CN108822145B - Sulfonamide compound and preparation method and application thereof - Google Patents
Sulfonamide compound and preparation method and application thereof Download PDFInfo
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
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- C07F7/083—Syntheses without formation of a Si-C bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Abstract
The invention relates to the technical field of organic synthesis, and particularly relates to a sulfonamide compound and a preparation method and application thereof, wherein the invention discloses a preparation method of the sulfonamide compound, which comprises the following steps: the compound of the formula (I) is a brand-new sulfonamide compound and can be applied to the field of biomedicine, the substrate of the compound is simple and easy to obtain, the direct carbon-hydrogen bond ethynylation reaction of primary or secondary sulfonamide without additional guide groups is avoided, the steps are few, the operation is simple and convenient, the atom economy and the industrial application value are good, and the technical problems that the existing sulfonamide compound is complex in synthesis steps and not beneficial to the application of industrial production are solved.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a sulfonamide compound and a preparation method and application thereof.
Background
Sulfonamide compounds are widely used in medicine, agricultural chemicals, dyes, etc. because of their important biological activities. Bayer corporation developed the first sulfonamide drug, bagadon (prontosil), in 1932, and acquired the nobel prize in 1939 for medicine. Bailangduo is the first drug found to be effective against bacteria in organisms so far, and plays a milestone role in the development of sulfonamide drugs. Many sulfonamide drugs have been used in clinical applications, and thus, interest in sulfonamide research has been stimulated. The pharmacological activity of the sulfonamide derivatives mainly comprises: antineoplastic, antiviral, antibacterial, antifungal, antituberculosis, and antiparasitic [ WANGXIANGLING, WANGXIALONG, GUNNUNCANG, MIYONG, CHINESE MEDICINAL MEDICINE, 2010,19,2050 ]. Over the last several decades, sulfonamides have been extensively developed, in addition to significant development in the antibacterial field, in the fields of anti-inflammation, anti-virus, anti-tumor, etc. [ a.
However, the synthesis of sulfonamides is very challenging, on the one hand, sulfur atoms are often strongly coordinating functional groups for transition metals and tend to poison transition metal catalysts [ i.p. beletskaya, v.p. ananikov, chem.rev.,2011,111,1596 ]; on the other hand, to achieve reactivity of the C-H bond functionality of aryl sulfonamides, the chemistry is often mounted on sulfonamides using additional directing groups to achieve a balance of reactivity and regioselectivity. However, the transformation requires additional introduction and removal of the guide group, and the reaction steps are increased, so that the reaction of the sulfonamide compounds is complicated, and the application of the reaction in practical production is not facilitated.
Therefore, the research and development of a simple, high-efficiency and industrially-valuable sulfonamide compound and a preparation method thereof are technical problems which need to be solved at present.
Disclosure of Invention
The invention provides a sulfonamide compound as well as a preparation method and application thereof, and solves the technical problem that the existing sulfonamide compound is complex in synthesis steps and unfavorable for application in actual production.
The invention provides a sulfonamide compound which has a structure shown in a formula (I);
wherein the content of the first and second substances,
is C6-C10 aryl, S, O-containing C2-C9 heterocycle or C2-C9 heteroaromaticsRadical, R1、R2Each represents a N, O, S-containing heterocycle of C4-C7, an N-containing heterocycle of C4, O, S,
or
R1、R2Each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino, alkoxy, aryl, benzyl or-NHCOR8；
R3、R4、R5、R6Each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, methylenedioxy group, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro group, cyano group, formyl chloride group, CO2R8、-OC(O)R9、-P(O)(R10)(R11)、-P(O)(OR10)(OR11)、-NR12R13、-C(O)NR14R15C6-C14 aryloxy, C6-C14 aryl, -C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic group,
or
R3、R4、R5、R6Wherein two adjacent groups and the carbon atom connected with the two adjacent groups form C3-C6 naphthenic base or C2-C9 heterocyclic group;
R7selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxyl group, acetoxyl group, silicon base or benzene ring;
R8、R9、R10、R11、R12、R13、R14each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, C2-C9 heteroaryl or C2-C9 heterocyclic radical;
R15selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 aryl sulfonyl group, C1-C10 alkyl sulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl group or C2-C9 heterocyclic group。
Preferably, R5Selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group, R6Is selected from saturated aliphatic hydrocarbon, unsaturated aliphatic hydrocarbon of C1-C40, phenyl, naphthyl or heterocyclic radical of C2-C9.
