CN113943252A - Pyrazolidinesulfonyl fluoride compounds and preparation method thereof - Google Patents
Pyrazolidinesulfonyl fluoride compounds and preparation method thereof Download PDFInfo
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- CN113943252A CN113943252A CN202111204992.6A CN202111204992A CN113943252A CN 113943252 A CN113943252 A CN 113943252A CN 202111204992 A CN202111204992 A CN 202111204992A CN 113943252 A CN113943252 A CN 113943252A
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- pyrazolidinesulfonyl
- fluoride
- fluoride compound
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- diphenylphosphino
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- -1 Pyrazolidinesulfonyl fluoride compounds Chemical class 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 239000011737 fluorine Substances 0.000 claims abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 26
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 14
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000010949 copper Substances 0.000 claims description 10
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 claims description 9
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 claims description 9
- BYPHZHGVWNKAFC-UHFFFAOYSA-N ethenesulfonyl fluoride Chemical compound FS(=O)(=O)C=C BYPHZHGVWNKAFC-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052802 copper Inorganic materials 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000006845 Michael addition reaction Methods 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 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 5
- 238000000034 method Methods 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- JBAKCAZIROEXGK-LNKPDPKZSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O JBAKCAZIROEXGK-LNKPDPKZSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-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 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000005935 Sulfuryl fluoride Substances 0.000 description 3
- XGCDHPDIERKJPT-UHFFFAOYSA-N [F].[S] Chemical compound [F].[S] XGCDHPDIERKJPT-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- NCYVXEGFNDZQCU-UHFFFAOYSA-N nikethamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1 NCYVXEGFNDZQCU-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- MZAAXPJDNXWVJS-UHFFFAOYSA-N 1-(4-bromophenyl)-2-diazonioethenolate Chemical compound BrC1=CC=C(C(=O)C=[N+]=[N-])C=C1 MZAAXPJDNXWVJS-UHFFFAOYSA-N 0.000 description 1
- CBAZRELTIGNKMX-UHFFFAOYSA-N 1-bromoethenesulfonyl fluoride Chemical compound FS(=O)(=O)C(Br)=C CBAZRELTIGNKMX-UHFFFAOYSA-N 0.000 description 1
- BVIDIQIESLQDNP-UHFFFAOYSA-N 2-diazonio-1-naphthalen-2-ylethenolate Chemical compound C1=CC=CC2=CC(C(=C[N+]#N)[O-])=CC=C21 BVIDIQIESLQDNP-UHFFFAOYSA-N 0.000 description 1
- CZAJUMLCEPCHSC-UHFFFAOYSA-N 5-(dimethyl-$l^{4}-sulfanylidene)-1-[(4-fluorophenyl)methyl]-1,3-diazinane-2,4,6-trione Chemical compound O=C1C(=S(C)C)C(=O)NC(=O)N1CC1=CC=C(F)C=C1 CZAJUMLCEPCHSC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical group F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 description 1
- 238000006115 defluorination reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical group FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 1
- 229960000909 sulfur hexafluoride Drugs 0.000 description 1
- LSJNBGSOIVSBBR-UHFFFAOYSA-N thionyl fluoride Chemical compound FS(F)=O LSJNBGSOIVSBBR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Epidemiology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a pyrazole alkyl sulfonyl fluoride compound and a preparation method thereof, wherein the molecular formula of the pyrazole alkyl sulfonyl fluoride compound is as follows:
Description
Technical Field
The invention belongs to the technical field of preparation of amides of sulfonic acid or halides thereof, and relates to a pyrazole alkyl sulfonyl fluoride compound and a preparation method thereof.
