CN112125856A - Preparation method of 2-trifluoromethyl substituted quinazolinone derivative - Google Patents
Preparation method of 2-trifluoromethyl substituted quinazolinone derivative Download PDFInfo
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- CN112125856A CN112125856A CN202010936182.9A CN202010936182A CN112125856A CN 112125856 A CN112125856 A CN 112125856A CN 202010936182 A CN202010936182 A CN 202010936182A CN 112125856 A CN112125856 A CN 112125856A
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- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 12
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- 239000000654 additive Substances 0.000 claims abstract 4
- 230000000996 additive effect Effects 0.000 claims abstract 4
- 239000003446 ligand Substances 0.000 claims abstract 4
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 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
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000000758 substrate Substances 0.000 abstract description 7
- -1 phenol ester Chemical class 0.000 abstract description 6
- 239000007787 solid Substances 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- CXILJIGAUFSZQX-UHFFFAOYSA-N 4-(trifluoromethyl)-3H-quinazolin-2-one Chemical group C1=CC=C2C(C(F)(F)F)=NC(=O)NC2=C1 CXILJIGAUFSZQX-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 6
- 238000004293 19F NMR spectroscopy Methods 0.000 description 5
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- NITMACBPVVUGOJ-UHFFFAOYSA-N 2,2,2-trifluoroethanimidamide Chemical class NC(=N)C(F)(F)F NITMACBPVVUGOJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 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
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of a 2-trifluoromethyl substituted quinazolinone derivative, which comprises the following steps: adding a palladium catalyst, a ligand, a carbon monoxide substitute, an additive, trifluoroethylimidoyl chloride and o-iodoaniline into an organic solvent, reacting for 16-30 hours at 90 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 2-trifluoromethyl-substituted quinazolinone derivative. The preparation method is simple and convenient to operate, the initial reaction raw materials are cheap and easy to obtain, the method is compatible with various substituents, the substrate applicability is good, trifluoromethyl quinazolinone derivatives substituted by different groups can be synthesized through substrate design, the operation is convenient, and the practicability of the method is widened. The method adopts 1,3, 5-tricarboxylate phenol ester as a substitute of solid carbon monoxide, and avoids the use of toxic colorless gas carbon monoxide.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 2-trifluoromethyl-substituted quinazolinone derivative.
Background
Quinazolinone derivatives are important fused-ring nitrogen-containing six-membered heterocycles, widely found in various natural products and drug molecules, and have spectral biological and pharmaceutical activities such as anti-inflammatory, antiviral, antifungal, anticonvulsant, and anticancer properties (eur.j.med.chem.,2015,90, 124). Many commercially available drugs contain a quinazolinone molecular backbone, such as fluoroquinolone, mequinone, mecloquinone and benzoquinacridone. Due to the special properties of fluorine atoms, the introduction of trifluoromethyl groups into the molecule can significantly improve the physicochemical properties of the parent molecule, such as electronegativity, bioavailability, metabolic stability, lipophilicity, etc. (j.med.chem.2015,58, 8315-.
The literature reports today are very rich on the synthesis of substituted quinazolinone derivatives, but the synthesis of quinazolinone derivatives substituted with trifluoromethyl in the 2-position is very limited. Common synthetic methods include 1) cyclization reaction of anthranilamide with ethyl trifluoroacetate, trifluoroacetic anhydride and trifluoroacetic acid under different conditions; 2) cyclization of anthranilic acid ester with unstable trifluoroacetamide; 3) cyclization reaction of isatoic anhydride and trifluoroacetic anhydride; 4) T3P promoted the tandem reaction of anthranilic acid, trifluoroacetic acid and an amine. The above-described synthesis methods generally have several disadvantages, such as harsh reaction conditions, expensive reaction substrates or the need for pre-activation, low yield, and narrow substrate range.
Based on the method, cheap and easily-obtained trifluoroethylimidoyl chloride and o-iodoaniline are used as starting materials, 1,3, 5-tricarboxylate phenol ester is used as a solid carbon monoxide substitute, and a carbonylation tandem reaction catalyzed by transition metal palladium is used for efficiently synthesizing the 2-trifluoromethyl substituted quinazolinone.
Disclosure of Invention
The invention provides a preparation method of a 2-trifluoromethyl-substituted quinazolinone derivative, which is simple and convenient to operate, cheap and easily available in reaction starting raw materials, compatible with various substituent groups and good in substrate applicability, and 1,3, 5-tricarboxylate is adopted as a solid carbon monoxide substitute, so that the use of toxic colorless gas carbon monoxide is avoided.
