CN113200915A - 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine and preparation method thereof - Google Patents
3-aryl-4, 5-dihydro-1H-pyrazole-5 amine and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 38
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 38
- -1 aryl propiolic alcohol Chemical compound 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 26
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 21
- 150000001412 amines Chemical class 0.000 claims abstract description 20
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 13
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 238000010791 quenching Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract description 3
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical class OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 150000007517 lewis acids Chemical group 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 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
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 26
- 125000003118 aryl group Chemical group 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- HIYUMYXSGIKHHE-UHFFFAOYSA-M bismuth trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F HIYUMYXSGIKHHE-UHFFFAOYSA-M 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 5
- 239000003446 ligand Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229950009195 phenylpropanol Drugs 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 150000001503 aryl iodides Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RASDPMXCBLHKCI-UHFFFAOYSA-N 2-amino-n-(1-hydroxy-1-phenylpropan-2-yl)-n-methylacetamide Chemical compound NCC(=O)N(C)C(C)C(O)C1=CC=CC=C1 RASDPMXCBLHKCI-UHFFFAOYSA-N 0.000 description 1
- DDOHNLJULYCMFE-UHFFFAOYSA-N 3-(4-chlorophenyl)prop-1-yn-1-ol Chemical compound OC#CCC1=CC=C(Cl)C=C1 DDOHNLJULYCMFE-UHFFFAOYSA-N 0.000 description 1
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 1
- FSOAHWQHVGEDAI-UHFFFAOYSA-N 3-phenylprop-1-yn-1-ol Chemical compound OC#CCC1=CC=CC=C1 FSOAHWQHVGEDAI-UHFFFAOYSA-N 0.000 description 1
- HHHDJHHNEURCNV-UHFFFAOYSA-N 4-chlorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C=C1 HHHDJHHNEURCNV-UHFFFAOYSA-N 0.000 description 1
- LFLSATHZMYYIAQ-UHFFFAOYSA-N 4-flourobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(F)C=C1 LFLSATHZMYYIAQ-UHFFFAOYSA-N 0.000 description 1
- MSFQEZBRFPAFEX-UHFFFAOYSA-N 4-methoxybenzenesulfonamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1 MSFQEZBRFPAFEX-UHFFFAOYSA-N 0.000 description 1
- QWKKYJLAUWFPDB-UHFFFAOYSA-N 4-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 QWKKYJLAUWFPDB-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000006661 Meyer-Schuster rearrangement reaction Methods 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- NYENCOMLZDQKNH-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)bismuthanyl trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F NYENCOMLZDQKNH-UHFFFAOYSA-K 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine and a preparation method thereof, which comprises the following steps: (1) sequentially adding aryl propiolic alcohol, N protected amine, acid and a solvent into a reaction bottle, and heating and refluxing; (2) after the reaction is completed within 1-8 hours, adding N-halogenated succinimide into the reaction system; (3) after the reaction is continued for 2-9 hours, cooling the reaction liquid to room temperature and adding hydrazine hydrate; (4) adding water into the reaction system for quenching reaction after 6-20 hours, and then extracting, separating liquid, concentrating and separating by a column to obtain pure 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine; (5) the yield of the reaction is between 7 and 70 percent. The application provides a synthesis method which is simple to operate, mild in reaction conditions and high in reaction yield for synthesizing the 3-aryl-4, 5-dihydro-1H-pyrazol-5 amine derivative.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine and a preparation method thereof.
Background
3-aryl-4, 5-dihydro-1H-pyrazole derivatives are important structural units which can be further converted into other nitrogen-containing heterocyclic compounds (J.heterocyclic. chem.1979,16, 311-321; Synth. Commun.1989,1989(4): 320-321). Baohe, T et al reported in 2009 a method for the synthesis of 3-aryl-4, 5-dihydro-1H-pyrazoles from acetophenone (bioorg. Med. chem. Lett.19(2009) 2162-. The synthesis route needs to be carried out under the condition of strong acid in the step a, the reaction condition is severe, and the operation is not easy:
if NH is introduced into the 5-position of the pyrazole ring, a compound ligand can form a hydrogen bond effect with stronger binding force with a protein receptor, so that the acting force between the ligand compound and the receptor protein is improved, and the biological activity of the compound is further improved, but the synthesis of the 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine derivative with amino substitution on the 5-position is not reported.
