CN117069761A - (Z) -gem-fluorophosphine compound and preparation method and application thereof - Google Patents
(Z) -gem-fluorophosphine compound and preparation method and application thereof Download PDFInfo
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- CN117069761A CN117069761A CN202311044343.3A CN202311044343A CN117069761A CN 117069761 A CN117069761 A CN 117069761A CN 202311044343 A CN202311044343 A CN 202311044343A CN 117069761 A CN117069761 A CN 117069761A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- -1 diaryl phosphorus oxide compound Chemical class 0.000 claims abstract description 28
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 claims abstract description 12
- APXPUJWNYZULFP-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-en-1-one Chemical compound FC(F)(F)C=C=O APXPUJWNYZULFP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 11
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 11
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 11
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 11
- 229910001392 phosphorus oxide Inorganic materials 0.000 claims abstract description 9
- 239000003112 inhibitor Substances 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 235000010290 biphenyl Nutrition 0.000 claims description 13
- 239000004305 biphenyl Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- 230000005526 G1 to G0 transition Effects 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 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 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000006267 biphenyl group Chemical class 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 5
- 239000011574 phosphorus Substances 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 3
- 238000006115 defluorination reaction Methods 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract description 2
- 230000000996 additive effect Effects 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000006366 phosphorylation reaction Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 150000002367 halogens Chemical group 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- QXXLTUGIYJSGIQ-UHFFFAOYSA-N O([P]Oc1ccccc1)c1ccccc1 Chemical compound O([P]Oc1ccccc1)c1ccccc1 QXXLTUGIYJSGIQ-UHFFFAOYSA-N 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- VWBYXJRDIQCSLW-UHFFFAOYSA-N O=[P](c1ccccc1)c1ccccc1 Chemical compound O=[P](c1ccccc1)c1ccccc1 VWBYXJRDIQCSLW-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 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
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- UJBHOFPPZWFQKO-UHFFFAOYSA-N dinaphthalen-2-yl(oxo)phosphanium Chemical compound C1=CC=CC2=CC([P+](C=3C=C4C=CC=CC4=CC=3)=O)=CC=C21 UJBHOFPPZWFQKO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Abstract
The invention discloses a (Z) -gem-fluorophosphine compound, a preparation method and application thereof. In the preparation method of the invention, phenyl silane is used as a hydrogen source and diaryl phosphorus oxide compound is used as a phosphorus source, and trifluoromethyl ketene is subjected to continuous hydrodefluorination and defluorination phosphorylation reaction under the metal-free condition, so that the (Z) -gem-fluorophosphine compound with high regioselectivity and cis-selectivity is prepared. The preparation method has the advantages of no addition of catalyst and additive, wide substrate range, mild reaction condition, simple operation, high yield, few byproducts, simple post-treatment, environmental protection, high economic benefit and the like; and the obtained compound shows a certain activity against human pancreatic cancer cells (PANC-1), and can be used for preparing an activity inhibitor against human pancreatic cancer cells.
Description
Technical Field
The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a (Z) -gem-fluorophosphine compound, and a preparation method and application thereof.
Background
The gem-fluorophosphine compounds are used as an important fragment in clinical medicine, agrochemistry, materials science and organic synthesis (org. Biomol. Chem.2007,5,1151). Binding of phosphorus atoms at the gem-fluorine position also confers their unique biophysical properties (j.am. Chem. Soc.2006,128, 5642). Strategies including Horner-Wittig olefin synthesis (j.chem.Soc.chem.Commun.1982, 1270), transition metal catalyzed or photocatalytic coupling (org.lett.2022, 24,8343), fluorine elimination (chem.Commun.2000, 1081), intermolecular defluorination (angel.chem.int.ed.2016, 55,14141), and others are commonly used to obtain fluorophosphine olefin products. However, these methods have some unavoidable limitations, such as: multistep pre-synthesis of specific functionalized precursors, reliance on expensive metal catalysts, use of hazardous/sensible reagents, and concomitant formation of competitive regioisomers and cis-trans isomers.