A preparation method of 2-trifluoromethyl substituted quinazolinone derivatives comprises the following steps: adding a palladium catalyst, 1, 3-bis (diphenylphosphino) propane, potassium tert-butoxide, TFBen (1,3, 5-tricresol phenolate), trifluoroethylimidoyl chloride and o-iodoaniline into an organic solvent, reacting for 16-30 hours at 90 ℃, and after the reaction is completed, carrying out post-treatment to obtain the 2-trifluoromethyl-substituted quinazolinone derivative;
the structure of the o-iodoaniline is shown as the formula (II):
the structure of the trifluoroethylimidoyl chloride is shown as a formula (III):
the structure of the 2-trifluoromethyl substituted quinazolinone derivative is shown as the formula (I):
in formulae (I) to (III), R1Is H, C1～C5Alkyl, halogen or trifluoromethyl; r2Is a substituted or unsubstituted aryl group;
the substituent on the aryl is selected from C1～C5Alkyl, alkoxy, halogen or nitro.
The molar ratio of the palladium catalyst to the 1, 3-bis (diphenylphosphino) propane to the potassium tert-butoxide is 0.05:0.05: 2;
the substitution position on the aryl group may be ortho, para or meta.
The reaction formula is as follows:
during the reaction, intermolecular carbon-nitrogen bond coupling promoted by potassium tert-butoxide may be firstly carried out to obtain a trifluoroacetamidine derivative, then a palladium catalyst is inserted into a carbon-iodine bond to form a divalent palladium intermediate, TFBen is decomposed under heating conditions to release carbon monoxide, the carbon-iodine bond is inserted into a carbon-palladium bond to form an acylpalladium intermediate, palladium-nitrogen base formation is promoted under the action of alkali to obtain a seven-membered ring palladium intermediate, and then reduction elimination is carried out to obtain the final 2-trifluoromethyl-substituted quinazolinone derivative.
In the present invention, the optional post-processing procedure includes: filtering, mixing the sample with silica gel, and finally performing column chromatography purification to obtain the corresponding 2-trifluoromethyl-substituted quinazolinone derivative, wherein the column chromatography purification is a technical means commonly used in the field.
Preferably, R1Is H, methyl, F, Cl, Br or-CF3；R2Is phenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl or 4-nitrophenyl, 1-naphthyl; at this time, the trifluoroethylimidoyl chloride and o-iodoaniline are easily obtained, and the yield of the reaction is high.
The prices of various types of trifluoroethylimidoyl chloride are low, the synthetic starting material aromatic amine widely exists in the nature, the synthetic process is simple, the dosage of the compound is excessive relative to the dosage of the o-iodoaniline, and preferably, the molar amount of the o-iodoaniline: trifluoroethylimidoyl chloride: palladium bis (triphenylphosphine) dichloride of 1:1 to 3:0.01 to 0.1; as a further preference, the molar amount of o-iodoaniline: trifluoroethylimidoyl chloride: palladium bis (triphenylphosphine) dichloride ═ 1:2: 0.05.
Preferably, the reaction time is 16 to 30 hours, and if the reaction time is too long, the reaction cost is increased, and on the contrary, the completion of the reaction is difficult to ensure.
In the present invention, the organic solvent capable of sufficiently dissolving the raw material can cause the reaction, but the difference in reaction efficiency is large, and the aprotic solvent is preferably an aprotic solvent which can effectively promote the reaction; preferably, the organic solvent is tetrahydrofuran, acetonitrile or dioxane; further preferably, the organic solvent is tetrahydrofuran, in which case various starting materials can be converted into products with high conversion.
The amount of the organic solvent can be used for better dissolving the raw materials, and the amount of the organic solvent used by 1mmol of o-iodoaniline is about 8-10 mL.
Preferably, the palladium catalyst is palladium bis (triphenylphosphine) dichloride, and the reaction efficiency is higher when the palladium bis (triphenylphosphine) dichloride is used as the catalyst in a plurality of palladium catalysts.
As a further preference, the 2-trifluoromethyl substituted quinazolinone derivative is one of the derivatives shown in formula (I-1) and formula (I-5):
in the preparation method, the various types of aromatic amine, phenol, formic acid, palladium bis (triphenylphosphine) dichloride and 1, 3-bis (diphenylphosphino) propane are generally commercially available products and can be conveniently obtained from the market, and the trifluoroethylimidoyl chloride can be quickly synthesized from corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid.
Compared with the prior art, the invention has the advantages that: the preparation method is convenient to operate and simple in post-treatment; the initial raw materials for the reaction are cheap and easy to obtain, the designability of the substrate is strong, the application range of the substrate functional group is wide, the reaction efficiency is high, trifluoromethyl-substituted quinazolinone derivatives substituted by different positions and groups can be designed and synthesized according to needs, and the practicability is high.
