CN114805208A - 4-trifluoromethyl-4, 5-dihydropyrazole derivative and preparation method thereof - Google Patents
4-trifluoromethyl-4, 5-dihydropyrazole derivative and preparation method thereof Download PDFInfo
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- XAAMFKTZCSHVMX-UHFFFAOYSA-N 4-(trifluoromethyl)-4,5-dihydro-1H-pyrazole Chemical class FC(F)(F)C1CNN=C1 XAAMFKTZCSHVMX-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- -1 4-trifluoromethyl-4, 5-dihydropyrazole compound Chemical class 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 229960001701 chloroform Drugs 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003756 stirring Methods 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 7
- 238000006352 cycloaddition reaction Methods 0.000 abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 229910000510 noble metal Inorganic materials 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000012156 elution solvent Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 description 2
- MCGBIXXDQFWVDW-UHFFFAOYSA-N 4,5-dihydro-1h-pyrazole Chemical compound C1CC=NN1 MCGBIXXDQFWVDW-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- 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
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a 4-trifluoromethyl-4, 5-dihydropyrazole derivative and a preparation method thereof, and relates to a 3+2 cycloaddition reaction method of N-phenyl benzonitrile chloride and alpha-trifluoromethyl olefin in a catalyst-free system. The method comprises the steps of adding N-phenyl cyanobenzene chloride, alpha-trifluoromethyl olefin derivative, alkali and solvent into a Schlenk reaction bottle, and stirring to react at a certain temperature under the air atmosphere condition to obtain the product 4-trifluoromethyl-4, 5-dihydropyrazole derivative. The method can prepare the target product with high selectivity and high yield without any catalyst. In addition, the reaction operation process is simple, the complicated operation of no water and no oxygen is not needed, and meanwhile, the use of a noble metal catalyst is avoided, so that the industrial application and production are facilitated; the method can be easily expanded to gram level, and provides possibility for large-scale synthesis and application of the compounds.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a 4-trifluoromethyl-4, 5-dihydropyrazole derivative by a 3+2 cycloaddition reaction under the promotion of alkali.
Background
4, 5-dihydropyrazole is an important skeleton in organic synthesis, derivatives thereof widely exist in natural product alkaloid and drug molecular structure, and have important application in drug synthesis and organic functional molecules (Bioorg Med Chem Lett 2021, 41, 127988). Meanwhile, the skeleton can be used as a multifunctional synthesis module in organic synthesis and can be conveniently converted into various pyrazole derivatives. Studies have shown that drugs containing such scaffolds tend to have analgesic and edema-inhibiting effects. Therefore, the efficient synthesis of the derivatives has gradually become a plurality of organic chemical industriesThe authors' research focused on hot spots. As is known, the introduction of fluorine-containing groups into the molecular structure of drugs can greatly enhance the lipid solubility of drugs in human bodies and improve the metabolic capability of drugs, thereby effectively improving the drug effect. For example, 4, 5-dihydropyrazole derivatives EPFCA3 and MPFCA4 containing trifluoromethyl have significant analgesic and anti-inflammatory effects: (Eur. J. Pharmacol. 2009, 616, 91-100.）。
However, the methods for directly synthesizing the dihydropyrazole containing the trifluoromethyl group in one step are less reported at present, most of the methods still need to realize the preparation and synthesis of fluorine-containing hydrogenated pyrazole derivatives through trifluoromethylation of the synthesized dihydropyrazole derivatives, most of fluorination reagents have high toxicity, and wastes brought by industrial production of the compounds bring considerable pressure on the ecological environment.
Therefore, it is a very challenging and urgent problem to develop a method which is green, economical, nontoxic, environment-friendly and simple to operate, thereby efficiently obtaining a hydrogenated pyrazole compound containing trifluoromethyl.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a green, efficient and direct synthesis method of 4-trifluoromethyl-4, 5-dihydropyrazole derivatives, which can prepare and obtain target products with high selectivity and high yield without any catalyst. In addition, the reaction operation process is simple, the complicated operation of no water and no oxygen is not needed, and meanwhile, the use of a noble metal catalyst is avoided, so that the industrial application and production are facilitated; the method can be easily expanded to gram level, and provides possibility for large-scale synthesis and application of the compounds.