Disclosure of Invention
The invention aims to solve the problems and provide a 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine and a preparation method thereof.
The purpose of the invention is realized by the following technical scheme:
a 3-aryl-4, 5-dihydro-1H-pyrazol-5 amine, the 3-aryl-4, 5-dihydro-1H-pyrazol-5 amine having the structure shown below:
wherein: ar is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl;
r is sulfonyl or acyl.
Further, Ar is phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl, 2-naphthyl or 3-thienyl.
Further, R is benzenesulfonyl, 4-nitro-benzenesulfonyl, 4-methoxy-benzenesulfonyl, 4-fluoro-benzenesulfonyl, 4-chloro-benzenesulfonyl, 4-methyl-benzenesulfonyl, methanesulfonyl.
A preparation method of 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine comprises the following steps:
(1) heating and refluxing aryl-substituted propargyl alcohol, an acid catalyst and an amine compound in a solvent, and obtaining a reaction solution containing a compound 1 after the aryl-substituted propargyl alcohol completely disappears;
(2) then adding N-halogenated succinimide into the reaction liquid to obtain reaction liquid containing the compound 2;
(3) cooling the reaction liquid to room temperature, and adding a proper amount of hydrazine hydrate into the reaction liquid to obtain reaction liquid containing 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine 3;
(4) finally, extracting the reaction solution by ethyl acetate, washing by saturated saline solution, evaporating, concentrating, and performing column separation to obtain a 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine derivative 3 with the purity of more than 98%;
the aryl-substituted propargyl alcohol of step (1) has the structure shown below:
the amine compound in the step (1) has the following structure: RNH2；
Step (a)1) The compound 1 has the following structure:
the compound 2 in the step (2) has the following structure:
the compound 3 in the step (3) has the following structure:
further, the heating reflux reaction temperature in the step (1) is 95-100 ℃, the time is 1-8 hours, stirring is carried out in the process, the stirring speed is 280-290 rpm, the reaction process is monitored by TLC, and when the aryl-substituted propargyl alcohol in the reaction liquid is completely reacted, the next step is carried out;
the acid catalyst is Lewis acid, the solvent is dioxane, dichloroethane, benzotrifluoride, toluene, benzene, tetrahydrofuran or methanol, and the ratio of the aryl-substituted propargyl alcohol to the solvent is 1: 5-10 mol/L.
Further, the reaction temperature in the step (2) is 95-100 ℃, the reaction time is 2-9 hours, stirring is carried out in the process, the stirring speed is 280-290 rpm, the reaction process is monitored by TLC, and when the compound 1 in the reaction liquid is completely converted, the next step is carried out.
Further, the reaction time in the step (3) is 6-20 hours, stirring is carried out in the process, the stirring speed is 280-290 rpm, the reaction process is monitored by TLC, when the compound 2 in the reaction solution is completely converted, water is added into the reaction solution to quench the reaction, and then 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine is obtained by extraction, liquid separation, washing, drying, concentration and column separation, and the chemical reaction formula is shown as follows:
further, in the step (2), the N-halogenated succinimide is NBS, NCS or NIS.
Further, in the step (1), the ratio of the number of moles of the arylpropynol to the number of volumes of the solvent is 1:5 to 10 mol/L.
Further, the molar ratio of the aryl propiolic alcohol, the N-protected amine, the N-halogenated succinimide, the acid and the hydrazine hydrate is 1: (1.00-3.00): (1.00-2.00): (0.05-0.40): (1.00-3.00).
Compared with the prior art, the invention has the beneficial effects that:
1. NH is introduced into the 5-position of the pyrazole ring, and a compound ligand can form a hydrogen bond effect with stronger binding force with a protein receptor, so that the acting force between the ligand compound and the receptor protein is improved, and the biological activity of the compound is further improved.
2. The 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine is obtained through tandem Meyer-Schuster rearrangement reaction/intermolecular addition/alpha-halogenation reaction/nucleophilic addition cyclization. The invention provides a brand new one-pot synthesis method for synthesizing 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine. The method has the advantages of simple and easily obtained raw materials, convenient and easy experimental operation, mild reaction conditions, high yield and the like.
Drawings
FIG. 1 is a photograph of the compound prepared in example 11H NMR spectrum;
FIG. 2 is a photograph of the compound prepared in example 113C NMR spectrum.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments.