Background
Hexavalent sulfur Fluoride Exchange chemistry (SuFEx) is a new generation of click chemistry (click chemistry) proposed by k.barry Sharpless in 2014 by nobel prize awarded by the nobel chemistry, and is characterized in that a sulfur fluorine bond can undergo defluorination reaction through nucleophilic substitution under specific conditions, and sulfuryl Fluoride (SO) is used2F2) Vinyl sulfonyl fluoride (ESF), and tetrafluoro sulfinyl fluoride (SOF)4) Hexavalent sulfur fluorine reagents such as 1-bromovinylsulfonyl fluoride (BESF) are used as synthons to be efficiently connected with nucleophilic reagents such as phenol, alcohol and amine, and sulfur fluorine exchange chemistry is widely applied to the research fields of polymer chemistry, pharmaceutical chemistry, surface chemistry and the like.
The pyrazolylalkylsulfonyl fluoride compound is used as an alkylsulfonylfluoride compound and contains pyrazolyl and sulfonyl fluoride groups at the same time. Because many compounds containing pyrazolyl or alkylsulfonyl fluoride groups have high biological activity, the combination of the two is expected to obtain a new compound with biological activity. Meanwhile, sulfonyl fluoride groups can also undergo sulfur-fluorine exchange (SuFEx) chemical reaction and can be used for modification of certain drug molecules, but no published reports of the compounds or preparation methods exist at present.
Disclosure of Invention
The invention aims to solve the technical problems in the prior art and provides a pyrazolidinesulfonyl fluoride compound and a preparation method thereof, the series of compounds have the characteristics of strong diversity and large quantity of functional groups, and are expected to be used in the fields of organic synthesis, pharmaceutical chemistry and the like, and meanwhile, the preparation method has the advantages of easily available raw materials, mild reaction conditions, good reaction selectivity, short reaction time, low requirements on instruments and equipment, simplicity in operation, easiness in purification of products and the like.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
provided is a pyrazolidinesulfonyl fluoride compound having a formula as follows:
wherein R is mono-substituted or multi-substituted phenyl or naphthyl, and the substituent is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethoxy, methoxy, nitro, cyano, carbomethoxy, carbethoxy, oxysulfonyl Fluoro (FO)2SO-). When there are a plurality of substituents, each substituent may be the same or different.
The invention also comprises a preparation method of the pyrazolidinesulfonyl fluoride compound, which comprises the following specific steps: the method comprises the steps of mixing phenylacetyl diazo serving as a raw material with vinyl sulfonyl fluoride (ESF), N-diethylnicotinamide, a copper catalyst, a ligand and a solvent, carrying out Michael addition reaction, and separating and purifying to obtain the pyrazolylalkyl sulfonyl fluoride compound.
The reaction formula is as follows:
wherein R is mono-substituted or multi-substituted phenyl or naphthyl, and the substituent is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethoxy, methoxy, nitro, cyano, carbomethoxy, carbethoxy, oxysulfonyl Fluoro (FO)2SO-). When there are a plurality of substituents, each substituent may be the same or different.
According to the scheme, the copper catalyst is selected from Cu (PF)6)(CH3CN)4(copper tetra-acetonitrile hexafluorophosphate), CuF2(copper fluoride, Cu (acac))2(copper acetylacetonate). The preferred catalyst is CuF2。
According to the above scheme, the ligand is selected from dppe (1, 2-bis (diphenylphosphino) ethane), dppp (1, 3-bis (diphenylphosphino) propane), dppf (1,1' -bis (diphenylphosphino) ferrocene), PPh3(triphenylphosphine), Xantphos (4, 5-bis diphenylphosphino-9, 9-dimethylxanthene). Preferably the ligand is Xantphos.
According to the scheme, the solvent is one or a mixture of more of N, N-dimethylformamide, 1,1, 2-trichloroethane, acetonitrile, toluene, 1, 4-dioxane and tetrahydrofuran.
Preferably, the solvent is 1, 4-dioxane and 1,1, 2-trichloroethane in a volume ratio of 3: 1.
According to the scheme, the molar ratio of the phenylacetyl diazo, the vinyl sulfonyl fluoride, the N, N-diethyl nicotinamide, the copper catalyst and the ligand is 1: 2-8: 1.1-4: 0.01-0.5: 0.01 to 0.5.
According to the scheme, the concentration of the phenylacetyl diazo in the solvent is 0.05-0.2M (mol/L).
