CN109970563A - A kind of fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- and the preparation method and application thereof - Google Patents
A kind of fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- and the preparation method and application thereof Download PDFInfo
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- CN109970563A CN109970563A CN201910382823.8A CN201910382823A CN109970563A CN 109970563 A CN109970563 A CN 109970563A CN 201910382823 A CN201910382823 A CN 201910382823A CN 109970563 A CN109970563 A CN 109970563A
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- Prior art keywords
- fluoroolefins
- fluoro
- acrylic acid
- acid methyl
- base
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- -1 acrylic acid methyl compound Chemical class 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 16
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 16
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 13
- 239000012298 atmosphere Substances 0.000 claims abstract description 12
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 11
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000011574 phosphorus Substances 0.000 claims abstract description 10
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 230000032050 esterification Effects 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- 239000002585 base Substances 0.000 claims description 33
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- RHDYQUZYHZWTCI-UHFFFAOYSA-N 1-methoxy-4-phenylbenzene Chemical group C1=CC(OC)=CC=C1C1=CC=CC=C1 RHDYQUZYHZWTCI-UHFFFAOYSA-N 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- BANUTYPBALYVJT-UHFFFAOYSA-N 1-phenyl-4-(trifluoromethoxy)benzene Chemical group C1=CC(OC(F)(F)F)=CC=C1C1=CC=CC=C1 BANUTYPBALYVJT-UHFFFAOYSA-N 0.000 claims description 4
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- SZLBBMYXVFEDFP-UHFFFAOYSA-N tert-butyl 2H-1,3-benzoxazole-3-carboxylate Chemical class C(C)(C)(C)OC(=O)N1COC2=C1C=CC=C2 SZLBBMYXVFEDFP-UHFFFAOYSA-N 0.000 claims description 3
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 2
- 239000004305 biphenyl Substances 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract description 10
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000001228 spectrum Methods 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000006473 carboxylation reaction Methods 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 1
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 150000001723 carbon free-radicals Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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Abstract
The invention discloses fluoro- 3- aromatic substituted acrylic acid methyl compounds of a kind of 2- and the preparation method and application thereof.The present invention passes through under carbon dioxide gas atmosphere, two fluoroolefins, photochemical catalyst, palladium catalyst, phosphorus ligand, alkali, reducing agent are added sequentially in solvent, obtain mixture, under carbon dioxide gas atmosphere, mixture is reacted into 48~96h under room temperature, blue light, the esterification that carboxyl is carried out to mixture, collects out the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- from reaction product.The compound can be used as the inhibitor of DPP IV.Raw material needed for the present invention are simple and easy to get, substrate spectrum is wide, and at low cost, reaction condition is mild, and required catalytic amount is few, also eliminate the need cumbersome pre- function dough step.
Description
Technical field
The invention belongs to organic chemical synthesis technical field more particularly to a kind of fluoro- 3- aromatic substituted acrylic acid methyl esters chemical combination of 2-
Object and the preparation method and application thereof.
Background technique
Fluorochemical has a wide range of applications in the synthesis of natural products and drug.In recent decades, fluorine-containing chemical combination
Object is especially the synthesis of fluorine-containing carboxylic acid compound by the extensive concern of scientists and has made great progress, but still
There is complex steps, the disadvantages of raw material is not easy to obtain, and obtained based on the carboxylation reaction that the compound with fluoro-containing group carries out
The product structure arrived is also relatively simple.The reactive intermediate generated using multi-fluorinated compounds cheap and easy to get through carbon-fluorine bond fracture is straight
One kind can be provided more for the synthesis of fluorine-containing carboxylic acid compound by connecing the strategy for carrying out carboxylated with carbon dioxide gas precursor reactant
Direct and inexpensive approach.But due to the universal bond energy with higher of carbon-fluorine bond, it is broken that carry out carboxylated anti-by carbon-fluorine bond
Should it not developed well.Transition metal-catalyzed halogen (class halogen) is for hydrocarbon (including iodine, bromine, chlorine, triflate at present
Deng) although relatively common by carbon-halogen bond fracture and carbon dioxide reaction progress carboxylated, but similar method is but difficult to answer
For the carboxylated of carbon-fluorine bond, reason is that oxidation addition of the carbon-fluorine bond for transition-metal catalyst is difficult to carry out.