The raw materials used in the examples are commercially available products, and therefore, no other contents need to be provided.
The catalyst, dioxane, dichloroethane, benzotrifluoride, toluene, benzene, tetrahydrofuran, ethyl acetate, petroleum ether, anhydrous sodium sulfate and the like used in the embodiments of the invention are all Chinese medicine reagents.
The information of the equipment and the manufacturers used in the embodiments of the present invention is as follows:
the stirrer is as follows: a Shanghai plum Yimpu MYPII-2 constant-temperature magnetic stirrer;
the circulating water pump is as follows: shanghai Yukang circulation multipurpose vacuum pump SHB-IIIA;
the rotary evaporator comprises: shanghai yukang rotary evaporator W.S 206B;
the oil pump is as follows: shanghai Yukang 2XZ-2 type rotary-vane vacuum pump;
in the examples, preparation of aryl-substituted propargyl alcohols: a round bottom flask of appropriate size was taken and charged with aryl iodide (99.8% pure, 25g per flask), PdCl2(PPh3)2CuI; then, vacuumizing the reaction bottle and protecting the reaction bottle with nitrogen, then placing the reaction bottle in an ice-water bath, slowly dropwise adding excessive propargyl alcohol (the purity is 99.9 percent and the specification is 500g per bottle) into the reaction bottle at the speed of about 5 seconds per drop, and the required dropwise adding time is about five minutes; after the dripping is finished, the reaction bottle is placed at room temperature, and is placed in an oil bath pot after the temperature of the reaction bottle is recovered to the room temperature, and the reaction is carried out at 55-60 ℃. Monitoring the reaction by TLC, and stopping the reaction after the aryl iodide is completely reacted; quenching the reaction by using a saturated sodium bicarbonate solution, extracting by using ethyl acetate, washing by using saturated saline solution, evaporating, concentrating and carrying out column separation to obtain the aryl-substituted propargyl alcohol compound with the purity of more than 98%.
The preparation method of the general 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine specifically comprises the following steps: adding aryl substituted propiolic alcohol (0.10mmol), a solvent (0.50-1.00 mL), acid (0.005-0.04 mmol), N protected amine (0.10-0.30 mmol), N-halogenated succinimide (0.1-0.2 mmol) and hydrazine hydrate (0.10-0.30 mmol) into a 10mL sealed tube in sequence, carrying out reaction at room temperature after refluxing, and monitoring the reaction by TLC.
And after the reaction is finished, adding water to quench the reaction, adding ethyl acetate to extract an organic phase, washing the obtained organic phase with saturated sodium chloride, drying the organic phase with anhydrous sodium sulfate, concentrating the dried organic phase on a rotary evaporator, and purifying the obtained concentrated solution by column chromatography to obtain the 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine.
Example 1
4-methyl-N- (3-phenyl-4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: phenyl propiolic alcohol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：68％.HRMS calculated for C16H18N3O2S([M+H]+):316.1120；found:316.1121.
1H NMR(500MHz,DMSO-d)δ8.24(d,J＝9.5Hz,1H),7.75(d,J＝8.0Hz,2H),7.62-7.60(m,2H),7.43(d,J＝8.0Hz,2H),7.34-7.32(m,3H),5.08-5.03(m,1H),3.19-3.15(m,1H),2.91-2.78(m,1H),2.42(s,3H).13C NMR(125MHz,Chloroform-d)δ151.12,143.73,139.03,131.82,130.48,129.26,129.13,127.39,126.66,57.43,52.92,21.76.IR(KBr,cm-1):3385,3168,3045,2809,2537,1629,1450,1330,1293,1159,1117,1093,1066,818,783,686,556.
FIG. 1 is a photograph of the compound prepared in example 11H NMR spectrum, FIG. 2 of the compound13C NMR spectrum.
Example 2
4-methyl-N- (3- (o-tolyl) -4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 2-Methylbenzpropiolic alcohol (0.10mmol), p-methylbenzenesulfonamide (0.10mmol), N-bromosuccinimide (0.15mmol), copper trifluoromethanesulfonate (0.02mmol),1, 2-dichloroethane (0.50mL), and hydrazine hydrate (0.10 mmol).
yield：66％.HRMS calculated for C17H20N3O2S([M+H]+):330.1276；found:330.1276.