According to the scheme, the Michael addition reaction conditions are as follows: reacting for 1-12 h at 50-80 ℃.
The invention also comprises the application of the pyrazolidinesulfonyl fluoride compound as an organic synthesis intermediate.
The invention also comprises the application of the pyrazolidinesulfonyl fluoride compound as an antibacterial agent.
ESF not only can be used as an olefin donor to participate in cycloaddition reaction to construct a pyrazole ring, but also can be used as a Michael addition acceptor to construct an alkyl sulfonyl fluoride side chain. N, N-diethylnicotinamide acts as an organic base to promote hydrolysis of sulfonyl fluoride to sulfonic acid, only then does SO removal 3 occur, allowing the removal of the sulfonyl fluoride group. In the reaction, the complex obtained by complexing the ligand and the catalyst can greatly increase the catalytic action of the copper catalyst and promote the removal of sulfonyl fluoride and the formation of a pyrazole ring.
The reaction mechanism of the present invention: the 3-dipolar cycloaddition reaction of phenylacetyl diazo (1) with vinyl sulfonyl fluoride (ESF, 2) produces adduct a, which is then hydrolyzed in the presence of a base to provide intermediate B, which can be further converted to pyrazole derivative C under basic conditions, promoted with a copper catalyst and oxygen. Finally, a classical Michael addition reaction of intermediate C with another ESF molecule gives the desired product pyrazolyl aliphatic sulfonyl fluoride 3.
The invention has the beneficial effects that: 1. the pyrazolidinesulfonyl fluoride compound provided by the invention has the characteristics of strong diversity and large quantity of functional groups, and has a plurality of special groups, and a plurality of substituent groups can be introduced into an aromatic ring region, so that the pyrazolidinesulfonyl fluoride compound has wide application prospects in the fields of medicinal chemistry, organic synthesis and the like; 2. the preparation method has the advantages of easily available raw materials, mild reaction conditions, good reaction selectivity, short reaction time, low requirements on instruments and equipment, simple operation, easy purification of products and suitability for large-scale synthesis.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the present invention is further described in detail with reference to the following examples.
Example 1
A preparation method of a pyrazolidinesulfonyl fluoride compound has a reaction formula as follows:
the preparation method comprises the following steps:
to the dry reaction tube were added phenylacetyldiazone (1.0mmol), vinylsulfonyl fluoride (4.0mmol), N-diethylnicotinamide (1.5mmol), and CuF2(0.05mmol), xanthphos (0.05mmol) and 10.0mL of a mixed solvent (1, 4-dioxane: 1,1, 2-trichloroethane: 3:1, volume ratio), the mixture was stirred and reacted at 80 ℃ for 12 hours, after the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 5:1(v/v)) to obtain 2- (3-benzoyl-1H-pyrazol-1-yl) ethane-1-sulfonyl fluoride (200mg, 71% yield) as a yellow viscous liquid.
The nuclear magnetic and mass spectral data for the product prepared in this example are as follows:1H NMR(500MHz,CDCl3)δ8.20(d,J＝7.5Hz,2H),7.63-7.60(m,2H),7.51(t,J＝7.6Hz,2H),6.96(d,J＝2.3Hz,1H),4.78(t,J＝6.3Hz,2H),4.09(q,J＝6.1Hz,2H).19F NMR(471MHz,CDCl3)δ57.5(s,J＝5.7Hz,1F).13C NMR(126MHz,CDCl3)δ187.6,152.2,137.1,132.9,131.8,130.4,128.3,109.9,50.4(d,J＝17.2Hz),46.4.HRMS ESI(m/z):calculated for C12H11FN2O3S[M+H]+:283.0545,found:283.0547.
example 2
A preparation method of a pyrazolidinesulfonyl fluoride compound has a reaction formula as follows:
the preparation method comprises the following steps:
to a dry reaction tube were added 1- (4-bromophenyl) -2-diazoethan-1-one (1.0mmol), vinylsulfonyl fluoride (4.0mmol), N-diethylnicotinamide (1.5mmol), CuF2(0.05mmol), Xantphos (0.05mmol) and 10.0mL of a mixed solvent (1, 4-dioxane: 1,1, 2-trichloroethane: 3:1 by volume) were stirred and reacted at 80 ℃ for 12 hours, after the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 5:1(v/v)) to obtain 2- (3- (4-bromobenzoyl) -1H-pyrazol-1-yl) ethane-1-sulfonyl fluoride (314mg, 87% yield) as a pale yellow solid.