More preferably, R5Is a C1-C10 saturated or unsaturated alkyl radical, R6Is C1-C10 saturated or unsaturated alkyl.
Most preferably, R5Selected from methyl or benzyl, R6Is a tert-butyl group.
Preferably, R7When the compound is a silicon group or a benzene ring, the benzene ring can contain a substituent, wherein the substituent can be halogen, nitro, cyano or formamide.
The silicon base comprises trimethyl silicon base, triisopropyl silicon base or tert-butyl dimethyl silicon base.
Preferably, the C6-C14 aryl group includes at least one first substituent;
the first substituent is selected from hydrogen, halogen, C1-C40 alkyl, C1-C10 acyl, C1-C40 alkoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, substituted amino, ester, cyano or phosphonyl.
More preferably, the substituents are selected from methyl, methoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, -NR15R16、-CO2R9Cyano, halogen, -P (O) (R)11)(R12) OR-P (O) (OR)11)(OR12)。
Preferably, when the C6-C14 aryl group contains no substituent, the C6-C14 aryl group is selected from phenyl or naphthyl.
More preferably, when the C6-C14 aryl group contains a substituent, the C6-C14 aryl group is selected from the group consisting of phenyl, o-tolyl, o-methoxyphenyl, o-trifluoromethylphenyl, o-arylphenyl, o-heteroarylphenyl, o-substituted aminophenyl, o-esterphenyl, o-cyanophenyl, o-halophenyl, m-tolyl, m-methoxyphenyl, m-substituted aminophenyl, m-trifluoromethylphenyl, m-halophenyl, m-arylphenyl, m-heteroarylphenyl, m-esterphenyl, m-cyanophenyl, p-tolyl, p-methoxyphenyl, p-substituted aminophenyl, p-trifluoromethylphenyl, p-halophenyl, p-esterphenyl, p-cyanophenyl, p-arylphenyl and p-heteroarylphenyl, 2, 3-bismethoxyphenyl, 1-naphthyl, 2-naphthyl and phosphonophenyl groups.
Preferably, said aryl, said C2-C9 heteroaryl, and said C2-C9 heterocyclyl all contain at least one second substituent;
the second substituent is selected from halogen, C1-C40 alkyl, C1-C10 acyl and C1-C40 alkoxy.
Preferably, the heteroaryl group of C2-C9 is selected from furyl, benzofuryl, thienyl, benzothienyl, indolyl, isoindolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyranyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, or carbazolyl.
More preferably, the heteroaryl group from C2 to C9 is selected from 2-furyl, 3-furyl, 2-benzofuryl, 3-benzofuryl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, 2-indolyl, 3-indolyl, 2-pyrrolyl, 3-pyrrolyl, 5-thiazolyl, 4-pyrazolyl, 3-pyridyl, 4-pyridyl, 6-quinolyl, 5-isoquinolyl, 2-pyridyl, 2-quinolyl, 2-pyrazinyl, 2-pyrimidinyl or 1-pyrazolyl, 2-thiazolyl.
Preferably, the C2-C9 heterocyclic group is selected from tetrahydroquinolyl, N-acyl tetrahydroquinolyl, oxazolinyl, substituted oxazolinyl, tetrahydroindolyl, N-acyl tetrahydroindolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl or imidazolinyl.
More preferably, the C2-C9 heterocyclyl is selected from 6-tetrahydroquinolinyl, N-acyltetrahydroquinolinyl, 5-tetrahydroindolyl, N-acyltetrahydroindolyl, oxazolinyl, substituted oxazolinyl, tetrahydroquinolinyl, tetrahydroindolyl, or 2-oxazolinyl.
