CN108822145B - A kind of sulfonamide compound and its preparation method and application - Google Patents

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

A kind of sulfonamide compound and its preparation method and application

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 technique

Due to their important biological activities, sulfonamide compounds are widely used in medicine, pesticides, dyes and so on. In 1932, Bayer developed the first sulfonamide drug, prontosil, which won the Nobel Prize in Medicine in 1939. Paloxacin is the first drug that has been found to be effective against bacteria in infected organisms so far, and it has played a milestone role in the development of sulfonamide drugs. A variety of sulfonamide drugs have been used clinically, therefore, people's research interest in sulfonamide has also been stimulated. The pharmacological activities of sulfonamide derivatives mainly include: antitumor, antiviral, antibacterial, antifungal, antituberculous and antiparasitic [Wang Xiaoling, Wang Xianlong, Geng Rongxia, Zhou Chenghe, China Journal of New Drugs, 2010,19,2050.] etc. aspect. In recent decades, sulfonamides have not only developed significantly in the field of antibacterial, but also in the fields of anti-inflammatory, antiviral, and antitumor [A.-M.Monforte, P.Logoteta, S.Ferro, L.D. Luca, N.Iraci, G.Maga, E.De Clercq, C.Pannecouque, Bioorg.Med.Chem., 2009, 17, 5962.] have been developed by leaps and bounds, and some of them have been used in clinical treatment.

However, the synthesis of sulfonamides is quite challenging. On the one hand, for transition metals, sulfur atoms are often strongly coordinating functional groups and easily poison the transition metal catalysts [I.P.Beletskaya, V.P.Ananikov, Chem.Rev ., 2011, 111, 1596.]; On the other hand, in order to realize the activity of the C-H bond functional group reaction of arylsulfonamide, chemists often use additional directing groups installed on the sulfonamide to achieve reactivity and regioselectivity balance. However, this transformation requires additional introduction and removal of the guiding group, which undoubtedly increases the reaction steps, makes the reaction of sulfonamide compounds complicated, and is not conducive to the application of this type of reaction in actual production.

Therefore, research and development of a simple, efficient, and industrially valuable sulfonamide compound and its preparation method are technical problems that need to be solved urgently at present.

SUMMARY OF THE INVENTION

The invention provides a sulfonamide compound, a preparation method and application thereof, and solves the technical problem that the existing sulfonamide compound has complicated synthesis steps and is not conducive to application in actual production.

The present invention provides a sulfonamide compound having the structure represented by formula (I);

为C6～C10芳基、含S、O的C2～C9杂环或C2～C9杂芳基，R¹、R²均表示C4～C7的含N、O、S的杂环、含C4、O、S的N杂环，in,

It is a C6-C10 aryl group, a C2-C9 heterocycle containing S and O, or a C2-C9 heteroaryl group, and both R ¹ and R ² represent a C4-C7 heterocycle containing N, O, and S, and a C4, O-containing heterocycle. , the N heterocycle of S,

or

R ¹ and R ² are each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino group, alkoxy group, aryl group, benzyl group or -NHCOR ⁸ ;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, C1-C40 alkylthio group, Methylenedioxy, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro, cyano, formyl chloride, CO ₂ R ⁸ , -OC(O)R ⁹ , -P(O)(R ¹⁰ )(R ¹¹ ), -P(O)(OR ¹⁰ )(OR ¹¹ ), -NR ¹² R ¹³ , -C( O) NR ¹⁴ R ¹⁵ , C6-C14 aryloxy, C6-C14 aryl, -C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic,

or

Two adjacent groups in R ³ , R ⁴ , R ⁵ and R ⁶ and the carbon atoms to which the two adjacent groups are connected together constitute a C3-C6 cycloalkyl group or a C2-C9 heterocyclic group;

R ⁷ is selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxy group, acetoxy group, silicon group or benzene ring;

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ are each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group , C2-C9 heteroaryl or C2-C9 heterocyclyl;

R ¹⁵ is selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 arylsulfonyl group, C1-C10 alkylsulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl or C2-C9 heterocyclyl.