Grew up in recent years utilization can with light-exposed redox catalysis promote carbon-fluorine bond cleavage strategy can be effective
Realization multi-fluorinated compounds defluorinate functionalization.As document 1 (J.Xie, J.Yu, M.Rudolph, F.Rominger,
AndA.S.K.Hashmi, Angew.Chem.Int.Ed.2016,55,9416-9421) disclosed in method in, in illumination condition
The carbon-fluorine bond fracture of lower two fluoroolefins, forms alkenyl carbon radicals, and coupling directly occurs with the carbon radicals in system and obtains
Obtain the amine-methylated product of defluorinate.
Simultaneously, it is seen that light promote also have certain research within carboxylation reaction nearly 2 years, as document 2 (K.Shimomaki,
K.Murata, R.Martin, and N.Iwasawa, J.Am.Chem.Soc.2018,140,17338-17342) disclosed in side
In method, the strategy of use be using visible light redox catalysis mediate reduction system promote palladium chtalyst aryl halide (bromine,
Chlorine) for the carboxylation reaction of hydrocarbon, and then aryl carboxylic acid product.
In view of the multifunctionality of exploitation visible light redox catalysis, using in conjunction with photocatalysis and transition metal-catalyzed side
Method develops efficient multi-fluorinated compounds carbon-fluorine bond carboxylation reaction for carbon dioxide conversion and the preparation containing carboxylic acid fluoride all has
It is significant.
Summary of the invention
The purpose of the present invention is to provide fluoro- 3- aromatic substituted acrylic acid methyl compound of a kind of 2- and preparation method thereof, this hairs
The raw material of bright use are simple and easy to get, substrate spectrum is wide, at low cost, and reaction condition is mild, using minimal amount of catalyst,
Also eliminate the need cumbersome pre- function dough step.
The invention is realized in this way a kind of fluoro- 3- aromatic substituted acrylic acid methyl compound of 2-, the chemical structure of the compound
Formula is as follows:
In above formula, R1For 4- xenyl, 4- (4- methoxyl biphenyl) base, 4- (4- trifluoromethoxy biphenyl) base, 4- naphthalene nucleus
Base phenyl, 4- pyrazole phenyl, 1- naphthalene nucleus, 2- naphthalene nucleus, 3- dibenzofurans, 1- benzothiophene, 6- (N-Boc benzoxazoles), 3,
5- difluorophenyl, 4- trifluoromethylbenzene, 4- (N, N- diethylformamide base) benzene, 4- methylsulfonyl phenyl, the tertiary fourth carbomethoxy benzene of 3-
Base, 3- trifluoromethyl, 3- cyano-phenyl or 2- trifluoromethyl；
R2For methyl, n-pentyl, 2- methyl 2- cyclobutenyl, cyclohexylmethylene, 3- oxinane ofmcthylene-based or 3- (N-
Boc piperidines) methylene.
The present invention further discloses the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of above-mentioned 2-, this method packets
Include following steps:
(1) under carbon dioxide gas atmosphere, by two fluoroolefins, photochemical catalyst, palladium catalyst, phosphorus ligand (or without matching
Body), alkali, reducing agent be added sequentially in solvent, obtain mixture；Wherein, two fluoroolefins, photochemical catalyst, palladium catalyst,
Phosphorus ligand (or without ligand), alkali, reducing agent molar ratio be 0.1mmol:1%mol:5%mol:20%mol:0.3mmol:
0.3mmol；
(2) under carbon dioxide gas atmosphere, mixture obtained in step (1) reacts to 48 under room temperature, blue light~
96h carries out the esterification of carboxyl to mixture, the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- is collected out from reaction product.