The invention also provides a preparation method of the sulfonamide compound, which comprises the following steps:
reacting a compound of a formula (II) with a compound of a formula (III) in the presence of an inert solvent under the action of a catalyst to obtain a compound of a formula (I);
wherein X is selected from hydrogen, bromine or iodine, when X is hydrogen, an oxidant is required to be added in the reaction,
represents C6-C10 aryl, C4-C8S, O-containing heterocycle or heteroaryl;
R1、R2each represents a C4-C7N heterocycle, a C4-O, S N heterocycle,
or
R1、R2Each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino, alkoxy, aryl, benzyl or-NHCOR8；
R3、R4、R5、R6Each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, methylenedioxy group, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro group, cyano group, formyl chloride group, CO2R8、-OC(O)R9、-P(O)(R10)(R11)、-P(O)(OR10)(OR11)、-NR12R13、-C(O)NR14R15C6-C14 aryloxy, C6-C14 aryl, -C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic group,
or
R3、R4、R5、R6Wherein two adjacent groups and the carbon atom connected with the two adjacent groups form C3-C6 naphthenic base or C2-C9 heterocyclic group;
R7selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxyl group, acetoxyl group, silicon base or benzene ring;
R8、R9、R10、R11、R12、R13、R14each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, C2-C9 heteroaryl or C2-C9 heterocyclic radical;
R15selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 aryl sulfonyl group, C1-C10 alkyl sulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl group or C2-C9 heterocyclic group.
Wherein the compound shown in the formula (II) is an aryl sulfonamide compound, and the compound shown in the formula (III) is a terminal alkyne compound.
Preferably, X is selected from hydrogen or bromine.
Preferably, R5Selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group, R6Selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group.
More preferably, R5Is a C1-C10 saturated or unsaturated alkyl radical, R6Is C1-C10 saturated or unsaturated alkyl;
most preferably, R5Selected from methyl or benzyl, R6Is tert-butyl;
preferably, R7When the compound is a silicon group or a benzene ring, the benzene ring can contain a substituent, wherein the substituent can be halogen, nitro, cyano or formamide. The silicon base comprises trimethyl silicon base, triisopropyl silicon base or tert-butyl dimethyl silicon base.
Preferably, the C6-C14 aryl group includes at least one first substituent;
the first substituent is selected from hydrogen, halogen, C1-C40 alkyl, C1-C10 acyl, C1-C40 alkoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, substituted amino, ester, cyano or phosphonyl.
More preferably, the first substituent is selected from methyl, methoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, -NR15R16、-CO2R9Cyano, halogen, -P (O) (R)11)(R12) OR-P (O) (OR)11)(OR12)。
Preferably, when the C6-C14 aryl group does not contain a first substituent, the C6-C14 aryl group is selected from phenyl or naphthyl.
More preferably, when C6-C14 contains a first substituent, the C6-C14 aryl group is selected from the group consisting of phenyl, o-tolyl, o-methoxyphenyl, o-trifluoromethylphenyl, o-arylphenyl, o-heteroarylphenyl, o-substituted aminophenyl, o-esterphenyl, o-cyanophenyl, o-halophenyl, m-tolyl, m-methoxyphenyl, m-substituted aminophenyl, m-trifluoromethylphenyl, m-halophenyl, m-arylphenyl, m-heteroarylphenyl, m-esterphenyl, m-cyanophenyl, p-tolyl, p-methoxyphenyl, p-substituted aminophenyl, p-trifluoromethylphenyl, p-halophenyl, p-esterphenyl, p-cyanophenyl, p-arylphenyl and p-heteroarylphenyl, 2, 3-bismethoxyphenyl, 1-naphthyl, 2-naphthyl and phosphonophenyl groups.
Preferably, said aryl, said C2-C9 heteroaryl, and said C2-C9 heterocyclyl all contain at least one second substituent;
the second substituent is selected from halogen, C1-C40 alkyl, C1-C10 acyl and C1-C40 alkoxy.