Preferably, R ⁵ is selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group, R ⁶ is selected from saturated aliphatic hydrocarbon group, C1-C40 unsaturated hydrocarbon group Saturated aliphatic hydrocarbon group, phenyl group, naphthyl group or C2-C9 heterocyclic group.

More preferably, R ⁵ is a C1-C10 saturated or unsaturated hydrocarbon group, and R ⁶ is a C1-C10 saturated or unsaturated hydrocarbon group.

Most preferably, ^R5 is selected from methyl or benzyl and R6 is tert ^- butyl.

Preferably, when R ⁷ is a silicon group or a benzene ring, when it is a benzene ring, the benzene ring may contain a substituent, wherein the substituent may be a halogen, a nitro group, a cyano group or a formamide group.

Silicon groups include trimethylsilyl, triisopropylsilyl or t-butyldimethylsilyl.

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 Amine, ester, cyano or phosphono.

More preferably, the substituent is selected from methyl, methoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, -NR ¹⁵ R ¹⁶ , -CO ₂ R ⁹ , cyano, Halogen, -P(O)(R ¹¹ )(R ¹² ) or -P(O)(OR ¹¹ )(OR ¹² ).

Preferably, when the C6-C14 aryl group has no substituent, the C6-C14 aryl group is selected from phenyl or naphthyl.

More preferably, when C6-C14 aryl groups contain substituents, C6-C14 aryl groups are selected from phenyl, o-tolyl, o-methoxyphenyl, o-trifluoromethylphenyl, o-arylphenyl, o-hetero- Arylphenyl, o-substituted aminophenyl, o-ester phenyl, o-cyanophenyl, o-halophenyl, m-tolyl, m-methoxyphenyl, m-substituted aminophenyl, m-trifluoro Methylphenyl, m-halophenyl, m-arylphenyl, m-heteroarylphenyl, m-esterylphenyl, m-cyanophenyl, p-tolyl, p-methoxyphenyl, p-substituted aminobenzene phenyl, p-trifluoromethylphenyl, p-halophenyl, p-esterylphenyl, p-cyanophenyl, p-arylphenyl and p-heteroarylphenyl, 2,3-bismethoxyphenyl , 1-naphthyl, 2-naphthyl or phosphonophenyl.

Preferably, the aryl group, the C2-C9 heteroaryl group and the C2-C9 heterocyclic group 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, C2-C9 heteroaryl is selected from furyl, benzofuranyl, thienyl, benzothienyl, indolyl, isoindolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, Imidazolyl, pyranyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl or carbazolyl.

More preferably, C2-C9 heteroaryl is selected from 2-furyl, 3-furyl, 2-benzofuryl, 3-benzofuryl, 2-thienyl, 3-thienyl, 2-benzofuryl thienyl, 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 tetrahydroquinolinyl, N-acyltetrahydroquinolinyl, oxazolinyl, substituted oxazolinyl, tetrahydroindolyl, N-acyltetrahydro Indolyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydrofuranyl, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl or imidazolinyl.

More preferably, the C2-C9 heterocyclic group is selected from 6-tetrahydroquinolinyl, N-acyltetrahydroquinolinyl, 5-tetrahydroindolyl, N-acyltetrahydroindolyl, oxazolinyl , substituted oxazolinyl, tetrahydroquinolinyl, tetrahydroindolyl or 2-oxazolinyl.