The invention provides a 3+2 cycloaddition reaction method, which takes N-phenyl benzonitrile chloride and alpha-trifluoromethyl olefin derivative as raw materials and specifically adopts the following technical scheme:
a preparation method of 4-trifluoromethyl-4, 5-dihydropyrazole derivatives uses N-phenyl benzonitrile chloride and alpha-trifluoromethyl olefin derivatives as raw materials, and reacts in the presence of alkali to obtain the 4-trifluoromethyl-4, 5-dihydropyrazole derivatives.
In the invention, the structure of the N-phenyl cyanobenzene chloride is shown as the formula (I):
the structure of the alpha-trifluoromethyl olefin derivative is shown as the formula (II):
the structure of the 4-trifluoromethyl-4, 5-dihydropyrazole compound is shown as the formula (III):
the reaction formula for preparing the 4-trifluoromethyl-4, 5-dihydropyrazole derivative is as follows:
in the above general formulae (I), (II) and (III):
R 1 is C 1 ~C 6 Substituted or unsubstituted alkyl, C 5 -C 12 Substituted or unsubstituted aryl; r 2 Is C 1 ~C 6 Substituted or unsubstituted alkyl, C 5 -C 14 Substituted or unsubstituted aryl; r 3 Is hydrogen, halogen, C 1 ~C 6 Substituted or unsubstituted alkyl, C 1 ~C 6 Substituted or unsubstituted alkoxy, C 5 -C 12 Substituted or unsubstituted aryl, C 1 ~C 6 A substituted or unsubstituted ester group; preferably, R 1 Is C 5 -C 12 Substituted or unsubstituted aryl; r 2 Is C 5 -C 14 Substituted or unsubstituted aryl; r 3 Is hydrogen, halogen, C 1 ~C 6 Substituted or unsubstituted alkyl, C 1 ~C 3 Substituted or unsubstituted alkoxy, C 1 ~C 3 Substituted or unsubstituted ester groups. Each of the above R 1 -R 3 Wherein the substituents are selected from halogen and C 1 -C 6 Alkyl radical, C 5 -C 12 Aryl, halogen substituted C 1 -C 6 An alkyl group.
In the present invention, N-phenylbenzonitrile chloride/α -trifluoromethylolefin compound/base = (1 to 2): 1 to 3) in terms of molar amount, and preferably, N-phenylbenzonitrile chloride/α -trifluoromethylolefin compound/base = 1.5: 1.0: 2 in terms of molar amount.
In the invention, the reaction time is 12-36 hours, preferably 18 hours; the reaction temperature is 0-50 ℃, and preferably 25 ℃.
In the reaction of the present invention, the solvent is any one or a mixture of several of methanol, ethanol, dichloromethane, chloroform, 1, 2-dichloroethane, toluene, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile, etc., preferably, the organic solvent is dichloromethane, and at this time, various raw materials can be converted into products with a high conversion rate.
In the present invention, the base is an inorganic base such as carbonate, further, potassium carbonate, cesium carbonate, etc.; the method can efficiently prepare the product 4-trifluoromethyl-4, 5-dihydropyrazole derivative without a catalyst or other additives through reaction in the air.
Compared with the prior art, the invention has the beneficial effects that: the reaction overcomes the defects of the prior art, and provides a green, efficient and direct synthesis method of the 4-trifluoromethyl-4, 5-dihydropyrazole compound, thereby avoiding the problem of low atom economy caused by the use of toxic fluorinating reagents and multi-step synthesis. In addition, the reaction does not need any catalyst, the operation process is simple, the complex operation of no water and no oxygen is not needed, and the target product can be prepared with high selectivity and high yield in the air atmosphere. The method can be easily expanded to gram level, and provides possibility for industrial synthesis application of the compounds.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the product obtained in example 1;
FIG. 3 is a nuclear magnetic resonance fluorine spectrum of the product obtained in example 1;
FIG. 4 is a schematic solution diagram of the product obtained in example 14.