Preferably, the heteroaryl group of C2-C9 is selected from furyl, benzofuryl, thienyl, benzothienyl, indolyl, isoindolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyranyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, or carbazolyl.
More preferably, the heteroaryl group from C2 to C9 is selected from 2-furyl, 3-furyl, 2-benzofuryl, 3-benzofuryl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, 2-indolyl, 3-indolyl, 2-pyrrolyl, 3-pyrrolyl, 5-thiazolyl, 4-pyrazolyl, 3-pyridyl, 4-pyridyl, 6-quinolyl, 5-isoquinolyl, 2-pyridyl, 2-quinolyl, 2-pyrazinyl, 2-pyrimidinyl or 1-pyrazolyl, 2-thiazolyl.
Preferably, the C2-C9 heterocyclic group is selected from tetrahydroquinolyl, N-acyl tetrahydroquinolyl, oxazolinyl, substituted oxazolinyl, tetrahydroindolyl, N-acyl tetrahydroindolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl or imidazolinyl.
More preferably, the C2-C9 heterocyclyl is selected from 6-tetrahydroquinolinyl, N-acyltetrahydroquinolinyl, 5-tetrahydroindolyl, N-acyltetrahydroindolyl, oxazolinyl, substituted oxazolinyl, tetrahydroquinolinyl, tetrahydroindolyl, or 2-oxazolinyl.
Preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:10 to 10: 1.
More preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:3 to 1:1, and still more preferably 1: 2-1: 1, most preferably 1: 2. 2: 3 and 1: 1.
preferably, the inert solvent is selected from toluene, ethylbenzene, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1, 2-dichloroethane, diethyl ether, ethylene glycol dimethyl ether, acetonitrile, ethyl acetate, dichloromethane or acetone;
more preferably, the inert solvent is 1, 2-dichloroethane.
Preferably, the catalyst is selected from the group consisting of iridium (pentamethylcyclopentadienyl) dichloride dimer, ruthenium (p-methylisophenyl) dichloride dimer, rhodium (pentamethylcyclopentadienyl) dichloride dimer, silver bis (trifluoromethanesulfonyl) imide or silver hexafluoroantimonate.
More preferably, the catalyst is selected from the group consisting of iridium dichloro (pentamethylcyclopentadienyl) dimer, ruthenium dichloro (p-methylisophenyl) dimer, silver bis (trifluoromethanesulfonyl) imide, and silver hexafluoroantimonate.
Preferably, the oxidizing agent is selected from silver acetate, silver oxide, silver carbonate, silver nitrate, copper acetate, copper sulfate, copper chloride or copper bromide.
Preferably, the amount of the catalyst is 0.1-20 mol% of the amount of the compound of formula (II).
More preferably, the catalyst is used in an amount of 0.2 to 20 mol%, more preferably 0.5 to 15 mol%, most preferably 2.5 mol% or 15 mol% of the compound of formula (II).
Preferably, the reaction temperature is 20-140 ℃;
the reaction time is 0.1-40 h.
More preferably, the reaction temperature is 80-120 ℃, and the reaction time is 12-24 h.
The invention also provides an application of the sulfonamide compound or the sulfonamide compound obtained by the preparation method of the sulfonamide compound in medicine synthesis.
Ordinary primary sulfonamide and secondary sulfonamide are relatively easily available raw materials, a method for quickly constructing complex sulfonamide derivatives is provided by directly introducing multifunctional and easily-converted functional groups on sulfonamide functional groups, and based on the potential biological activity of sulfonamide molecules, a later derivatization reaction can be directly carried out on drug molecules containing sulfonamides, so that a brand new thought is provided for the development of new sulfonamides, and a new method is provided for quickly constructing a drug molecule library [ P.R.Patel, C.Ramalingan, Y. -T.park, bioorg.Med.Chem.,2007,17,6610 ].