The present invention also proposes a preparation method of a sulfonamide compound, comprising the following steps:

In the presence of an inert solvent and under the action of a catalyst, the compound of formula (II) is reacted with the compound of formula (III) to obtain the compound of formula (I);

Wherein, X is selected from hydrogen, bromine or iodine, when X is hydrogen, described reaction needs to add oxidant,

Represents C6-C10 aryl, C4-C8 heterocycle or heteroaryl containing S and O;

R ¹ and R ² both represent N heterocycles of C4-C7, N heterocycles containing C4, O and S,

or

R ¹ and R ² are each independently selected from hydrogen, C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, substituted amino group, alkoxy group, aryl group, benzyl group or -NHCOR ⁸ ;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C1-C40 alkoxy group, C1-C40 alkylthio group, C1-C40 alkylthio group, Methylenedioxy, halogenated C1-C40 saturated aliphatic hydrocarbon group, halogenated C1-C40 unsaturated aliphatic hydrocarbon group, halogenated C1-C40 alkoxy group, halogen, nitro, cyano, formyl chloride, CO ₂ R ⁸ , -OC(O)R ⁹ , -P(O)(R ¹⁰ )(R ¹¹ ), -P(O)(OR ¹⁰ )(OR ¹¹ ), -NR ¹² R ¹³ , -C( O) NR ¹⁴ R ¹⁵ , C6-C14 aryloxy, C6-C14 aryl, -C1-C10 alkoxy, C2-C9 heteroaryl, C2-C9 heterocyclic,

or

Two adjacent groups in R ³ , R ⁴ , R ⁵ and R ⁶ and the carbon atoms to which the two adjacent groups are connected together constitute a C3-C6 cycloalkyl group or a C2-C9 heterocyclic group;

R ⁷ is selected from C1-C4 saturated aliphatic hydrocarbon group, C1-C4 unsaturated aliphatic hydrocarbon group, methoxy group, acetoxy group, silicon group or benzene ring;

R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ are each independently selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group , C2-C9 heteroaryl or C2-C9 heterocyclyl;

R ¹⁵ is selected from hydrogen, C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, C6-C14 aryl group, C6-C14 arylsulfonyl group, C1-C10 alkylsulfonyl group, C1-C10 acyl group, C2-C9 heteroaryl or C2-C9 heterocyclyl.

Wherein, the compound of formula (II) is an arylsulfonamide compound, and the compound of formula (III) is a terminal alkyne compound.

Preferably, X is selected from hydrogen or bromine.

Preferably, R ⁵ is selected from C1-C40 saturated aliphatic hydrocarbon group, C1-C40 unsaturated aliphatic hydrocarbon group, phenyl, naphthyl or C2-C9 heterocyclic group, R ⁶ is selected from C1-C40 saturated aliphatic hydrocarbon group, C1 ~C40 unsaturated aliphatic hydrocarbon group, phenyl group, naphthyl group or C2~C9 heterocyclic group.

More preferably, R ⁵ is a C1-C10 saturated or unsaturated hydrocarbon group, and R ⁶ is a C1-C10 saturated or unsaturated hydrocarbon group;

Most preferably, R ⁵ is selected from methyl or benzyl, and R ⁶ is tert-butyl;

Preferably, when R ⁷ is a silicon group or a benzene ring, when it is a benzene ring, the benzene ring may contain a substituent, wherein the substituent may be a halogen, a nitro group, a cyano group or a formamide group. Silicon groups include trimethylsilyl, triisopropylsilyl or t-butyldimethylsilyl.

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 Amine, ester, cyano or phosphono.

More preferably, the first substituent is selected from methyl, methoxy, trifluoromethyl, C6-C14 aryl, C2-C9 heteroaryl, -NR ¹⁵ R ¹⁶ , -CO ₂ R ⁹ , cyano group, halogen, -P(O)(R ¹¹ )(R ¹² ) or -P(O)(OR ¹¹ )(OR ¹² ).

Preferably, when the C6-C14 aryl group does not contain the first substituent, the C6-C14 aryl group is selected from phenyl or naphthyl.