Detailed Description
The invention carries out intensive research on the 3+2 cycloaddition reaction between N-phenyl benzonitrile chloride and alpha-trifluoromethyl olefin derivative under the promotion of alkali, and provides a method for finally generating a corresponding 4-trifluoromethyl-4, 5-dihydropyrazole derivative through the 3+2 cycloaddition process between the N-phenyl benzonitrile chloride and the alpha-trifluoromethyl olefin derivative; the method does not need to use a catalyst, has simple and easily obtained raw materials and mild and green reaction conditions, can be enlarged to gram-scale, and provides possibility for large-scale synthesis and application of the compounds. The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The method comprises the steps of adding N-phenyl benzonitrile chloride shown in formula (I), alpha-trifluoromethyl olefin derivative shown in formula (II), solvent and alkali into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the air atmosphere condition, carrying out conventional stirring reaction, and after the reaction is finished, carrying out post-treatment to obtain the 4-trifluoromethyl-4, 5-dihydropyrazole compound (III). The invention finally obtains the corresponding 4-trifluoromethyl-4, 5-dihydropyrazole compound by the 3+2 cycloaddition reaction between the N-phenyl benzonitrile chloride and the alpha-trifluoromethyl olefin compound. Optional post-processing procedures include: filtering, mixing the sample with silica gel, and finally performing column chromatography purification to obtain the corresponding 4-trifluoromethyl-4, 5-dihydropyrazole derivative, wherein the column chromatography purification is a technical means commonly used in the field.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, if not otherwise specified, are commercially available and/or may be prepared according to known methods.
Example 1
To a Schlenk bottle, N-phenylbenzonitrile chloride I-1 (0.3 mmol) represented by formula 1 and α -trifluoromethylolefin compound II-1 (0.2 mmol) were added dissolved in dichloromethane (2 mL) solvent, followed by addition of potassium carbonate (0.4 mmol) to the above mixture. Stirring and reacting for 18 hours at 25 ℃ in an air atmosphere, after the reaction is finished, adding 10 mL of dichloromethane into a reaction system for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to remove a solvent, and separating a residue by column chromatography, wherein an elution solvent is: ethyl acetate/n-hexane gave product III-1 as a colorless oil (67% yield), as characterized in fig. 1-3.
1 H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 8.2 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.48 – 7.38 (m, 2H), 7.12 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 4.18 (d, J = 18.1 Hz, 1H), 3.93 (s, 3H), 3.60 (d, J = 18.2 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 166.40, 145.06, 142.72 (d, J = 15.3 Hz), 131.49, 130.54, 130.39, 129.44, 128.87, 128.58, 126.55 (d, J = 1.8 Hz), 125.94, 121.31, 116.94, 75.39 (q, J = 27.6 Hz), 52.40, 49.56. 19 F NMR (377 MHz, Chloroform-d) δ -69.70。
Example 2
The solvent was replaced with acetonitrile (2 mL) and the same procedure as in example 1 was repeated except that the yield of the objective compound III-1 was 52%.
Example 3
The solvent was replaced with DMF (2 mL) for methylene chloride under the same conditions as in example 1 to give the desired product III-1 in a yield of 35%.
Example 4
The yield of the objective product III-1 was 63% under the same conditions as in example 1, except that 4A molecular sieve (40 mg) was additionally added as an additive to the system.
Example 5
By Cs 2 CO 3 (0.4 mmol) in place of potassium carbonate as a base under the same conditions as in example 1 gave the desired product III-1 in a yield of 82%.
Example 6
The reaction temperature was raised to 50 deg.C o And C, the rest conditions are the same as the example 1, and the yield of the target product III-1 is 67%.
Example 7
The reaction temperature is reduced to 0 o And C, the other conditions are the same as the example 1, and the yield of the target product III-1 is 63 percent.
Example 8
The amount of the base used was reduced to 1 equivalent (0.2 mmol), and the other conditions were the same as in example 1, whereby the yield of the objective product III-1 was 39%.