Disclosure of Invention
The primary object of the present invention is to provide a process for the preparation of (Z) -gem-fluorophosphine compounds, which aims to solve the problems of various limitations existing in the existing processes for the preparation of (Z) -gem-fluorophosphine compounds.
It is still another object of the present invention to provide the above (Z) -gem-fluorophosphine compound.
It is a further object of the present invention to provide the use of the (Z) -gem-fluorophosphine compounds described above.
The invention is realized in such a way that a (Z) -gem-fluorophosphine compound has a chemical structural formula shown in the following formula (I):
wherein R is 1 Any one selected from phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, biphenyl, thienyl, naphthyl, pyridyl and cyclohexyl;
R 2 any one selected from phenyl, halogen substituted phenyl and benzothienyl;
R 3 any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl;
R 4 any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl.
The invention further discloses a preparation method of the (Z) -gem-fluorophosphine compound, which comprises the following steps:
(1) Adding diaryl phosphorus oxide, trifluoromethyl ketene, phenylsilane and alkali into a solvent, and stirring and reacting for 6-12 h in a nitrogen atmosphere at room temperature-80 ℃; wherein,
the chemical structural formula of the diaryl phosphorus oxide compound is shown as the following formula (II):
in the formula (II), R 3 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl; r is R 4 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl;
the chemical structural formula of the trifluoromethyl ketene is shown as the following formula (III):
in the formula (III), R 1 Any one selected from phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, biphenyl, thienyl, naphthyl, pyridyl and cyclohexyl; r is R 2 Any one selected from phenyl, halogen substituted phenyl and benzothienyl;
(2) After the reaction is finished, quenching and extracting the reaction products in sequence, washing, drying and concentrating the combined organic phases sequentially to obtain a crude product, and purifying the crude product to obtain the (Z) -gem-fluorophosphene compound.
Preferably, in step (1), the base is selected from any one of cesium carbonate, potassium carbonate, sodium carbonate, lithium hydroxide, triethylenediamine, triethylamine, and potassium phosphate.
Preferably, in step (1), the solvent is selected from any one of acetonitrile, toluene, tetrahydrofuran, dichloroethane, N-dimethylformamide and 1, 4-dioxane.
Preferably, in step (1), 0.3mmol of trifluoromethyl ketene, 0.3 to 0.9mmol of diaryl phosphorus oxide compound, 0.45 to 0.75mmol of phenylsilane, and 0.75 to 1.35mmol of base are added to 3.5mL of solvent.
Preferably, in step (2), the reaction solution is saturated with NH 4 The Cl solution was quenched and extracted 3 times with ethyl acetate, and the combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product.
Preferably, in step (2), the purification is silica gel column chromatography purification, and the column chromatography separation conditions are: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate A and petroleum ether B, and the mobile phase is changed in procedure A: b is 1:2.
the invention further discloses application of the (Z) -gem-fluorophosphine compound in preparing an activity inhibitor of human pancreatic cancer cells (PANC-1).
The invention overcomes the defects of the prior art and provides a (Z) -gem-fluorophosphine compound, a preparation method and application thereof. In the preparation method of the invention, phenyl silane is used as a hydrogen source and diaryl phosphorus oxide compound is used as a phosphorus source, and trifluoromethyl ketene is subjected to continuous hydrodefluorination and defluorination phosphorylation reaction under the metal-free condition, so that the (Z) -gem-fluorophosphine compound with high regioselectivity and cis-selectivity is prepared.