More preferably, when C6-C14 contains the first substituent, C6-C14 arylaryl is selected from phenyl, o-tolyl, o-methoxyphenyl, o-trifluoromethylphenyl, o-arylphenyl, o-heteroarylphenyl, o-substituted aminophenyl, o-ester phenyl, o-cyanophenyl, o-halophenyl, m-tolyl, m-methoxyphenyl, m-substituted aminophenyl, m Trifluoromethylphenyl, m-halophenyl, m-arylphenyl, m-heteroarylphenyl, m-esterylphenyl, m-cyanophenyl, p-tolyl, p-methoxyphenyl, p-substituted amine phenyl, p-trifluoromethylphenyl, p-halophenyl, p-esterylphenyl, p-cyanophenyl, p-arylphenyl and p-heteroarylphenyl, 2,3-bismethoxyphenyl Phenyl, 1-naphthyl, 2-naphthyl or phosphonophenyl.

Preferably, the aryl group, the C2-C9 heteroaryl group and the C2-C9 heterocyclic group 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, C2-C9 heteroaryl is selected from furyl, benzofuranyl, thienyl, benzothienyl, indolyl, isoindolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, Imidazolyl, pyranyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl or carbazolyl.

More preferably, C2-C9 heteroaryl is selected from 2-furyl, 3-furyl, 2-benzofuryl, 3-benzofuryl, 2-thienyl, 3-thienyl, 2-benzofuryl thienyl, 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 tetrahydroquinolinyl, N-acyltetrahydroquinolinyl, oxazolinyl, substituted oxazolinyl, tetrahydroindolyl, N-acyltetrahydro Indolyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydrofuranyl, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl or imidazolinyl.

More preferably, the C2-C9 heterocyclic group 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 1:10-10:1.

More preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:3 to 1:1, more preferably 1:2 to 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,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone , dimethyl sulfoxide, 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 dichloro(pentamethylcyclopentadienyl)iridium dimer, dichloro(p-methylcumene)ruthenium dimer, dichloro(pentamethylcyclopentadienyl)dimer alkenyl) rhodium dimer, silver bis(trifluoromethanesulfonyl)imide or silver hexafluoroantimonate.

More preferably, the catalyst is selected from the group consisting of dichloro(pentamethylcyclopentadienyl) iridium dimer, dichloro(p-methylcumene) ruthenium dimer, bis(trifluoromethanesulfonyl)imide Silver amine or 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 dosage of the catalyst is 0.1-20 mol% of the dosage of the compound of formula (II).

More preferably, the catalyst is used in an amount of 0.2-20 mol% of the amount of the compound of formula (II), more preferably 0.5-15 mol%, most preferably 2.5 mol% or 15 mol%.

Preferably, the reaction temperature is 20-140°C;

The reaction time is 0.1-40h.

More preferably, the reaction temperature is 80-120° C., and the reaction time is 12-24 h.

The present invention also provides an application of the sulfonamide compound or the sulfonamide compound obtained by the preparation method of the sulfonamide compound in the synthesis of medicines.

Common primary and secondary sulfonamides are relatively readily available raw materials, and the introduction of multifunctional and easily transformable functional groups directly on such sulfonamide functional groups will provide a rapid construction of complex sulfonamides. Derivative method, based on the potential biological activity of sulfonamide molecules, we can directly carry out the late derivatization reaction of drug molecules containing sulfonamide, which will provide a new idea for the development of new sulfonamide drugs, and will also provide new ideas for the development of new sulfonamide drugs. Rapid construction of drug molecule libraries provides new methods [P.R.Patel, C. Ramalingan, Y.-T.Park, Bioorg.Med.Chem., 2007, 17, 6610.].

The present invention uses simple and readily available primary and secondary sulfonamides as substrates, and realizes the alkynylation reaction of the carbon-hydrogen bonds of common sulfonamides through C-H activation, in order to pass the subsequent efficient conversion of carbon-carbon triple bonds. However, This type of reaction is chemoselective: that is, the competition reaction of the N-H bond of the primary and secondary sulfonamide with the functionalization of the aromatic ring C-H bond, given the bond energy of the N-H bond and the aryl C-H bond, and the discovery of sulfonamide by Stahl et al. The N-H bond of sulfonamide has better reactivity [T.Hamada, X.Ye, S.S.Stahl, J.Am.Chem.Soc., 2008, 130, 833.], therefore, the selectivity is achieved in the presence of sulfonamide N-H bond Activating C-H bonds is challenging.