Example 9
To a Schlenk bottle, N-phenylbenzonitrile chloride I-1 (0.3 mmol) represented by formula 2 and α -trifluoromethylolefin compound II-2 (0.2 mmol) were added in a dichloromethane (2 mL) solvent, and Cs was then added to the above mixture 2 CO 3 (0.4 mmol). Stirring and reacting for 15 hours at 25 ℃ in an air atmosphere, after the reaction is finished, adding 10 mL of dichloromethane into a reaction system for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to remove a solvent, and separating a residue by column chromatography, wherein an elution solvent is: ethyl acetate/n-hexane to give product III-2 as a white solid (73% yield).
1 H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.83 (m, 3H), 7.73 (d, J = 7.8 Hz, 2H), 7.54 – 7.49 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.43 – 7.34 (m, 3H), 7.12 – 7.02 (m, 4H), 6.79 (t, J = 6.8 Hz, 1H), 4.17 (d, J = 18.2 Hz, 1H), 3.64 (d, J = 18.2 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 144.96, 143.08, 135.01, 132.99, 132.79, 131.68, 129.57, 129.20, 128.77, 128.66, 128.63, 128.51, 128.46, 127.66, 127.06, 126.87, 125.84, 125.19 (d, J = 2.3 Hz), 123.89, 120.98, 116.82, 75.57 (q, J = 27.3 Hz).49.35. 19 F NMR (377 MHz, Chloroform-d) δ -69.62。
Example 10
To a Schlenk bottle, N-phenylbenzonitrile chloride I-1 (0.3 mmol) represented by formula 3 and α -trifluoromethylolefin compound II-3 (0.2 mmol) were added in a dichloromethane (2 mL) solvent, and Cs was then added to the above mixture 2 CO 3 (0.4 mmol). Stirring and reacting for 18 hours at 25 ℃ in an air atmosphere, after the reaction is finished, adding 10 mL of dichloromethane into a reaction system for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to remove a solvent, and separating a residue by column chromatography, wherein an elution solvent is: ethyl acetate/n-hexane gave product III-3 as a colorless oil (75% yield).
1 H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J = 7.8 Hz, 2H), 7.41 (q, J= 11.9, 9.6 Hz, 5H), 7.10 (dt, J = 16.3, 8.1 Hz, 4H), 6.90 (d, J = 8.7 Hz, 2H), 6.84 (t, J = 7.0 Hz, 1H), 4.12 (d, J = 18.1 Hz, 1H), 3.81 (s, 3H), 3.58 (d, J = 18.1 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 159.46, 144.99, 143.12, 131.85, 129.73, 129.20, 128.82, 128.47, 127.72 (d, J = 1.8 Hz), 126.28 (q, J= 290.9 Hz), 125.86, 124.84, 120.89, 116.90, 114.58, 75.14 (q, J = 27.3 Hz), 74.74. 19 F NMR (377 MHz, Chloroform-d) δ -70.12.
Example 11
To a Schlenk bottle, N-phenylbenzonitrile chloride I-1 (0.3 mmol) represented by formula 4 and α -trifluoromethylolefin compound II-4 (0.2 mmol) were added in a dichloromethane (2 mL) solvent, and Cs was then added to the above mixture 2 CO 3 (0.4 mmol). Stirring and reacting for 18 hours at 25 ℃ in an air atmosphere, after the reaction is finished, adding 10 mL of dichloromethane into a reaction system for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to remove a solvent, and separating a residue by column chromatography, wherein an elution solvent is: ethyl acetate/n-hexane gave product III-4 as a colorless oil (63% yield).
1 H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 7.7 Hz, 2H), 7.49 (d, J= 7.6 Hz, 2H), 7.39 (m, 6H), 7.15 – 7.07 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.83 (t, J = 7.0 Hz, 1H), 4.14 (d, J = 18.2 Hz, 1H), 3.60 (d, J = 18.1 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 144.84, 142.91, 137.77, 131.64, 129.30, 129.15, 128.73, 128.67 (m), 128.48, 128.45, 128.37, 126.24 (d, J = 1.5 Hz), 125.78, 120.83, 116.72, 75.31(q, J = 27.4 Hz), 49.53. 19 F NMR (377 MHz, Chloroform-d) δ -69.80.