Preferably, in step (1), two fluoroolefins be in monosubstituted two fluoroolefins and disubstituted two fluoroolefins extremely
Few one kind；Wherein,
Monosubstituted two fluoroolefins includes two fluoroolefins of 4- xenyl, two fluoroolefins of 4- (4- methoxyl biphenyl) base, 4-
Two fluoroolefins of (4- trifluoromethoxy biphenyl) base, two fluoroolefins of 4- naphthalene nucleus base phenyl, two fluoroolefins of 4- pyrazole phenyl, 1- naphthalene nucleus two
(N-Boc benzo is disliked by fluoroolefins, two fluoroolefins of 2- naphthalene nucleus, two fluoroolefins of 3- dibenzofurans, two fluoroolefins of 1- benzothiophene, 6-
Azoles) two fluoroolefins, two fluoroolefins of 3,5- difluorophenyl, two fluoroolefins of 4- trifluoromethyl, 4- (N, N- diethylformamide
Base) two fluoroolefins of phenyl, two fluoroolefins of 4- methylsulfonyl phenyl, tertiary two fluoroolefins of fourth carbomethoxyphenyl of 3-, 3- trifluoromethyl
Two fluoroolefins of two fluoroolefins, two fluoroolefins of 3- cyano-phenyl and 2- trifluoromethyl；
Disubstituted two fluoroolefins includes two fluoroolefins of 2- naphthalene nucleus base 2- methyl, 2- naphthalene nucleus base -2- n-pentyl difluoro alkene
Hydrocarbon, 2- naphthalene nucleus base -2- (2- methyl 2- cyclobutenyl) two fluoroolefins, two fluoroolefins of 2- naphthalene nucleus base -2- cyclohexylmethylene, 2- naphthalene nucleus
Base -2- (3- oxinane methylene) two fluoroolefins and 2- naphthalene nucleus base -2- [3- (N-Boc piperidines) methylene] two fluoroolefins.
Preferably, in step (1), the photochemical catalyst is Ir [dF (CF3)ppy]2(dtbpy)(PF6)。
Preferably, in step (1), the palladium catalyst is palladium chloride.
Preferably, in step (1), the phosphorus ligand is triphenylphosphine.
Preferably, in step (1), the alkali is cesium carbonate.
Preferably, in step (1), the reducing agent is n,N-diisopropylethylamine.
Preferably, in step (1), the solvent is n,N-dimethylacetamide.
The present invention further discloses the fluoro- 3- aromatic substituted acrylic acid methyl compounds of above-mentioned 2- to press down as DPP IV
Effect in terms of preparation.The fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- of the present invention plays extremely important in biology and medicine
Role, for example, DPP IV (DPP IV, EC3.4.14.5, CD26) be one kind in cell surface and epicyte knot
The serine protease of conjunction, the effect after degradation and translation that DPP IV passes through peptide in metabolism and regulation is increasingly by weight
Depending on.It is potentially controlled because it is found that DPP IV is inhibited to have in terms of adjusting the synthesis of glucagon-like peptide and inhibiting immune response
Treatment effect, thus it is urgently to be resolved to the exploration of the mortifier of DPP IV.(Z) the double bond conformational energy of single fluoroolefins isomers is effectively
The proline key in trans- P2 original dipeptides is simulated, the inactivation rate of DPP IV can be made to significantly improve, therefore, the fluoro- 3- of 2- of the present invention
Single fluoroolefins structure in aromatic substituted acrylic acid methyl compound is exactly effective inhibitor of DPP IV.