Alkynyl, as an important functional group in the fields of materials and medicines, can be easily converted into other functional groups, such as alkyl and alkene; it can also be easily converted into multifunctional groups through electrophilic addition, nucleophilic addition and other reactions. At the same time, alkynes can also be applied to organisms through Click reaction. It can be seen that the direct introduction of alkynyl moieties into molecules is very practical. At present, the direct introduction of alkynyl groups into molecules faces challenges such as few existing synthetic methods, low synthesis efficiency, difficult to obtain raw materials, and easy self-coupling of alkynyl groups. It should be pointed out that there are no reports on simple primary and secondary sulfonamide-directed alkynylation reactions. Therefore, the development of common primary and secondary sulfonamide-promoted C-H functionalization reactions without additional directing groups is highly anticipated.

It should be noted that the ortho-alkynylated sulfonamide products obtained by the preparation method of the present invention, especially based on the synthesis methods before the primary and secondary sulfonamide products and their lack thereof, mainly focus on the sulfonamide substituted by the ortho-halogen. coupling reactions for which substrates are extremely difficult to obtain.

To sum up, the present invention has the following advantages:

1. The present invention adopts primary and secondary sulfonamide as substrates to prepare sulfonamide compounds, and the raw materials are simple and easy to obtain;

2. The alkynylation reaction of the direct carbon-hydrogen bond of ordinary primary and secondary amides without the assistance of an additional guiding group in the present invention has few steps, simple and convenient operation, economical and environmental protection, and has industrial application value;

3. The present invention does not need to install additional guiding groups such as pyridine or quinoline on the nitrogen atom of the sulfonamide in the process of preparing the arylsulfonamide compounds, so that the guiding group does not need to be removed through harsh conditions, and only needs to be removed. The hydrogen atoms or halogen atoms of the two substrates have good atom economy;

4. The aromatic ring ortho-alkynyl-substituted sulfonamide derivatives prepared by the present invention can be used as very multifunctional synthons to further synthesize more complex functional molecules, which can be rapidly transformed by the chemically rich alkynyl groups (such as through regio- and stereoselective electrophilic addition, affinity addition, etc.), and the intramolecular amine functionalization reaction can be realized directly by means of catalysis to obtain polysubstituted cyclic cyclic compounds that are widely used in medicine. sulfonamide molecules, providing a modular synthesis method for the diversified synthesis of such drug molecules;

5. The sulfonamide compound prepared by the present invention is a brand-new sulfonamide compound, which can be used as a simple organic raw material for synthesizing complex molecules, and is widely used in the fields of medicine and materials;

6. The preparation method of the present invention has good chemical selectivity, that is, the reaction only occurs on the carbon-hydrogen bond, and does not act on the nitrogen-hydrogen bond, that is, the nitrogen-hydrogen bond of the amide remains unchanged during the reaction process;

7. The preparation method of the present invention has very good regioselectivity, that is, the reaction only occurs at the ortho position of the benzene ring of the arylsulfonamide, and no product substituted by an alkynyl group at the meta or para position of the benzene ring is observed. This is impossible to achieve by direct electrophilic substitution reaction in the past.

Description of drawings

In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only These are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained based on these drawings without any creative effort.