The chemical structural formula of the diaryl phosphorus oxide compound is shown as the following formula (II):
in the formula (II), R 3 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl; r is R 4 Selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted benzeneAny one of a group and a biphenyl group;
the chemical structural formula of the trifluoromethyl ketene is shown as the following formula (III):
in the formula (III), R 1 Any one selected from phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, biphenyl, thienyl, naphthyl, pyridyl and cyclohexyl; r is R 2 Any one selected from phenyl, halogen substituted phenyl and benzothienyl;
the chemical structure of the (Z) -gem-fluorophosphene compound is shown in the following formula (I):
the chemical equation (exemplary) for this reaction is:
compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects: the preparation method has the advantages of no addition of catalyst and additive, wide substrate range, mild reaction condition, simple operation, high yield, few byproducts, simple post-treatment, environmental protection, high economic benefit and the like; and the obtained compound shows a certain activity against human pancreatic cancer cells (PANC-1), and can be used for preparing an activity inhibitor against human pancreatic cancer cells.
Drawings
FIG. 1 is a hydrogen spectrum of compound a of example 1 of the present invention;
FIG. 2 is a fluorine spectrum of the compound a of example 1 of the present invention;
FIG. 3 is a phosphorus spectrum of compound a of example 1 of the present invention;
FIG. 4 is a carbon spectrum of compound a of example 1 of the present invention;
FIG. 5 is a hydrogen spectrum of compound b of example 2 of the present invention;
FIG. 6 is a fluorine spectrum of the compound b of example 2 of the present invention;
FIG. 7 is a phosphorus spectrum of compound b of example 2 of the present invention;
FIG. 8 is a carbon spectrum of compound b of example 2 of the present invention;
FIG. 9 is a hydrogen spectrum of compound c of example 3 of the present invention;
FIG. 10 is a fluorine spectrum of the compound c of example 3 of the present invention;
FIG. 11 is a phosphorus spectrum of compound c of example 3 of the present invention;
FIG. 12 is a carbon spectrum of compound c of example 3 of the present invention;
FIG. 13 shows the results of an anti-human pancreatic cancer cell (PANC-1) activity test of compound a in the application example of the present invention;
FIG. 14 shows the results of an anti-human pancreatic cancer cell (PANC-1) activity test of compound b in the application example of the present invention;
FIG. 15 shows the results of an anti-human pancreatic cancer cell (PANC-1) activity test of compound c in the application example of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The starting diaryl phosphine oxide compound used in the examples below was prepared according to the method reported in the reference (Eur. J. Org. Chem.2022,87,7720); the trifluoromethyl ketene compounds were prepared according to the methods reported in the references (org. Lett.2018,20,1638). Other materials were purchased commercially, unless otherwise specified.
Example 1
(1) To a 10mL Schlenk tube were added in order (E) -4, 4-trifluoro-1, 3-diphenylbut-2-en-1-one (82.9 mg,0.3mmol,1 equiv.), diphenylphosphorus oxide (91.0 mg,0.45mmol,1.5 equiv.), phenylsilane (48.7 mg,0.45mmol,1.5 equiv.), tetrahydrofuran (3.5 mL), and cesium carbonate (244.4 mg,0.75mmol,2.5 equiv.) and the reaction mixture was stirred under nitrogen at 50℃for 6h.
(2) After the reaction of step (1), saturated NH is used 4 The Cl solution was quenched and extracted with ethyl acetate (20 mL. Times.3); the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product; the crude product was purified by silica gel column chromatography, column chromatography separation conditions: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A: B) is 1:2, 91.6mg of compound a (white solid) was finally obtained, calculated to be 69%.
The characterization of the above compound a, as shown in fig. 1 to 4, is specifically:
1 H NMR(400MHz,CDCl 3 ):δ＝7.62-7.55(m,2H),7.49-7.43(m,2H),7.40-7.35(m,3H),7.34-7.27(m,8H),7.22-7.13(m,5H),4.56(t,J＝7.1Hz,1H),3.48-2.90(m,3H)ppm.