Example 12
To a Schlenk bottle, N-phenylbenzonitrile chloride I-2 (0.3 mmol) represented by formula 5 and α -trifluoromethylolefin compound II-1 (0.2 mmol) were added in a dichloromethane (2 mL) solvent, and Cs was then added to the above mixture 2 CO 3 (0.4 mmol). Stirring and reacting for 24 hours at 25 ℃ in an air atmosphere, and reactingAdding 10 mL of dichloromethane into the system for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove a solvent, and separating a residue by using column chromatography, wherein an elution solvent is: ethyl acetate/n-hexane gave product III-5 as a colorless oil (68% yield).
1 H NMR (400 MHz, Chloroform-d) δ 8.16 – 8.01 (m, 3H), 7.58 (d, J = 8.2 Hz, 2H), 7.11 (t, J = 8.0 Hz, 2H), 6.98 (d, J = 8.4 Hz, 3H), 6.89 – 6.81 (m, 2H), 4.24 (dd, J = 18.9, 2.7 Hz, 1H), 3.93 (s, 3H), 3.77 – 3.61 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 166.42, 163.51 (dd, J = 252.7, 12.1 Hz), 160.61 (dd, J = 253.6, 11.7 Hz), 142.50 (d, J = 2.7 Hz), 140.91 (m), 130.57, 130.42, 129.74 (dd, J = 9.6, 5.0 Hz), 128.64, 126.56 (d, J = 1.7 Hz), 121.54, 116.94, 116.11 (dd, J = 11.5, 4.0 Hz), 112.48 (dd, J = 21.7, 3.3 Hz), 104.68 (t, J = 25.8 Hz), 75.33 (qd, J = 27.5, 2.7 Hz), 51.31 (d, J = 8.4 Hz). 19 F NMR (377 MHz, Chloroform-d) δ -69.92, -105.27 – -110.29 (m), -111.16 (q, J = 8.6 Hz)。
Example 13
To a Schlenk bottle, N-phenylbenzonitrile chloride I-2 (0.3 mmol) represented by formula 6 and α -trifluoromethylolefin compound II-2 (0.2 mmol) were added in a dichloromethane (2 mL) solvent, and Cs was then added to the above mixture 2 CO 3 (0.4 mmol). Stirring and reacting for 18 hours at 25 ℃ in an air atmosphere, after the reaction is finished, adding 10 mL of dichloromethane into a reaction system for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to remove a solvent, and separating a residue by column chromatography, wherein an elution solvent is: ethyl acetate/n-hexane to give product III-6 as a white solid (75% yield).
1 H NMR (400 MHz, Chloroform-d) δ 8.11 (q, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.91 – 7.79 (m, 3H), 7.57 – 7.51 (m, 2H), 7.48 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 4.3 Hz, 4H), 6.97 (t, J = 8.3 Hz, 1H), 6.88 – 6.78 (m, 2H), 4.30 – 4.21 (m, 1H), 3.75 (d, J = 18.8 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 163.41 (dd, J = 252.6, 12.0 Hz), 160.59 (dd, J = 253.8, 11.8 Hz), 142.88, 140.90 (m), 134.9, 133.04, 132.87, 129.68, 128.73, 128.58, 127.75, 127.19, 126.99, 126.20 (q, J = 290.3 Hz), 125.28 (d, J = 2.3 Hz), 123.96, 121.28, 116.90, 112.41 (dd, J = 21.6, 3.4 Hz), 104.66 (t, J = 25.8 Hz), 75.58 (dd, J= 27.4, 2.8 Hz), 51.20 (d, J = 9.1 Hz).