Detailed Description
The invention is further described with reference to specific examples.
Adding palladium bis (triphenylphosphine) dichloride, 1, 3-bis (diphenylphosphino) propane, TFBen, potassium tert-butoxide, o-iodoaniline (II), trifluoroethylimidoyl chloride (III) and 2mL of an organic solvent into a 35mL Schlenk tube according to the raw material ratio of Table 1, uniformly mixing and stirring, reacting for 16-30 hours according to the reaction conditions of Table 2, filtering, stirring with silica gel, and purifying by column chromatography to obtain the corresponding 2-trifluoromethyl-substituted quinazolinone derivative (I), wherein the reaction process is shown as the following formula:
TABLE 1 raw material addition amounts of examples 1 to 15
TABLE 2
In tables 1 and 2, T is the reaction temperature, T is the reaction time, Ph is phenyl, napthyl is naphthyl, Me is methyl, T-Bu is T-butyl, CF3Is trifluoromethyl and THF is tetrahydrofuran.
Structure confirmation data of the derivatives prepared in examples 1 to 5:
nuclear magnetic resonance of 2-trifluoromethyl-substituted quinazolinone derivative (I-1) prepared in example 1: (1H NMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)7.97-7.90(m,2H),7.98-7.90(m,1H),7.56-7.53(m,3H),7.32-7.28(m,2H).
13C NMR(101MHz,CDCl3)162.7(d,J(C-F)＝252.7Hz),161.2,142.0,134.7,131.5(d,J(C-F)＝8.5Hz),130.2,129.5,129.1,126.4,123.9(d,J(C-F)＝24.1Hz),120.6,118.0(q,J(C-F)＝277.4Hz),112.8(d,J(C-F)＝24.1Hz).
19F NMR(377MHz,CDCl3)-63.9,-107.8.
M.p.124-125℃
HRMS(ESI):[M+H]+calcd.for C15H9F4N2O 309.0646,found 309.0651.
nuclear magnetic resonance of 2-trifluoromethyl-substituted quinazolinone derivative (I-2) prepared in example 2: (1H NMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)8.26(d,J＝8.5Hz,1H),7.90(s,1H),7.60(d,J＝8.5Hz,1H),7.57-7.53(m,3H),7.30(d,J＝3.7Hz,2H).
13C NMR(101MHz,CDCl3)161.3,146.3,143.6(q,J(C-F)＝36.3Hz),141.8,134.6,130.3,129.5,129.1,129.0,128.4,120.7,117.8(q,J(C-F)＝277.8Hz).
19F NMR(377MHz,CDCl3)-64.1.
M.p.125-126℃
HRMS(ESI):[M+H]+calcd.for C15H9ClF3N2O 325.0350,found 325.0354.
nuclear magnetic resonance of 2-trifluoromethyl-substituted quinazolinone derivative (I-3) prepared in example 3: (1H NMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)8.33(d,J＝7.7Hz,1H),7.93-7.85(m,2H),7.65(t,J＝6.2Hz,1H),7.56-7.51(m,2H),7.22(d,J＝8.0Hz,2H),1.38(s,9H).
13C NMR(101MHz,CDCl3)162.0,153.2,145.4,142.6(q,J(C-F)＝35.1Hz),135.3,132.1,129.6,128.8,128.5,127.6,126.4,122.3,118.0(q,J(C-F)＝277.4Hz),31.4.
19F NMR(377MHz,CDCl3)-64.0.
M.p.181-182℃
HRMS(ESI):[M+H]+calcd.for C19H18F3N2O 347.1366,found 347.1369.
nuclear magnetic resonance of 2-trifluoromethyl-substituted quinazolinone derivative (I-4) prepared in example 4: (1H NMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)8.44-8.38(m,2H),8.31(d,J＝7.9Hz,1H),7.92(d,J＝3.7Hz,2H),7.73-7.64(m,1H),7.53(d,J＝8.6Hz,2H).
13C NMR(101MHz,CDCl3)161.3,148.7,145.1,141.2(q,J(C-F)＝36.0Hz),140.6,135.9,130.7,130.2,129.1,127.6,124.8,121.9,117.6(q,J(C-F)＝277.5Hz).
19F NMR(377MHz,CDCl3)-63.8.