Compared with the prior art the shortcomings that and deficiency, the invention has the following advantages:
(1) present invention has carried out abundantization to the functional group of substrate, to obtain more fluorine-containing carboxylic acid compounds；
(2) present invention using two fluoroolefins as reaction substrate, using light-catalysed mode be broken carbon-fluorine bond formed it is unstable
Alkenyl radical, then it is captured by palladium, rare monovalence palladium intermediate is obtained, since it is with very strong nucleophilic energy
Power, so, the present invention can be such that carbon-fluorine bond is broken in the form of free radical very mild mode (illumination), and at a low price
Metal captures and its unstable alkenyl carbon radicals carry out nucleophilic attack to inert electrophilic reagent carbon dioxide in turn and obtain
Fluorine-containing carboxylated product, compared in the past using equivalent heavy metal as the reaction of reducing agent for, the condition of this synthetic method is more
For mild environmental protection, substrate is more abundant extensive, and product plays very important effect in medicine synthesis；
(3) raw material needed for the present invention are simple and easy to get, substrate spectrum is wide, and at low cost, reaction condition is mild, required catalyst
Amount is few, also eliminates the need cumbersome pre- function dough step.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1
(1) under carbon dioxide gas atmosphere, by two fluoroolefins of 0.1mmol4- xenyl, 1%mol photochemical catalyst Ir [dF
(CF3)ppy]2(dtbpy)(PF6), 5%mol palladium catalyst palladium chloride, 20%mol phosphorus ligand triphenylphosphine, 0.3mmol carbonic acid
Caesium, 0.3mmol reducing agent n,N-diisopropylethylamine are added sequentially in solvent n,N-dimethylacetamide, obtain mixture；
(2) under carbon dioxide gas atmosphere, mixture obtained in step (1) reacts to 48 under room temperature, blue light~
96h carries out the esterification of carboxyl to mixture, the fluoro- 3- aromatic substituted acrylic acid methyl compound 1 of 2- is collected out from reaction product.
Embodiment 2
(1) under carbon dioxide gas atmosphere, by two fluoroolefins of 0.1mmol4- (4- methoxyl biphenyl) base, 1%mol light
Catalyst Ir [dF (CF3)ppy]2(dtbpy)(PF6), 5%mol palladium catalyst palladium chloride, 20%mol phosphorus ligand triphenylphosphine,
0.3mmol cesium carbonate, 0.3mmol reducing agent n,N-diisopropylethylamine are added sequentially in solvent n,N-dimethylacetamide,
Obtain mixture；
(2) under carbon dioxide gas atmosphere, mixture obtained in step (1) reacts to 48 under room temperature, blue light~
96h carries out the esterification of carboxyl to mixture, the fluoro- 3- aromatic substituted acrylic acid methyl compound 2 of 2- is collected out from reaction product.
Embodiment 3
(1) under carbon dioxide gas atmosphere, by two fluoroolefins of 0.1mmol4- (4- trifluoromethoxy biphenyl) base, 1%
Mol photochemical catalyst Ir [dF (CF3)ppy]2(dtbpy)(PF6), 5%mol palladium catalyst palladium chloride, 20%mol phosphorus ligand triphen
Base phosphine, 0.3mmol cesium carbonate, 0.3mmol reducing agent N, N- diisopropylethylamine are added sequentially to solvent N, N- dimethylacetamide
In amine, mixture is obtained；
(2) under carbon dioxide gas atmosphere, mixture obtained in step (1) reacts to 48 under room temperature, blue light~
96h carries out the esterification of carboxyl to mixture, the fluoro- 3- aromatic substituted acrylic acid methyl compound 3 of 2- is collected out from reaction product.
Embodiment 4~20
Embodiment 4~20 is same as Example 3, the difference is that:
1 embodiment 4~20 of table
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of fluoro- 3- aromatic substituted acrylic acid methyl compound of 2-, which is characterized in that the following institute of the chemical structural formula of the compound
Show:
In above formula, R1For 4- xenyl, 4- (4- methoxyl biphenyl) base, 4- (4- trifluoromethoxy biphenyl) base, 4- naphthalene nucleus base benzene
Base, 4- pyrazole phenyl, 1- naphthalene nucleus, 2- naphthalene nucleus, 3- dibenzofurans, 1- benzothiophene, 6- (N-Boc benzoxazoles), 3,5- bis-
Fluorophenyl, 4- trifluoromethylbenzene, 4- (N, N- diethylformamide base) benzene, 4- methylsulfonyl phenyl, the tertiary fourth carbomethoxyphenyl of 3-, 3-
Trifluoromethyl, 3- cyano-phenyl or 2- trifluoromethyl；
R2For methyl, n-pentyl, 2- methyl 2- cyclobutenyl, cyclohexylmethylene, 3- oxinane ofmcthylene-based or 3- (N-Boc piperazine
Pyridine) methylene.
2. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- described in claim 1, which is characterized in that this method
The following steps are included:
(1) under carbon dioxide gas atmosphere, successively by two fluoroolefins, photochemical catalyst, palladium catalyst, phosphorus ligand, alkali, reducing agent
It is added in solvent, obtains mixture；Wherein, two fluoroolefins, photochemical catalyst, palladium catalyst, phosphorus ligand, alkali, reducing agent
Molar ratio be 0.1mmol:1%mol:5%mol:20%mol:0.3mmol:0.3mmol；
(2) under carbon dioxide gas atmosphere, mixture obtained in step (1) is reacted into 48~96h under room temperature, blue light,
The esterification that carboxyl is carried out to mixture, collects out the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- from reaction product.
3. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- as claimed in claim 2, which is characterized in that in step
Suddenly in (1), two fluoroolefins is at least one of monosubstituted two fluoroolefins and disubstituted two fluoroolefins；Wherein,
Monosubstituted two fluoroolefins includes two fluoroolefins of 4- xenyl, two fluoroolefins of 4- (4- methoxyl biphenyl) base, 4- (4- tri-
Fluorine methoxyl group biphenyl) two fluoroolefins of base, two fluoroolefins of 4- naphthalene nucleus base phenyl, two fluoroolefins of 4- pyrazole phenyl, 1- naphthalene nucleus difluoro alkene
Hydrocarbon, two fluoroolefins of 2- naphthalene nucleus, two fluoroolefins of 3- dibenzofurans, two fluoroolefins of 1- benzothiophene, 6- (N-Boc benzoxazoles) two
Fluoroolefins, two fluoroolefins of 3,5- difluorophenyl, two fluoroolefins of 4- trifluoromethyl, 4- (N, N- diethylformamide base) phenyl
Two fluoroolefins, two fluoroolefins of 4- methylsulfonyl phenyl, tertiary two fluoroolefins of fourth carbomethoxyphenyl of 3-, 3- trifluoromethyl difluoro alkene
Two fluoroolefins of hydrocarbon, two fluoroolefins of 3- cyano-phenyl and 2- trifluoromethyl；
Disubstituted two fluoroolefins includes two fluoroolefins of 2- naphthalene nucleus base 2- methyl, two fluoroolefins of 2- naphthalene nucleus base -2- n-pentyl, 2-
Naphthalene nucleus base -2- (2- methyl 2- cyclobutenyl) two fluoroolefins, two fluoroolefins of 2- naphthalene nucleus base -2- cyclohexylmethylene, 2- naphthalene nucleus base -2-
(3- oxinane methylene) two fluoroolefins and 2- naphthalene nucleus base -2- [3- (N-Boc piperidines) methylene] two fluoroolefins.
4. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- as claimed in claim 2, which is characterized in that in step
Suddenly in (1), the photochemical catalyst is Ir [dF (CF3)ppy]2(dtbpy)(PF6)。
5. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- as claimed in claim 2, which is characterized in that in step
Suddenly in (1), the palladium catalyst is palladium chloride.
6. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- as claimed in claim 2, which is characterized in that in step
Suddenly in (1), the phosphorus ligand is triphenylphosphine.
7. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- as claimed in claim 2, which is characterized in that in step
Suddenly in (1), the alkali is cesium carbonate.
8. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- as claimed in claim 2, which is characterized in that in step
Suddenly in (1), the reducing agent is n,N-diisopropylethylamine.
9. the preparation method of the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- as claimed in claim 2, which is characterized in that in step
Suddenly in (1), the solvent is n,N-dimethylacetamide.
10. the fluoro- 3- aromatic substituted acrylic acid methyl compound of 2- described in claim 1 is in terms of as inhibitors of dipeptidyl IV
Effect.
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| CN113773167A (en) * | 2021-09-10 | 2021-12-10 | 滁州学院 | Synthesis method of monofluoroolefin |
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