The invention uses simple and easily obtained primary and secondary sulfamide as substrates, realizes the alkynylation reaction of the carbon-hydrogen bond of the common sulfamide through C-H activation, and aims to realize the high-efficiency conversion of the subsequent carbon-carbon triple bond, however, the reactions have chemical selectivity: i.e., competing reactions of the N-H bond of the primary and secondary sulfonamides with functionalization of the C-H bond of the aromatic ring, is somewhat challenging to achieve selective activation of the C-H bond in the presence of the N-H bond of the sulfonamide, given the bond energies of the N-H bond and the C-H bond of the aryl, and the better reactivity of the N-H bond of the sulfonamide found by Stahl et al [ t.hamada, x.ye, s.s.stahl, j.am.chem.soc.,2008,130,833 ].
Alkynyl is an important functional group in the fields of materials, medicaments and the like, and can be conveniently converted into other functional groups such as alkyl and olefin; the compound can be conveniently converted into a multi-functionalized compound through reactions such as electrophilic addition, nucleophilic addition and the like; meanwhile, alkyne can also be applied to organisms through Click reaction. It can be seen that it is very practical to introduce alkynyl fragments directly into the molecule. However, the existing synthetic methods are few, low in synthetic efficiency, not easy to obtain raw materials, easy to couple alkynyl per se and the like. It is to be noted that there is currently no report on a simple primary, secondary sulfonamide-directed alkynylation reaction. Therefore, it would be desirable to develop a C-H bond functionalization reaction facilitated by a common primary and secondary sulfonamide without additional directing groups.
It should be noted that the ortho-alkynylated sulfonamide products obtained by the preparation method of the present invention, especially the synthesis methods based on the primary and secondary sulfonamide products and their deficiencies, mainly focus on the coupling reaction of ortho-halogen substituted sulfonamides, while the substrates thereof are extremely difficult to obtain.
In conclusion, the invention has the following advantages:
1. the invention adopts primary and secondary sulfamide as substrates to prepare the sulfonamide compound, and the raw materials are simple and easy to obtain;
2. the method has the advantages that the direct carbon-hydrogen bond alkynylation reaction of common primary and secondary amides without additional guide group assistance is less in steps, simple and convenient to operate, economic and environment-friendly, and has industrial application value;
3. in the process of preparing the aryl sulfonamide compound, no pyridine or quinoline or other guide groups are required to be additionally arranged on the nitrogen atom of the sulfonamide, so that the guide groups are not required to be removed under severe conditions, only the hydrogen atoms or halogen atoms of two substrates are required to be removed, and the aryl sulfonamide compound has good atom economy;
4. the aromatic ring ortho alkynyl substituted sulfonamide derivative prepared by the invention can be used as a very multifunctional synthon to further synthesize more complex functional molecules, can be used for quickly modifying alkynyl with rich chemical activity (such as electrophilic addition, affinity addition and the like through region and stereoselectivity), and can directly realize the amine functionalization reaction in molecules in a catalytic mode to obtain a multi-substituted annular sulfonamide molecule which is widely applied in medicines, thereby providing a modular synthesis mode for the diversified synthesis of the medicine molecules;
5. the sulfonamide compound prepared by the invention is a brand-new sulfonamide compound, can be used as a simple organic raw material for synthesizing complex molecules, and is widely applied to the fields of medicines and materials;
6. the preparation method has good chemical selectivity, namely, the reaction only occurs on the carbon-hydrogen bond, but does not act on the nitrogen-hydrogen bond, namely, the nitrogen-hydrogen bond of the amide is kept unchanged in the reaction process;
7. the preparation method has very good regioselectivity, namely, the reaction only occurs at the ortho position of the benzene ring of the aryl sulfonamide, and any product substituted by alkynyl at the meta position or the para position of the benzene ring is not observed. This has not been possible with the conventional direct electrophilic substitution reactions.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without inventive exercise.