Fig. 1 2-((triisopropylsilyl)acetylene)benzenesulfonamide (3a) nuclear magnetic resonance ¹ H spectrum provided in Example 1 of the present invention;

2-((triisopropylsilyl)acetylene)benzenesulfonamide (3a) nuclear magnetic resonance ^13C spectrum provided in Example 1 of the present invention;

Figure 3 4-methyl-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3b) nuclear magnetic resonance ¹ H spectrum provided in Example 2 of the present invention;

Figure 4 4-methyl-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3b) nuclear magnetic resonance ^13C spectrum provided in Example 2 of the present invention;

Figure 5 4-((2Z,3E)1-methyl-3-phenyl-2-propenylhydrazone)-2-((triisopropylsilyl)acetylene)benzenesulfone provided in Example 3 of the present invention ^1H NMR spectrum of amide (3c);

Figure 6 4-((2Z,3E)1-methyl-3-phenyl-2-propenylhydrazone)-2-((triisopropylsilyl)acetylene)benzenesulfone provided in Example 3 of the present invention ^13C NMR spectrum of amide (3c);

Figure 7 4-(5-Tolyl-3-trifluoromethylmonohydropyrazolyl)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3d) provided in Example 4 of the present invention Nuclear magnetic resonance ¹ H spectrum;

Figure 8 4-(5-Tolyl-3-trifluoromethylmonohydropyrazolyl)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3d) provided in Example 4 of the present invention Nuclear magnetic resonance ¹³ C spectrum;

Figure 9 4-N,N-dipropylsulfonamido-3,5-bis-(triisopropylsilyl)ethynylbenzoyl chloride (3e) nuclear magnetic resonance ¹ H spectrum provided in Example 5 of the present invention picture;

Figure 10 4-N,N-dipropylsulfonamido-3,5-bis-(triisopropylsilyl)ethynylbenzoyl chloride (3e) nuclear magnetic resonance ^13C spectrum provided in Example 5 of the present invention picture.

Detailed ways

The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, other embodiments obtained by persons of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The sulfonamide compounds provided by the present invention and the raw materials and reagents used in the preparation method and application thereof can be purchased from the market.

A sulfonamide compound provided by the present invention and its preparation method and application are further described below.

Example one 2-((triisopropylsilyl)acetylene)benzenesulfonamide (3a)

Under nitrogen atmosphere, arylsulfonamide compound 1a (14.4 mg, 0.10 mmol), alkynylation reagent 2 (28 μL, 0.20 mmol, when X=Br or I, no additional oxidizing agent was added in sequence to a 15 mL Schlenk reaction tube; AgOAc (2equiv.);), dichloro(pentamethylcyclopentadienyl)iridium dimer (2.3 mg, 0.0025 mmol) or dichloro(p-cymene) are required when X=H Ruthenium dimer (1.5mg, 0.0025mmol), silver bis(trifluoromethanesulfonyl)imide (4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36 mmol), 1,2-dichloroethane (DCE, 1 mL), and reacted at 120°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, and concentrated to obtain a crude product. The crude product is separated by chromatography on the prepared silica gel plate, and the selected developing solvent or eluent is petroleum ether and the volume ratio of ethyl acetate is 3:1 to obtain the product 2-((triisopropylsilyl)acetylene ) Benzenesulfonamide (3a): yellow liquid, yield 63% (21.2 mg).

2-((triisopropylsilyl)acetylene)benzenesulfonamide (3a) H NMR spectrum measurement results are: ¹ H NMR (400MHz, CDCl ₃ )δ8.03-8.01(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).

2-((Triisopropylsilyl)acetylene)benzenesulfonamide (3a) C NMR spectrum measurement results are: ¹³ C NMR (100MHz, CDCl ₃ )δ142.5, 134.0, 131.0, 127.7, 126.1, 119.4, 102.2, 100.7, 17.6, 10.3.

Example two 4-methyl-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3b)

Under nitrogen atmosphere, arylsulfonamide compound 1b (17.1 mg, 0.10 mmol), alkynylation reagent 2 (20 μL, 0.15 mmol, when X=Br or I, no additional oxidizing agent was added in sequence to a 15 mL Schlenk reaction tube; When X=H, AgOAc (2equiv.);), dichloro(pentamethylcyclopentadienyl)iridium dimer (2.3 mg, 0.0025 mmol) or dichloro(p-cymene) are required Ruthenium dimer (1.5mg, 0.0025mmol), silver bis(trifluoromethanesulfonyl)imide (4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36 mmol), 1,2-dichloroethane (DCE, 1 mL), and reacted at 120°C for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, and concentrated to obtain a crude product. The crude product is separated by chromatographic separation with the prepared silica gel plate, and the selected developing agent or eluent is that the volume ratio of petroleum ether and ethyl acetate is 3:1 to obtain the product 2-(4-methyl-2-(( Triisopropylsilyl)acetylene)benzenesulfonamide (3b): yellow liquid, 38% yield (13.4 mg).