Example 3
4-methyl-N- (3- (m-tolyl) -4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 3-Methylbenzpropiolic alcohol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.20mmol), copper trifluoromethanesulfonate (0.02mmol), trifluorotoluene (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：62％.HRMS calculated for C17H20N3O2S([M+H]+):330.1276；found:330.1275.
Example 4
4-methyl-N- (3- (p-tolyl) -4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 4-Methylbenzpropiolic alcohol (0.10mmol), p-methylbenzenesulfonamide (0.20mmol), N-chlorosuccinimide (0.20mmol), ferric trifluoromethanesulfonate (0.04mmol), toluene (0.50mL), and hydrazine hydrate (0.30 mmol).
yield：65％.HRMS calculated for C17H20N3O2S([M+H]+):330.1276；found:330.1276.
Example 5
N- (3- (4-bromophenyl) -4, 5-dihydro-1H-pyrazol-5-yl) -4-methylbenzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: phenylpropanol (0.10mmol), p-methylbenzenesulfonamide (0.30mmol), N-chlorosuccinimide (0.15mmol), silver triflate (0.02mmol), benzene (0.80mL), and hydrazine hydrate (0.20 mmol).
yield：58％.HRMS calculated for C16H17BrN3O2S([M+H]+):394.0225；found:394.0224.
Example 6
N- (3- (4-chlorophenyl) -4, 5-dihydro-1H-pyrazol-5-yl) -4-methylbenzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 4-Chlorophenylpropynol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-iodosuccinimide (0.15mmol), scandium trifluoromethanesulfonate (0.005mmol), tetrahydrofuran (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：82％.HRMS calculated for C16H17ClN3O2S([M+H]+):350.0730；found:350.0731.
Example 7
N- (3- ([ [1,1' -biphenyl ] -4-yl) -4, 5-dihydro-1H-pyrazol-5-yl) -4-methylbenzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 4-Benzenepropanol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), scandium trifluoromethanesulfonate (0.04mmol), methanol (1.00mL), and hydrazine hydrate (0.20 mmol).
yield：59％.HRMS calculated for C22H22N3O2S([M+H]+):392.1433；found:392.1432.
Example 8
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 4-Methoxybenzene propiolic alcohol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), silver triflate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：57％.HRMS calculated for C17H20N3O3S([M+H]+):346.1225；found:346.1224.
Example 9
N- (3- (3-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-5-yl) -4-methylbenzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 3-methoxyphenylpropargyl alcohol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-iodosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：70％.HRMS calculated for C17H20N3O3S([M+H]+):346.1225；found:346.1224.
Example 10
N- (3- (2-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-5-yl) -4-methylbenzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: 2-Methoxybenzene propiolic alcohol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (1.00mL), and hydrazine hydrate (0.20 mmol).
yield：82％.HRMS calculated for C17H20N3O3S([M+H]+):346.1225；found:346.1224.
Example 11
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: thiophene propiolic alcohol (0.10mmol), p-methylbenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：56％.HRMS calculated for C14H16N3O3S2([M+H]+):338.0633；found:338.0632.
Example 12
4-nitro-N- (3-phenyl-4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamides
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: phenylpropanol (0.10mmol), p-nitrobenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：51％.HRMS calculated for C15H15N4O4S([M+H]+):347.0814；found:347.0814.
Example 13
4-methoxy-N- (3-phenyl-4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: phenyl propynol (0.10mmol), p-methoxybenzenesulphonamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth triflate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：82％.HRMS calculated for C16H18N3O3S([M+H]+):332.1069；found:332.1069.
Example 14
4-fluoro-N- (3-phenyl-4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: phenyl propiolic alcohol (0.10mmol), p-fluorobenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：42％.HRMS calculated for C15H15FN3O2S([M+H]+):320.0869；found:320.0868.
Example 15
4-chloro-N- (3-phenyl-4, 5-dihydro-1H-pyrazol-5-yl) benzenesulfonamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: phenyl propiolic alcohol (0.10mmol), p-chlorobenzenesulfonamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：45％.HRMS calculated for C15H15ClN3O2S([M+H]+):336.0574；found:336.0574.