19 F NMR(376MHz,CDCl 3 ):δ＝-112.2(d,J＝87.9Hz,1F)ppm.
31 P NMR(162MHz,CDCl 3 ):δ＝20.99(d,J＝86.7Hz)ppm.
13 C NMR(100MHz,CDCl 3 ):δ＝150.7(dd,J＝275.7,128.1Hz),143.6,137.5(dd,J＝18.0,10.2Hz),134.3(d,J＝7.2Hz),132.0(dd,J＝6.7,2.9Hz),131.56(dd,J＝26.5,10.1Hz),131.55,131.4(d,J＝10.4Hz),130.5(d,J＝10.3Hz),129.3,128.39,128.38(dd,J＝13.0,4.3Hz),127.7,127.2(d,J＝149.5Hz),71.8,41.7(t,J＝5.9Hz)ppm.
HRMS(m/z):calcd for C 28 H 25 FO 2 P[M+H] + 443.1571,found:443.1576.
according to the characterization data, the prepared compound a is (Z) - (1-fluoro-4-hydroxy-2, 4-diphenyl but-1-en-1-yl) diphenyl phosphine oxide (purity > 98%), and the compound has the structural formula:
example 2
(1) To a 10mL Schlenk tube was added successively (E) -3- (4-bromophenyl) -4, 4-trifluoro-1-phenylbut-2-en-1-one (106.5 mg,0.3mmol,1 equiv.) diphenyloxyphosphorus (91.0 mg,0.45mmol,1.5 equiv.), phenylsilane (48.7 mg,0.45mmol,1.5 equiv.), tetrahydrofuran (3.5 mL) and cesium carbonate (244.4 mg,0.75mmol,2.5 equiv.) and the reaction mixture was stirred under nitrogen at 50℃for 6h.
(2) After the reaction of step (1), saturated NH is used 4 The Cl solution was quenched and extracted with ethyl acetate (20 mL. Times.3); the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product; the crude product was purified by silica gel column chromatography, column chromatography separation conditions: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A: B) is 1:2, 136.1mg of compound b (colorless oily liquid) was finally obtained, and the yield was calculated to be 87%.
The characterization of the above compound b, as shown in fig. 5 to 8, is specifically:
1 H NMR(400MHz,CDCl 3 ):δ＝7.61-7.53(m,2H),7.47(q,J＝6.9Hz,2H),7.41-7.28(m,10H),7.25-7.23(m,3H),6.97(d,J＝8.2Hz,2H),4.54(t,J＝6.6Hz,1H),3.09-2.89(m,3H)ppm.
19 F NMR(376MHz,CDCl 3 ):δ＝-111.3(d,J＝89.4Hz,1F)ppm.
31 P NMR(162MHz,CDCl 3 ):δ＝20.93(d,J＝101.9Hz)ppm.
13 C NMR(100MHz,CDCl 3 ):δ＝151.3(dd,J＝277.1,126.5Hz),143.4,136.4(dd,J＝17.8,11.1Hz),133.4(d,J＝7.1Hz),132.2(dd,J＝7.2,2.9Hz),131.7(dd,J＝23.4,10.2Hz),131.4,131.0,130.3(d,J＝10.5Hz),128.8(d,J＝481.5Hz),128.6-128.5(m,2C),128.0,122.8,71.9,41.5(t,J＝5.7Hz)ppm.
HRMS(m/z):calcd for C 28 H 24 BrFO 2 P[M+H] + 521.0676,found:521.0676.
as can be seen from the characterization data, the prepared compound b is (Z) - (2- (4-bromophenyl) -1-fluoro-4-hydroxy-4-phenylbut-1-en-1-yl) diphenylphosphine oxide (purity > 98%), and the compound has the structural formula:
example 3
(1) To a 10mL Schlenk tube, (E) -4, 4-trifluoro-1, 3-diphenylbut-2-en-1-one (82.9 mg,0.3mmol,1 equiv.) is added sequentially, bis (naphthalen-2-yl) phosphine oxide (136.0 mg,0.45mmol,1.5 equiv.) phenylsilane (48.7 mg,0.45mmol,1.5 equiv.), tetrahydrofuran (3.5 mL) and cesium carbonate (244.4 mg,0.75mmol,2.5 equiv.) and the reaction mixture is stirred under nitrogen at 50℃for 6h.