The nuclear magnetic and mass spectral data for the product prepared in this example are as follows:1H NMR(500MHz,CDCl3)δ8.09(d,J＝8.2Hz,2H),7.63(d,J＝8.2Hz,2H),7.59(d,J＝1.5Hz,1H),6.97(d,J＝2.0Hz,1H),4.77(t,J＝6.3Hz,2H),4.06(q,J＝5.6Hz,2H).19F NMR(471MHz,CDCl3)δ57.8(d,J＝5.8Hz 1F).13C NMR(126MHz,CDCl3)δ186.2,152.0,135.7,132.0,131.9,131.6,128.1,110.0,50.4(d,J＝17.3Hz),46.4.HRMS ESI(m/z):calculated for C12H10BrFN2O3S[M+H]+:360.9760,found:360.9763.
example 3
A preparation method of a pyrazolidinesulfonyl fluoride compound has a reaction formula as follows:
the preparation method comprises the following steps:
adding 1- (4-methyl) -2-diazoethane into a dry reaction tube-1-ketone (0.4mmol), vinylsulfonyl fluoride (1.6mmol), N-diethylnicotinamide (1.5mmol), CuF2(0.05mmol), xanthphos (0.05mmol) and 4.0mL of a mixed solvent (1, 4-dioxane: 1,1, 2-trichloroethane ═ 3:1, volume ratio), and the mixture was stirred at 80 ℃ to react for 12 hours, after the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate ═ 5:1(v/v)) to obtain 2- (3- (4-methylbenzoyl) -1H-pyrazol-1-yl) ethane-1-sulfonyl fluoride (99mg, 84% yield) as a pale yellow powder.
The nuclear magnetic and mass spectral data for the product prepared in this example are as follows:1H NMR(500MHz,CDCl3)δ8.09(d,J＝8.1Hz,2H),7.56(d,J＝2.3Hz,1H),7.29(d,J＝8.0Hz,2H),6.92(d,J＝2.3Hz,1H),4.76(t,J＝6.4Hz,2H),4.06(q,J＝6.4Hz,2H),2.43(s,3H).19F NMR(471MHz,CDCl3)δ57.6(s,1F).13C NMR(126MHz,CDCl3)δ187.3,152.3,143.8,134.5,131.6,130.5,129.0,109.8,50.4(d,J＝17.2Hz),46.4,21.7.HRMS ESI(m/z):calculated for C13H13FN2O3S[M+H]+297.0765,found 297.0766.
example 4
A preparation method of a pyrazolidinesulfonyl fluoride compound has a reaction formula as follows:
the preparation method comprises the following steps:
to the dry reaction tube were added 1- (2-naphthyl) -2-diazoethane-1-one (1.0mmol), vinylsulfonyl fluoride (4.0mmol), N-diethylnicotinamide (1.5mmol), CuF2(0.05mmol), xanthphos (0.05mmol) and 10.0mL of a mixed solvent (1, 4-dioxane: 1,1, 2-trichloroethane: 3:1 by volume) were stirred and reacted at 80 ℃ for 12 hours, after the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 5:1(v/v)) to obtain 2- (3- (2-naphthoyl) -1H-pyrazol-1-yl) ethane-1-sulfonyl fluoride (294mg, 88% yield) as a yellow solid.