Example 16
N- (3-phenyl-4, 5-dihydro-1H-pyrazol-5-yl) benzamide
The aryl substituted propargyl alcohol, the N protected amine, the N-halogenated succinimide, the acid, the solvent and the hydrazine hydrate respectively have the following types and the use amounts: phenylpropanol (0.10mmol), benzamide (0.12mmol), N-bromosuccinimide (0.15mmol), bismuth trifluoromethanesulfonate (0.02mmol),1, 4-dioxane (0.50mL), and hydrazine hydrate (0.20 mmol).
yield：7％.HRMS calculated for C16H16N3O([M+H]+):266.1293；found:266.1293.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A 3-aryl-4, 5-dihydro-1H-pyrazol-5 amine, wherein the 3-aryl-4, 5-dihydro-1H-pyrazol-5 amine has the structure shown below:
wherein: ar is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl;
r is sulfonyl or acyl.
2. A 3-aryl-4, 5-dihydro-1H-pyrazol-5 amine according to claim 1, wherein Ar is phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl, 2-naphthyl, or 3-thienyl.
3. A 3-aryl-4, 5-dihydro-1H-pyrazol-5 amine according to claim 1, wherein R is benzenesulfonyl, 4-nitro-benzenesulfonyl, 4-methoxy-benzenesulfonyl, 4-fluoro-benzenesulfonyl, 4-chloro-benzenesulfonyl, 4-methyl-benzenesulfonyl, or methanesulfonyl.
4. A process for the preparation of 3-aryl-4, 5-dihydro-1H-pyrazol-5-amines according to any one of claims 1 to 3, comprising the steps of:
(1) heating and refluxing aryl-substituted propargyl alcohol, an acid catalyst and an amine compound in a solvent, and obtaining a reaction solution containing a compound 1 after the aryl-substituted propargyl alcohol completely disappears;
(2) then adding N-halogenated succinimide into the reaction liquid to obtain reaction liquid containing the compound 2;
(3) cooling the reaction liquid to room temperature, and adding a proper amount of hydrazine hydrate into the reaction liquid to obtain reaction liquid containing 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine 3;
(4) finally, extracting the reaction solution by ethyl acetate, washing by saturated saline solution, evaporating, concentrating, and performing column separation to obtain a 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine derivative 3 with the purity of more than 98%;
the aryl-substituted propargyl alcohol of step (1) has the structure shown below:
the amine compound in the step (1) has the following structure: RNH2；
The compound 1 in the step (1) has the following structure:
the compound 2 in the step (2) has the following structure:
the compound 3 in the step (3) has the following structure:
5. the preparation method of 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine according to claim 4, characterized in that in the step (1), the heating reflux reaction temperature is 95-100 ℃, the time is 1-8H, stirring is carried out in the process, the stirring speed is 280-290 rpm, the reaction process is monitored by TLC, and when aryl-substituted propargyl alcohol in the reaction solution completely reacts, the next step is carried out;
the acid catalyst is Lewis acid, the solvent is dioxane, dichloroethane, benzotrifluoride, toluene, benzene, tetrahydrofuran or methanol, and the ratio of the aryl-substituted propargyl alcohol to the solvent is 1: 5-10 mol/L.
6. The preparation method of 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine according to claim 4, wherein the reaction temperature in the step (2) is 95-100 ℃, the reaction time is 2-9H, stirring is performed in the process, the stirring speed is 280-290 rpm, the reaction progress is monitored by TLC, and when the compound 1 in the reaction solution is completely converted, the next step is performed.
7. The preparation method of 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine according to claim 4, characterized in that the reaction time in the step (3) is 6-20H, stirring is performed during the process, the stirring speed is 280-290 rpm, the reaction process is monitored by TLC, when the compound 2 in the reaction solution is completely converted, water is added into the reaction solution to quench the reaction, and then 3-aryl-4, 5-dihydro-1H-pyrazole-5 amine is obtained by extraction, liquid separation, washing, drying, concentration and column separation, and the chemical reaction formula is as follows:
8. the method for preparing 3-aryl-4, 5-dihydro-1H-pyrazol-5-amine according to claim 4, wherein in step (2), the N-halogenated succinimide is NBS, NCS, NIS.
9. The process according to claim 4, wherein the ratio of the number of moles of arylpropynol to the number of volumes of solvent in step (1) is 1:5 to 10 mol/L.
10. The method of claim 4, wherein the molar ratio of arylpropiolic alcohol, N-protected amine, N-halosuccinimide, acid and hydrazine hydrate is 1: (1.00-3.00): (1.00-2.00): (0.05-0.40): (1.00-3.00).
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