2-(4-Methyl(triisopropylsilyl)acetylene)benzenesulfonamide (3b) H NMR spectrum measurement result: ¹ H NMR (400MHz, CDCl ₃ )δ7.90(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).

2-(4-Methyl (triisopropylsilyl) acetylene) benzenesulfonamide (3b) carbon nuclear magnetic resonance spectrum measurement results are: ¹³ C NMR (100MHz, CDCl ₃ )δ141.8,139.9,134.4,128.3,126.2, 119.3, 102.3, 100.0, 20.1, 17.62, 10.32.

Example three 4-((2Z,3E)1-methyl-3-phenyl-2-propenylhydrazone)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3c)

Under nitrogen atmosphere, sulfonamide compound 1c (31.5 mg, 0.10 mmol), alkynylation reagent 2 (20 μL, 0.15 mmol) were added to a 15 mL Schlenk reaction tube in sequence, when X=Br or I, no additional oxidant was required; when X=Br or I, no additional oxidant was required; =H, AgOAc (2equiv.);), dichloro(pentamethylcyclopentadienyl)iridium dimer (2.3 mg, 0.0025 mmol) or dichloro(p-methylcumene)ruthenium bismuth are required Polymer (1.5mg, 0.0025mmol), silver bis(trifluoromethanesulfonyl)imide (4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36mmol) ), 1,2-dichloroethane (DCE, 1 mL), and reacted at 120° C. for 18 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, and concentrated to obtain a crude product. The crude product is separated by chromatography on the prepared silica gel plate, and the selected developing agent or eluent is petroleum ether and the volume ratio of ethyl acetate is 3:1 to obtain the product 4-((2Z,3E)-1-methyl. yl-3-phenyl-2-propenylhydrazone)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3c), yellow liquid, yield 89% (44.1 mg).

Result of 4-((2Z,3E)1-methyl-3-phenyl-2-propenylhydrazone)-2-((triisopropylsilyl)acetylene)benzenesulfonamide(3c) H NMR are: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.65 (d, J=8.0 Hz, 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).

4-((2Z,3E)1-methyl-3-phenyl-2-propenylhydrazone)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3c) CNMR measurement results As: ¹³ C NMR (100 MHz, CDCl ₃ ) δ 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 transformation of the synthesis reaction in this example can be well compatible with the multifunctional hydrazone functional group, and the hydrazone can be used as the precursor of metal carbene or carbocation, and the allyl hydrazone can be used as the pyrazole derivative of the important structural skeleton of the pesticide molecule Therefore, the product of this transformation has good potential for application.

Example 4 4-(5-Tolyl-3-trifluoromethylmonohydropyrazolyl)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3d)

Under nitrogen atmosphere, sulfonamide compound 1d (38.1 mg, 0.10 mmol), alkynylation reagent 2 (20 μL, 0.15 mmol) were sequentially added to a 15 mL Schlenk reaction tube, when X=Br or I, no additional oxidizing agent was required; =H, AgOAc (2equiv.);), dichloro(pentamethylcyclopentadienyl)iridium dimer (2.3 mg, 0.0025 mmol) or dichloro(p-methylcumene)ruthenium bismuth are required Polymer (1.5mg, 0.0025mmol), silver bis(trifluoromethanesulfonyl)imide (4.2mg, 0.015mmol) or silver hexafluoroantimonate (5.0mg, 0.015mmol), cesium acetate (30mg, 0.36mmol) ), 1,2-dichloroethane (DCE, 1 mL), and reacted at 110° C. for 24 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, and concentrated to obtain a crude product. The crude product is separated by chromatography on the prepared silica gel plate, and the selected developing agent or eluent is petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain 4-(5-methylphenyl-3-trifluoromethane). (3d), yellow solid, yield 63% (35.3 mg).