FIG. 1 shows the nuclear magnetic resonance of 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) provided in the first embodiment of the present invention1H, spectrogram;
FIG. 2 shows the nuclear magnetic resonance of 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) provided in the first embodiment of the present invention13C, spectrum;
FIG. 3 Nuclear magnetic resonance 4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b) provided in example two of the present invention1H, spectrogram;
FIG. 4 Nuclear magnetic resonance 4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b) provided in example two of the present invention13C, spectrum;
FIG. 5 Nuclear Magnetic Resonance (NMR) of 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenylhydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) provided in example III of the present invention1H, spectrogram;
FIG. 6 NMR of 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenylhydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) provided in example III of the present invention13C, spectrum;
FIG. 7 NMR of 4- (5-tolyl-3-trifluoromethylmonohydropyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) provided in example IV of the present invention1H, spectrogram;
FIG. 8 NMR of 4- (5-tolyl-3-trifluoromethylmonohydropyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) provided in example IV of the present invention13C, spectrum;
FIG. 9 NMR of 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e) provided in EXAMPLE five of this invention1H, spectrogram;
FIG. 10 NMR of 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e) provided in EXAMPLE five of this invention13And C, spectrum.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Other embodiments, which can be derived by one of ordinary skill in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The sulfonamide compound, the preparation method thereof and the raw materials and reagents used in the application can be purchased from the market.
The sulfonamide compound provided by the present invention, the preparation method and the application thereof are further described below.
EXAMPLE one 2- ((Triisopropylsilyl) acetylene) benzenesulfonamide (3a)
To a 15mL Schlenk reaction tube, an arylsulfonamide compound 1a (14.4mg,0.10mmol), an alkynylating agent 2(28 μ L,0.20mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);, dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 120 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 3:1, obtaining a product 2- ((triisopropylsilyl) acetylene) benzene sulfonamide (3 a): yellow liquid, yield 63% (21.2 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of the 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) is as follows:1H NMR(400MHz,CDCl3)8.03-8.01(m,1H),7.67-7.65(m,1H),7.53-7.49(m,1H),7.44-7.43(m,1H),1.18-1.14(m,21H)。
the nuclear magnetic resonance carbon spectrum measurement result of the 2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3a) is as follows:13C NMR(100MHz,CDCl3)142.5,134.0,131.0,127.7,126.1,119.4,102.2,100.7,17.6,10.3。
example bis 4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b)
To a 15mL Schlenk reaction tube, an arylsulfonamide compound 1b (17.1mg,0.10mmol), an alkynylating agent 2(20 μ L,0.15mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);, dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 120 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 3:1 to obtain the product 2- (4-methyl-2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3b) as a yellow liquid with a yield of 38% (13.4 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of the 2- (4-methyl (triisopropylsilyl) acetylene) benzenesulfonamide (3b) is as follows:1H NMR(400MHz,CDCl3)7.90(d,J＝8.0Hz,1H),7.45(s,1H),7.24(d,J＝8.0Hz,1H),2.40(s,3H),1.18–1.14(m,21H)。
the nuclear magnetic resonance carbon spectrum measurement result of the 2- (4-methyl (triisopropylsilyl) acetylene) benzenesulfonamide (3b) is as follows:13C NMR(100MHz,CDCl3)141.8,139.9,134.4,128.3,126.2,119.3,102.3,100.0,20.1,17.62,10.32。
example tris 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenylhydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c)
To a 15mL Schlenk reaction tube, a sulfonamide compound 1c (31.5mg,0.10mmol), an alkynylating agent 2(20 μ L,0.15mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);), dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 120 ℃ for 18 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. The crude product was chromatographed on a prepared silica gel plate using a developing solvent or eluent selected from petroleum ether and ethyl acetate at a volume ratio of 3:1 to give 4- ((2Z,3E) -1-methyl-3-phenyl-2-propenyl hydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) as a yellow liquid in 89% yield (44.1 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenyl hydrazone) -2- ((triisopropylsilyl) acetylene) benzene sulfonamide (3c) is as follows:1H NMR(400MHz,CDCl3)7.97(s,1H),7.65(d,J＝8.0Hz,1H),7.23-7.19(m,3H),7.12-7.07(m,3H),6.33(s,1H),5.96(d,J＝14.4Hz,2H),2.39(s,3H),0.97-0.96(m,21H)。
the result of nuclear magnetic resonance carbon spectrum measurement of 4- ((2Z,3E) 1-methyl-3-phenyl-2-propenyl hydrazone) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3c) is as follows:13C NMR(100MHz,CDCl3)150.5,145.3,144.4,142.7,131.5,129.4,129.1,128.6,128.4,128.0,126.5,123.5,106.8,100.5,99.7,18.4,13.3,11.1。
the conversion of the synthetic reaction in the embodiment can be well compatible with multifunctional hydrazone functional groups, hydrazone can be used as a precursor of metal carbene or a carbocation ion, and allyl hydrazone can be used as a precursor of a pyrazole derivative of an important structural framework of a pesticide molecule, so that the converted product has better application potential.