(2) After the reaction of step (1), saturated NH is used 4 The Cl solution was quenched and extracted with ethyl acetate (20 mL. Times.3); the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product; the crude product was purified by silica gel column chromatography, column chromatography separation conditions: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A: B) is 1:2, 71.6mg of compound c (white solid) was finally obtained, calculated as 44% yield.
The compound c is characterized as shown in fig. 9 to 12, specifically:
1 H NMR(400MHz,CDCl 3 ):δ＝8.35(d,J＝14.6Hz,1H),8.22(d,J＝14.5Hz,1H),7.89-7.77(m,6H),7.67-7.46(m,6H),7.33(s,5H),7.22(dd,J＝6.5,2.9Hz,2H),7.13-7.08(m,3H),4.70-4.67(m,1H),3.29-3.00(m,2H),2.51(brs,1H)ppm.
19 F NMR(376MHz,CDCl 3 ):δ＝-112.1(d,J＝87.9Hz,1F)ppm.
31 P NMR(162MHz,CDCl 3 ):δ＝20.64(d,J＝86.7Hz)ppm.
13 C NMR(100MHz,CDCl 3 ):δ＝151.6(dd,J＝276.5,127.6Hz),143.6,137.6(dd,J＝18.1,10.4Hz),134.9-134.8(m,1C),134.4(d,J＝7.1Hz),133.9(dd,J＝12.6,9.8Hz),132.5(dd,J＝14.0,3.3Hz),129.4,129.1-129.0(m,2C),128.6,128.5,128.3-128.2(m,2C),128.0-127.9(m,2C),126.9(d,J＝3.2Hz),126.5(d,J＝11.3Hz),126.4-126.3(m,2C),72.1,41.9(t,J＝5.8Hz)ppm.
HRMS(m/z):calcd for C 36 H 29 FO 2 P[M+H] + 543.1884,found:543.1887.
as can be seen from the characterization data, the prepared compound c is (Z) - (1-fluoro-4-hydroxy-2, 4-diphenylbut-1-en-1-yl) bis (naphthalen-2-yl) phosphine oxide (purity > 98%), and the compound has a structural formula:
example 4
Example 4 is essentially the same as example 1, except that in step (1), the reaction is carried out for 12 hours and the base is different, as shown in Table 1 below:
TABLE 1
| Alkali | Yield (%) |
| Cs 2 CO 3 | 65 |
| K 2 CO 3 | trace |
| Na 2 CO 3 | trace |
| Li 2 CO 3 | trace |
| LiOH | trace |
| DABCO | trace |
| Et 3 N | trace |
| K 3 PO 4 | trace |
As can be seen from Table 1, cesium carbonate (Cs 2 CO 3 ) When the alkali is used, the reaction yield is 65% at most at 12 hours; other bases are less effective with only trace amounts of product.
Example 5
Example 5 is essentially the same as example 1, except that in step (1), the molar ratio of the trifluoromethyl ketene compound and diphenyloxyphosphorus is different at 12 hours of reaction, as shown in Table 2 below:
TABLE 2
| Trifluoromethyl ketene compound (mmol) | Diphenyl phosphorus oxide (mmol) | Yield (%) |
| 0.3 | 0.3 | 19 |
| 0.3 | 0.36 | 51 |
| 0.3 | 0.45 | 55 |
| 0.3 | 0.54 | 37 |
| 0.3 | 0.6 | 22 |
| 0.3 | 0.9 | 22 |
As can be seen from Table 2, under the same reaction conditions, the reaction yield was increased and then decreased by increasing the molar amount of diphenyloxyphosphorus under the condition that the molar amount of the trifluoromethyl ketene compound was fixed, and especially, the reaction yield was 55% at the maximum when 0.3mmol of the trifluoromethyl ketene compound and 0.45mmol of diphenyloxyphosphorus were used.