4-(5-Tolyl-3-trifluoromethylmonohydropyrazolyl)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3d) H NMR spectroscopy results: ¹ H NMR (400MHz, CDCl ₃ ) δ 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).

4-(5-Tolyl-3-trifluoromethylmonohydropyrazolyl)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3d) CNMR measurement results: ¹³ C NMR (100MHz, CDCl ₃ ) δ145.5, 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.

4-(5-Tolyl-3-trifluoromethyl-monohydropyrazolyl)-2-((triisopropylsilyl)acetylene)benzenesulfonamide (3d) NMR fluorine spectrum determined: ¹⁹ F NMR (300 MHz, _CDCl3 ) delta-62.4.

The transformation of the synthesis reaction in this example can directly use the drug molecule celebrex as a substrate to participate in the alkynylation reaction of the direct carbon-hydrogen bond, and celecoxib capsules can be used to relieve the symptoms and signs of osteoarthritis , Relieve the symptoms and signs of rheumatoid arthritis in adults, and treat acute pain in adults. Therefore, the transformed molecules are expected to exhibit better medicinal activities.

Example 5 4-N,N-dipropylsulfonamido-3,5-bis-(triisopropylsilyl)ethynylbenzoyl chloride (3e)

Under nitrogen atmosphere, sulfonamide compound 1e (30.3 mg, 0.10 mmol), alkynylation reagent 2 (40 μL, 0.25 mmol) were sequentially added to a 15 mL Schlenk reaction tube, when X=Br or I, no additional oxidizing agent was needed; =H, AgOAc (2equiv.);), dichloro(pentamethylcyclopentadienyl)iridium dimer (2.3 mg, 0.0025 mmol) or dichloro(p-methylcumene)ruthenium bismuth are required Polymer (1.5mg, 0.0025mmol), silver bis(trifluoromethanesulfonyl)imide (3.7mg, 0.010mmol) or silver hexafluoroantimonate (5.2mg, 0.015mmol), cesium acetate (30mg, 0.36mmol) ), 1,2-dichloroethane (DCE, 1 mL), and reacted at 100° C. for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, and concentrated to obtain a crude product. The crude product is separated by chromatography on the prepared silica gel plate, and the selected eluent is that the volume ratio of petroleum ether and ethyl acetate is 3:1 to obtain 4-N,N-dipropylsulfonamido-3-( Triisopropylsilyl)ethynylbenzoyl chloride (3e), yellow solid, 67% yield (44.4 mg).

4-N,N-Dipropylsulfonamido-3,5-bis-(triisopropylsilyl)ethynylbenzoyl chloride (3e) H NMR spectrum determined as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.04(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).

4-N,N-dipropylsulfonamido-3,5-bis-(triisopropylsilyl)ethynylbenzoyl chloride (3e) was determined by carbon nuclear magnetic resonance spectrum: ¹³ C NMR (100MHz, CDCl ₃ ) δ164.3, 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 transformation of the synthesis reaction in this example can be compatible with the acid chloride functional group, and the acid chloride as an active functional group can be directly transformed into ester, ketone, amide, and tertiary sulfonamide can also participate in this kind of transformation well, so this transformation has the potential as an important synthetic building blocks to rapidly construct biologically active molecules.

It can be seen from the above examples that the substrates in the embodiments of the present invention are simple and easy to obtain, have few synthesis steps, and can simply and efficiently prepare amide compounds, which have industrial application value.

As mentioned above, the above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand: The technical solutions described in the embodiments are modified, or some technical features thereof are equivalently replaced; and these modifications or replacements do not make the essence of the corresponding technical solutions depart from the spirit and scope of the 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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