JF-C＝278.4Hz),145.3,144.3, 136.4,134.7(d,3JF-C＝5.2Hz),134.1,130.6,130.5,128.9,128.6,128.5,127.7, 127.6,112.9(d,2JF-C＝23.6Hz),50.4,50.4,50.2,49.0,21.5；
19F NMR(376MHz,DMSO-d6)δ-85.9(d,J＝11.3Hz,1F)；
IR(KBr):2921,1639,1355,1163,741cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.For C25H25FN2O4S2+H,501.0318；found, 501.1316.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
example 19:
the synthesis method of the cyclic lactam derivative in the monofluoro olefin modified heteroatom of the embodiment includes the following specific synthesis steps:
adding 0.2 mmol of 7- [ p-toluenesulfonylaminomethyl ] -indole, 0.6 mmol of cesium carbonate, 0.3 mmol of alpha-trifluoromethylstyrene and 2 ml of N, N-dimethylformamide into a 25 ml test tube in sequence, stirring and reacting at room temperature for 24 hours, stopping stirring, adding ethyl acetate and water to extract a reaction solution, decompressing and rotary-steaming to remove a solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent petroleum ether is used, and the yield of the product is 52%.
The structural characterization data of the main products of the product obtained in this example are as follows:
1H NMR(400MHz,CDCl3)δ7.54(d,J＝7.6Hz,2H),7.45–7.49(m,3H), 7.31–7.39(m,3H),7.24(s,1H),7.05(d,J＝8.0Hz,2H),6.94–7.01(m,2H),6.64 (s,1H),5.18(d,J＝15.2Hz,1H),4.79(d,J＝15.2Hz,1H),4.67(d,J＝13.2Hz, 1H),4.03(d,J＝13.6Hz,1H),2.31(s,3H)；
13C NMR(101MHz,CDCl3)δ148.8(d,1JF-C＝266.7Hz),143.2,136.4,136.0, 134.1(d,3JF-C＝4.0Hz),129.5,129.1(d,4JF-C＝2.4Hz),128.8,128.2(d,3JF-C＝ 5.0Hz),128.0,127.4,127.1,125.7,122.0,122.0,117.7,106.9,101.2(d,2JF-C＝21.3Hz),47.4(d,3JF-C＝7.2Hz),46.1,21.5；
19F NMR(376MHz,CDCl3)δ-87.5(s,1F)；
IR(KBr):3050,2939,1689,1339,779cm-1；
HRMS(APCI,m/z):[M+H]+Calcd.For C25H21FN2O2S+H,433.1381；found, 433.1375.
from the above data, it is concluded that the structure of the product obtained in this example is shown below:
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. A synthetic method of a cyclic lactone or lactam derivative in a monofluoro olefin modified heteroatom, which is characterized by comprising the following steps:
adding alkali, amino alcohol or diamine or diol and trifluoromethyl olefin into an organic solvent, stirring for reaction, adding an extraction liquid for extraction, and performing reduced pressure rotary evaporation on an extracted organic layer to remove the solvent to obtain a crude product; purifying the crude product by column chromatography to obtain monofluoroolefin modified heteroatom cyclic lactone or lactam derivative;
the synthesis method has the specific reaction formula as follows:
wherein R is1Hydrogen, methyl, isopropyl, benzyl, cyclohexyl; r2Hydrogen, cyclohexyl, 7-indolyl; r is3Is phenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-naphthyl, 3-quinolyl, phenylethynyl, triisopropylsilylnyl, octynyl, 3 ', 4' -methylenedioxyphenyl.
2. The method of claim 1, wherein the base is at least one of potassium carbonate, cesium carbonate, lithium tert-butoxide, sodium tert-butoxide.
3. The method of claim 1, wherein the organic solvent is selected from one of dimethylsulfoxide and N, N-dimethylformamide.
4. The method of claim 1, wherein the molar ratio of the aminoalcohol, diamine, or diol to the trifluoromethylolefin is 1: 1.5-2.
5. The method of claim 1, wherein the molar ratio of the base to the amine alcohol or diamine or diol is 3-4: 1.
6. the method for synthesizing a cyclic lactone or lactam derivative in a monofluoroolefin-modified heteroatom of claim 1, wherein the reaction temperature is 25-40 ℃ and the reaction time is 12-24 h.
7. The method of claim 1, wherein the extraction solution comprises ethyl acetate and water.
8. The method for synthesizing the monofluoroolefin-modified cyclic lactone or lactam derivative in a heteroatom, as claimed in claim 1, wherein the column chromatography purification is a mixture of petroleum ether and ethyl acetate in a volume ratio of 5-50: 0-1, and then column chromatography purification of an eluent.
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