Example 6
Example 6 is substantially the same as example 1 except that in step (1), the molar ratio of the trifluoromethyl ketene compound and the phenylsilane is different at the time of reaction for 12 hours, specifically as shown in the following table 3:
TABLE 3 Table 3
| Trifluoromethyl ketene compound (mmol) | Phenylsilane (mmol) | Yield (%) |
| 0.3 | 0.3 | 32 |
| 0.3 | 0.45 | 63 |
| 0.3 | 0.6 | 54 |
| 0.3 | 0.75 | trace |
As can be seen from Table 3, under the same reaction conditions, the reaction yield was at most 63% with the molar amount of the trifluoromethyl ketene compound fixed, especially at 0.3mmol of the trifluoromethyl ketene compound and 0.45mmol of the phenylsilane (1.5 equivalent).
Example 7
Example 7 is substantially the same as example 1, except that in step (1), the reaction time is 12 hours and the reaction solvent is different, as shown in the following table 4:
TABLE 4 Table 4
| Reaction solvent | Yield (%) |
| MeCN | 32 |
| Toluene | 23 |
| THF | 55 |
| DCE | 44 |
| DMF | 19 |
| 1,4-dioxane | 52 |
As can be seen from table 4, under the same reaction conditions, solvents were used, such as: acetonitrile (MeCN), toluene (tolene), N-Dimethylformamide (DMF), lower yields; with Dichloroethane (DCE) as solvent, the reaction yield was 44%; in the case of 1,4-dioxane (1, 4-dioxane), the reaction yield was 52%; when Tetrahydrofuran (THF) was used as the solvent, the reaction yield was the highest, 55%.
Example 8
Example 8 is essentially the same as example 1, except that in step (1), the reaction times are different, as shown in Table 5 below:
TABLE 5
| Reaction time | Yield (%) |
| 3h | 63 |
| 6h | 69 |
| 12h | 55 |
As can be seen from table 5, shortening or lengthening the reaction time under the same reaction conditions is detrimental to the increase in reaction yield; the reaction yield was highest at 69% when 6h was used.
Example 9
Example 9 is essentially the same as example 1, except that in step (1), the temperature is different at 6h of reaction, as shown in Table 6 below:
TABLE 6
| Temperature (. Degree. C.) | Yield (%) |
| Room temperature | 21 |
| 40 | 68 |
| 50 | 69 |
| 60 | 68 |
| 80 | 43 |
As can be seen from table 6, the reaction yield was highest at 50 ℃ reaction temperature under the same reaction conditions; further lowering or increasing the reaction temperature, in turn, results in a decrease in the reaction yield.
Example 10
Example 10 is substantially the same as example 1 except that in step (1), the molar ratio of the trifluoromethyl ketene compound and cesium carbonate is different at the time of reaction for 6 hours, specifically as shown in Table 7 below
TABLE 7
| Trifluoromethyl ketene compound (mmol) | Cesium carbonate (mmol) | Yield (%) |
| 0.3 | 0.6 | 47 |
| 0.3 | 0.75 | 69 |
| 0.3 | 0.9 | 22 |
| 0.3 | 1.05 | 14 |
| 0.3 | 1.35 | 22 |
Example 11
Example 11 was substantially the same as in example 1 except that in step (1), trifluoromethyl ketene was different, and the objective product was obtained as shown in the following Table 8:
TABLE 8
Example 12
Example 12 is essentially the same as example 3, except that in step (1), the diphenyloxyphosphorus-containing compound is different, and the objective product is obtained as shown in Table 9 below:
TABLE 9
Application examples
The compounds a, b, and c obtained in the above examples 1 to 3 were subjected to a preliminary activity test against human pancreatic cancer cells (PANC-1), and cell viability was determined by measuring ATP levels. The testing method comprises the following steps: exponentially growing cells (PANC-1 cells)Series/4×10 3 Individual cells/100 μl/well) were incubated with the test compound for 48 hours. The test compounds were increased to 1000 spots in complete medium at 3-fold dilution starting at a concentration of 0.1. Mu.M and at 37℃with humid CO 2 And 95% air in an incubator. Control wells containing no compound dimethyl sulfoxide (DMSO) were also included in the experiment. Stock solutions of compounds were initially dissolved in DMSO and then further diluted in PBS. After incubation, 20 μl of CTG reagent was added to each well. Then shake for 7 minutes and incubate for 10 minutes at room temperature. Readings were recorded on a microwell reader as absorbance at 570 nm. The cytotoxic effect is expressed as a 50% lethal dose, i.e. the concentration of compound that causes a 50% decrease in cell viability compared to cells in the medium alone. EC (EC) 50 The values are estimated as described.