19 F NMR (377 MHz, Chloroform-d) δ -69.87 (s), -101.24 – -109.61 (m), -111.12 (q, J = 8.5 Hz)。
Example 14 gram Scale Up experiment
To a Schlenk bottle, N-phenylbenzonitrile chloride I-1 (15.0 mmol) represented by formula 1 and α -trifluoromethylolefin compound II-1 (10.0 mmol) were added in a dichloromethane (40 mL) solvent, and Cs was then added to the above mixture 2 CO 3 (20.0 mmol). Stirring and reacting for 18 hours at 25 ℃ in an air atmosphere, after the reaction is finished, adding 50 mL of dichloromethane into a reaction system for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to remove a solvent, and separating a residue by column chromatography, wherein an elution solvent is: ethyl acetate/n-hexane gave product III-1 as a colorless oil (77% yield).
As can be seen from the smooth implementation of the gram-scale amplification experiment, the reaction is easy to amplify and synthesize, and is expected to provide technical support for the industrial synthesis of the 4-trifluoromethyl-4, 5-dihydropyrazole derivative. Moreover, the product of the invention can be prepared into solution, see fig. 4, thereby being applied to coatings, composite materials and the like as an additive, and playing roles in halogen flame retardance and heat resistance of benzene rings. The embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (10)
1. A preparation method of 4-trifluoromethyl-4, 5-dihydropyrazole derivatives is characterized in that N-phenyl benzonitrile chloride and alpha-trifluoromethyl olefin derivatives are used as raw materials and react in the presence of alkali to obtain the 4-trifluoromethyl-4, 5-dihydropyrazole derivatives.
2. The method for preparing 4-trifluoromethyl-4, 5-dihydropyrazole derivative according to claim 1, wherein the structure of the N-phenylbenzonitrile chloride is represented by the following formula (I):
the structure of the alpha-trifluoromethyl olefin derivative is shown as the formula (II):
the structure of the 4-trifluoromethyl-4, 5-dihydropyrazole compound is shown as the formula (III):
3. process for preparing 4-trifluoromethyl-4, 5-dihydropyrazole derivatives according to claim 2A process for the preparation, characterized in that in the general formulae (I), (II) and (III): r 1 Is C 1 ~C 6 Substituted or unsubstituted alkyl, C 5 -C 12 Substituted or unsubstituted aryl; r 2 Is C 1 ~C 6 Substituted or unsubstituted alkyl, C 5 -C 14 Substituted or unsubstituted aryl; r 3 Is hydrogen, halogen, C 1 ~C 6 Substituted or unsubstituted alkyl, C 5 -C 12 Substituted or unsubstituted aryl, C 1 ~C 6 Substituted or unsubstituted alkoxy, C 1 ~C 6 Substituted or unsubstituted ester groups.
4. The process for producing 4-trifluoromethyl-4, 5-dihydropyrazole derivative according to claim 3, wherein R is 1 Is C 5 -C 12 Substituted or unsubstituted aryl; r 2 Is C 5 -C 14 Substituted or unsubstituted aryl; r 3 Is hydrogen, halogen, C 1 ~C 6 Substituted or unsubstituted alkyl, C 1 ~C 3 Substituted or unsubstituted alkoxy, C 1 ~C 3 Substituted or unsubstituted ester groups.
5. The process for producing a 4-trifluoromethyl-4, 5-dihydropyrazole derivative according to claim 1, wherein the molar ratio of N-phenylbenzonitrile chloride to α -trifluoromethylolefin compound to base is (1-2) to 1 to (1-3).
6. The method for producing a 4-trifluoromethyl-4, 5-dihydropyrazole derivative according to claim 1, wherein the reaction time is 12 to 36 hours; the reaction temperature is 0-50 ℃.
7. The process for producing 4-trifluoromethyl-4, 5-dihydropyrazole derivatives according to claim 1, wherein the reaction is carried out in a solvent; the solvent is any one or a mixture of more of methanol, ethanol, dichloromethane, trichloromethane, 1, 2-dichloroethane, toluene, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile and the like.
8. The process for producing 4-trifluoromethyl-4, 5-dihydropyrazole derivatives according to claim 1, wherein the base is an inorganic base.
9. The 4-trifluoromethyl-4, 5-dihydropyrazole derivative according to claim 1.
Use of N-phenylbenzonitrile chloride and an alpha-trifluoromethylolefin derivative in the presence of a base to prepare a 4-trifluoromethyl-4, 5-dihydropyrazole derivative.
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