Example tetrakis 4- (5-tolyl-3-trifluoromethylpyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d)
To a 15mL Schlenk reaction tube, a sulfonamide compound 1d (38.1mg,0.10mmol), an alkynylating agent 2(20 μ L,0.15mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);), dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (4.2mg,0.015mmol) or hexafluoroantimonate silver (5.0mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 110 ℃ for 24 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 3:1, 4- (5-tolyl-3-trifluoromethylmonohydropyrazolyl) - -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is obtained in 63% yield (35.3mg) as a yellow solid.
The result of nuclear magnetic resonance hydrogen spectrum measurement of 4- (5-tolyl-3-trifluoromethyl monohydroxypyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is:1H NMR(400MHz,CDCl3)8.10(s,1H),7.85-7.83(m,1H),7.37(d,J＝8.4Hz,1H),7.09(s,4H),6.74(s,1H),5.06(brs,1H),5.04(brs,1H),2.32(s,3H),0.97-0.96(m,21H)。
the result of nuclear magnetic resonance carbon spectrum measurement of 4- (5-tolyl-3-trifluoromethyl monohydroxypyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is:13C NMR(100MHz,CDCl3)145.5,143.1,142.0,138.4,130.8,128.5,128.3,127.1,125.5,124.3,123.3,103.3,99.8,98.6,20.2,17.4,10.0.
the result of nuclear magnetic resonance fluorine spectrum measurement of 4- (5-tolyl-3-trifluoromethyl monohydroxypyrazolyl) -2- ((triisopropylsilyl) acetylene) benzenesulfonamide (3d) is:19F NMR(300MHz,CDCl3)-62.4。
in the conversion of the synthetic reaction, the drug molecule celecoxib (celebrex) can be directly used as a substrate to participate in the ethynylation reaction of the direct carbon-hydrogen bond, and the celecoxib capsule can be used for relieving symptoms and signs of osteoarthritis, relieving symptoms and signs of adult rheumatoid arthritis, treating acute pain of adults and the like. Therefore, the molecule obtained by the conversion is expected to exhibit better pharmaceutical activity.
Example five 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e)
To a 15mL Schlenk reaction tube, a sulfonamide compound 1e (30.3mg,0.10mmol), an alkynylating agent 2(40 μ L,0.25mmol, when X ═ Br or I, no additional oxidant is needed; when X ═ H, AgOAc (2 equiv.);), dichloro (pentamethylcyclopentadienyl) iridium dimer (2.3mg,0.0025mmol) or dichloro (p-methylisophenyl) ruthenium dimer (1.5mg,0.0025mmol), bis (trifluoromethanesulfonyl) imide silver (3.7mg,0.010mmol) or hexafluoroantimonate silver (5.2mg,0.015mmol), cesium acetate (30mg,0.36mmol), 1, 2-dichloroethane (DCE,1mL) were sequentially added under a nitrogen atmosphere, and reacted at 100 ℃ for 8 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. The crude product was chromatographed on a preparative silica gel pad using a 3:1 volume ratio of petroleum ether to ethyl acetate eluent to give 4-N, N-dipropylsulfonamido-3- (triisopropylsilyl) ethynyl benzoyl chloride (3e) as a yellow solid in 67% yield (44.4 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of the 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e) is as follows:1H NMR(400MHz,CDCl3)8.04(s,1H),7.94(s,1H),5.71(s,1H),3.20-3.17(m,4H),1.63-1.57(m,4H),1.19-1.17(m,21H),1.12-1.10(m,21H),0.91(t,J＝7.4Hz,6H)。
the result of nuclear magnetic resonance carbon spectrum measurement of 4-N, N-dipropylsulfonamido-3, 5-di- (triisopropylsilyl) ethynyl benzoyl chloride (3e) is as follows:13C NMR(100MHz,CDCl3)164.3,154.8,146.6,140.6,132.6,127.2,123.5,118.8,104.2,104.1,100.0,50.2,22.3,19.1,18.9,12.0,11.6,11.5。
the conversion of the synthetic reaction in the embodiment can be compatible with acyl chloride functional groups, acyl chloride as an active functional group can be directly converted into esters, ketones and amides, and the tertiary sulfonamide can also well participate in the conversion, so that the conversion has potential as an important synthetic block to quickly construct molecules with biological activity.