The nuclear magnetic and mass spectral data for the product prepared in this example are as follows:1H NMR(500MHz,CDCl3)δ8.80(s,1H),8.20(d,J＝8.5Hz,1H),7.98(d,J＝8.1Hz,1H),7.94-7.88(m,2H),7.62-7.59(m,2H),7.57-7.54(m,1H),6.99(d,J＝2.1Hz,1H),4.78(t,J＝6.4Hz,2H),4.08(q,J＝5.9Hz,2H).19F NMR(471MHz,CDCl3)δ57.9(d,J＝5.7Hz 1F).13CNMR(126MHz,DMSO)δ187.5,152.3,135.6,134.4,132.6,132.4,131.7,129.8,128.5,128.1,127.8,126.7,125.7,110.0,50.5(d,J＝18.2Hz),46.4.HRMS ESI(m/z):calculated for C16H13FN2O3S[M+H]+:333.0780,found:333.0779.
the typical structure and the reaction yield of the pyrazolylalkylsulfonyl fluoride synthesized by the method are shown as follows, and the molecular structural formula of the pyrazolylalkylsulfonyl fluoride compound is not taken as a limitation to the protection scope of the invention.
The pyrazolidinesulfonyl fluoride compounds prepared in this example are useful as antibacterial agents.
Claims (10)
1. A pyrazolidinesulfonyl fluoride compound characterized by the following molecular formula:
wherein R is mono-substituted or multi-substituted phenyl or naphthyl, and the substituent is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethoxy, methoxy, nitro, cyano, carbomethoxy, carbethoxy and oxysulfonyl fluoro.
2. A method for preparing a pyrazolidinesulfonyl fluoride compound according to claim 1, characterized by comprising the steps of: mixing phenylacetyl diazo serving as a raw material with vinyl sulfonyl fluoride, N-diethyl nicotinamide, a copper catalyst, a ligand and a solvent, carrying out Michael addition reaction, and separating and purifying to obtain a pyrazolidinyl sulfonyl fluoride compound;
the reaction formula is as follows:
wherein R is mono-substituted or multi-substituted phenyl or naphthyl, and the substituent is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethoxy, methoxy, nitro, cyano, carbomethoxy, carbethoxy and oxysulfonyl fluoro.
3. The process for preparing pyrazolidinesulfonyl fluoride compounds according to claim 2, wherein said copper catalyst is selected from Cu (PF)6)(CH3CN)4，CuF2(copper fluoride, Cu (acac))2One kind of (1).
4. The process for preparing a pyrazolidinesulfonyl fluoride compound according to claim 2, wherein said ligand is one selected from the group consisting of 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1,1' -bis (diphenylphosphino) ferrocene, triphenylphosphine, 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene.
5. The process for preparing pyrazolidinesulfonyl fluoride compounds according to claim 2, wherein said solvent is one or a mixture of N, N-dimethylformamide, 1,1, 2-trichloroethane, acetonitrile, toluene, 1, 4-dioxane, tetrahydrofuran.
6. The process according to claim 2, characterized in that said phenylacetyl diazo, vinyl sulfonyl fluoride, N-diethylnicotinamide, copper catalyst and ligand are present in a molar ratio of 1: 2-8: 1.1-4: 0.01-0.5: 0.01 to 0.5.
7. The method according to claim 2, characterized in that the concentration of said phenylacetyl diazo in the solvent is 0.05 to 0.2M.
8. The process for preparing a pyrazolidinesulfonyl fluoride compound according to claim 2, wherein said michael addition reaction conditions are: reacting for 1-12 h at 50-80 ℃.
9. Use of the pyrazolidinesulfonyl fluoride compound according to claim 1 as an intermediate in organic synthesis.
10. Use of the pyrazolidinesulfonyl fluoride compound according to claim 1 as an antibacterial agent.
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| CN114989035A (en) * | 2022-07-08 | 2022-09-02 | 扬州工业职业技术学院 | Sulfuryl fluoride promoted reaction method for converting beta-diketone to alkyne |
| CN115974733A (en) * | 2022-12-28 | 2023-04-18 | 绍兴市上虞区武汉理工大学高等研究院 | Preparation and application of novel alkene sulfamide fluoride compound with anti-tumor effect |
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