M.p.179-180℃
HRMS(ESI):[M+H]+calcd.for C15H9F3N3O3 336.0591,found 336.0593.
nuclear magnetic resonance of 2-trifluoromethyl-substituted quinazolinone derivative (I-5) prepared in example 5: (1H NMR、13C NMR and19f NMR) the data were:
1H NMR(400MHz,CDCl3)8.38(d,J＝9.0Hz,1H),8.05(d,J＝8.3Hz,1H),7.98(t,J＝7.6Hz,2H),7.93(t,J＝7.0Hz,1H),7.69(t,J＝6.9Hz,1H),7.65-7.59(m,1H),7.57-7.53(m,1H),7.53-7.48(m,2H),7.43(d,J＝8.3Hz,1H).
13C NMR(101MHz,CDCl3)161.7,145.6,143.1(q,J(C-F)＝36.0Hz),135.5,134.3,131.6,130.9,130.7,129.8,129.0,128.8,127.9,127.8,127.5,126.9,125.2,122.2,121.8,117.9(q,J(C-F)＝277.6Hz).
19F NMR(377MHz,CDCl3)-64.8.
M.p.168-169℃
HRMS(ESI):[M+H]+calcd.for C19H12F3N2O 341.0896,found 341.0904.
Claims (9)
1. a preparation method of a 2-trifluoromethyl substituted quinazolinone derivative is characterized by comprising the following steps: adding a palladium catalyst, a ligand, a carbon monoxide substitute, an additive, trifluoroethylimidoyl chloride and o-iodoaniline into an organic solvent, reacting for 16-30 hours at 80-100 ℃, and after the reaction is completed, carrying out aftertreatment to obtain the 2-trifluoromethyl-substituted quinazolinone derivative;
the structure of the o-iodoaniline is shown as the formula (II):
the structure of the trifluoroethylimidoyl chloride is shown as a formula (III):
the structure of the 2-trifluoromethyl substituted quinazolinone derivative is shown as the formula (I):
in formulae (I) to (III), R1Is H, C1～C5Alkyl, halogen or trifluoromethyl；R2Is a substituted or unsubstituted aryl group;
the substituent on the aryl is selected from C1～C5Alkyl, alkoxy, halogen or nitro.
2. The method for preparing 2-trifluoromethyl-substituted quinazolinone derivatives according to claim 1, wherein R is1Is H, methyl, F, Cl, Br or-CF3。
3. The method for preparing 2-trifluoromethyl-substituted quinazolinone derivatives according to claim 1, wherein R is2Is phenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl, 4-nitrophenyl or 1-naphthyl.
4. The process for preparing a 2-trifluoromethyl-substituted quinazolinone derivative according to claim 1, characterized in that the molar ratio of o-iodoaniline: trifluoroethylimidoyl chloride: carbon monoxide substitute: palladium catalyst: ligand: the additive is 1: 1-3: 2-4: 0.01-0.1: 1-3.
5. The method for preparing a 2-trifluoromethyl-substituted quinazolinone derivative according to claim 1, wherein said organic solvent is tetrahydrofuran.
6. The method for preparing a 2-trifluoromethyl-substituted quinazolinone derivative according to claim 1, wherein said palladium catalyst is bis-triphenylphosphine palladium dichloride;
the ligand is 1, 3-bis (diphenylphosphino) propane.
7. The method for preparing a 2-trifluoromethyl-substituted quinazolinone derivative according to claim 1, wherein said additive is potassium tert-butoxide.
8. The method of claim 1, wherein the carbon monoxide substitute is phenol 1,3, 5-tricarboxylate.
9. The method for preparing a 2-trifluoromethyl-substituted quinazolinone derivative according to claim 1, wherein said 2-trifluoromethyl-substituted quinazolinone derivative is one of the derivatives represented by formula (I-1) to formula (I-5):
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113307790A (en) * | 2021-05-24 | 2021-08-27 | 杭州职业技术学院 | Preparation method of 3-quinolyl-5-trifluoromethyl substituted 1,2, 4-triazole compound |
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-
2020
- 2020-09-08 CN CN202010936182.9A patent/CN112125856A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| LE-CHENG WANG等: "FeCl3‑Mediated Synthesis of 2‑(Trifluoromethyl)quinazolin-4(3H)‑ones from Isatins and Trifluoroacetimidoyl Chlorides", 《ORG. LETT.》 * |
| ZHAOYAN ZHENG等: "Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines with Imidoyl Chlorides to Produce Quinazolin-4(3H)-ones", 《ORG. LETT.》 * |
| ZHENGKAI CHEN等: "Palladium-catalyzed three-component carbonylative synthesis of 2-(trifluoromethyl)quinazolin-4(3H)-ones from trifluoroacetimidoyl chlorides and amines", 《ORGANIC CHEMISTRY FRONTIERS》 * |
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