The above examples show that the substrate in the examples of the invention is simple and easy to obtain, the synthesis steps are few, and the amide compound can be simply and efficiently prepared, so that the method has industrial application value.
The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (4)
1. A preparation method of sulfonamide compounds with the structure shown as a formula (I) is characterized by comprising the following steps:
reacting a compound of a formula (II) with a compound of a formula (III) in the presence of an inert solvent under the action of a catalyst, an oxidant and cesium acetate to obtain a compound of a formula (I);
wherein, X is hydrogen,
represents an aryl group of C6 to C10, a S, O-containing heteroaryl group of C4 to C8;
R1、R2are all hydrogen;
R3、R4、R5、R6each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro group, cyano group, chloroformyl group, -NR12R13C6-C14 aryloxy, C6-C14 aryl, substituted C6-C14 aryl, C2-C9 heteroaryl, substituted C2-C9 heteroaryl, C2-C9 heterocyclic group or substituted C2-C9 heterocyclic group,
or
R3、R4、R5、R6Wherein two adjacent groups and the carbon atom connected with the two adjacent groups form C3-C6 naphthenic base, C2-C9 heterocyclic group or takeA heterocyclic group having at least one substituent selected from the group consisting of C2 to C9;
R7is silicon base;
R12、R13each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, substituted C6-C14 aryl, C2-C9 heteroaryl, substituted C2-C9 heteroaryl, C2-C9 heterocyclic group or substituted C2-C9 heterocyclic group;
the substituted C6-C14 aryl is substituted by at least one first substituent;
the first substituent is selected from halogen, C1-C40 alkyl, C1-C10 acyl, C1-C40 alkoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, substituted C2-C9 heteroaryl, -CO2R9Cyano, -P (O) (R)11)(R12) OR-P (O) (OR)11)(OR12)；
R9、R11、R12Each independently selected from hydrogen, C1-C40 saturated aliphatic alkyl, C1-C40 unsaturated aliphatic alkyl, C6-C14 aryl, C2-C9 heteroaryl or C2-C9 heterocyclic radical;
said substituted C2-C9 heteroaryl and said substituted C2-C9 heterocyclyl are substituted with at least one second substituent;
the second substituent is selected from halogen, C1-C40 alkyl, C1-C10 acyl and C1-C40 alkoxy;
the catalyst is selected from one of dichloro (pentamethylcyclopentadienyl) iridium dimer, dichloro (p-cymene) ruthenium dimer and dichloro (pentamethylcyclopentadienyl) rhodium dimer, and one of silver bis (trifluoromethanesulfonyl) imide and silver hexafluoroantimonate;
the oxidant is selected from silver acetate, silver oxide, silver carbonate or silver nitrate;
the inert solvent is selected from tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, 1, 2-dichloroethane, diethyl ether, ethylene glycol dimethyl ether, acetonitrile, ethyl acetate, dichloromethane or acetone.
2. The preparation method according to claim 1, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:10 to 10: 1.
3. The method according to claim 1, wherein the catalyst is used in an amount of 0.1 to 20 mol% based on the compound of formula (II).
4. The preparation method according to claim 1, wherein the reaction temperature is 20 to 140 ℃;
the reaction time is 0.1-40 h.
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