The results of the tests of the compounds a, b and c are shown in FIGS. 13 to 15, respectively, and it can be seen that EC 50 The values were 24 μm, 20 μm and 55 μm, respectively, and each of the compounds a, b, c showed a function of inhibiting the activity of human pancreatic cancer cells (PANC-1).
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (8)
1. A (Z) -gem-fluorophosphine compound, characterized in that the chemical structural formula of the compound is shown as the following formula (I):
wherein R is 1 Any one selected from phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, biphenyl, thienyl, naphthyl, pyridyl and cyclohexyl;
R 2 any one selected from phenyl, halogen substituted phenyl and benzothienyl;
R 3 selected from benzeneAny one of a group, a methoxy-substituted phenyl group, a methyl-substituted phenyl group, a tert-butyl-substituted phenyl group, a halogen-substituted phenyl group, and a biphenyl group;
R 4 any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl.
2. A process for the preparation of (Z) -gem-fluorophosphine compounds according to claim 1, characterized in that it comprises the steps of:
(1) Adding diaryl phosphorus oxide, trifluoromethyl ketene, phenylsilane and alkali into a solvent, and stirring and reacting for 6-12 h in a nitrogen atmosphere at room temperature-80 ℃; wherein,
the chemical structural formula of the diaryl phosphorus oxide compound is shown as the following formula (II):
in the formula (II), R 3 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl; r is R 4 Any one selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, tert-butyl substituted phenyl, halogen substituted phenyl and biphenyl;
the chemical structural formula of the trifluoromethyl ketene is shown as the following formula (III):
in the formula (III), R 1 Any one selected from phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, biphenyl, thienyl, naphthyl, pyridyl and cyclohexyl; r is R 2 Any one selected from phenyl, halogen substituted phenyl and benzothienyl;
(2) After the reaction is finished, quenching and extracting the reaction products in sequence, washing, drying and concentrating the combined organic phases sequentially to obtain a crude product, and purifying the crude product to obtain the (Z) -gem-fluorophosphene compound.
3. The method according to claim 2, wherein in step (1), the base is selected from any one of cesium carbonate, potassium carbonate, sodium carbonate, lithium hydroxide, triethylenediamine, triethylamine, and potassium phosphate.
4. The method according to claim 2, wherein in step (1), the solvent is selected from any one of acetonitrile, toluene, tetrahydrofuran, dichloroethane, N-dimethylformamide, and 1, 4-dioxane.
5. The process according to claim 2, wherein in step (1), 0.3mmol of trifluoromethyl ketene, 0.3 to 0.9mmol of diaryl phosphorus oxide compound, 0.45 to 0.75mmol of phenylsilane, and 0.75 to 1.35mmol of base are added to 3.5mL of solvent.
6. The method according to claim 2, wherein in the step (2), the reaction solution is saturated with NH 4 The Cl solution was quenched and extracted 3 times with ethyl acetate, and the combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product.
7. The method of claim 2, wherein in step (2), the purification is a silica gel column chromatography purification, and the column chromatography separation conditions are: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate A and petroleum ether B, and the mobile phase is changed in procedure A: b is 1:2.
8. use of a (Z) -gem-fluorophospholine compound according to claim 1 for the preparation of an inhibitor of the activity of human pancreatic cancer cells (PANC-1).
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