阅读说明：本技术 一种磺胺类化合物的合成方法 (Synthetic method of sulfonamide compound ) 是由 练仲 贾秀稳 于 2020-11-20 设计创作，主要内容包括：本发明属于有机合成技术领域,具体涉及一种磺胺类化合物的合成方法。针对现有技术中磺胺类化合物合成方法的缺陷,本发明的技术方案是：向芳基碘代物和胺的混合物溶液通入SO_2气体进行反应,得到磺胺类化合物。本发明进一步提供了一种新的SO_2气体的产生方式,并且与two-chamber(两腔式)反应系统相结合,将原位生成的二氧化硫气体直接插入芳基碘代物和胺中,一步生成磺酰胺类化合物。该发明提供的合成方法原料来源广泛、廉价易得；反应操作简单；底物普适性强；经济实用。因此,本发明具有很强的实用价值和广泛的应用前景。(The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a sulfonamide compound. Aiming at the defects of the synthesis method of the sulfonamide compound in the prior art, the technical scheme of the invention is as follows: introducing SO into a mixture solution of aryl iodide and amine 2 Reacting the gas to obtain the sulfonamide compound. The invention further provides a novel SO 2 The generation mode of the gas is combined with a two-chamber reaction system, sulfur dioxide gas generated in situ is directly inserted into aryl iodide and amine, and sulfonamide compounds are generated in one step. The synthesis method provided by the invention has the advantages that the raw materials are wide in source, cheap and easy to obtain; the reaction operation is simple; the substrate universality is strong; is economical and practical. Therefore, the invention has strong practical value and wide application prospect.)

1. A synthesis method of sulfonamide compounds is characterized in that SO is introduced into a mixture solution of aryl iodide and amine₂Reacting the gas to obtain the sulfonamide compound.

2. A synthesis process according to claim 1, characterized in that the reaction is carried out by the following reaction scheme:

reacting the compound 3 with SO₂Reacting the gas with the compound 4 to obtain a sulfonamide compound;

wherein Ar is selected from the group consisting of at least one R_Ar1Substituted or unsubstituted C₆～C₂₀An aryl group;

the R is_Ar1Each independently selected from C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy radical, C₁～C₁₀Alkylthio radical, C₆～C₂₀Aryloxy radical, quilt R_Ar2Substituted or unsubstituted C₃-C₁₀Cycloalkyl radical, C₆～C₂₀Aryl, halogen, by R_Ar2A substituted or unsubstituted 3-to 20-membered heteroaryl; the halogen is selected from F, Cl or Br;

or two R_Ar1Are linked to form a quilt R_Ar2A substituted or unsubstituted 3-to 20-membered heteroaryl;

the R is_Ar2Each independently selected from halogen substituted or unsubstituted C₆～C₂₀Aryl, halogen substituted or unsubstituted C₁～C₁₀An alkyl group; the halogen is selected from F, Cl or Br;

the R is₁、R₂Each is independently selected from R₃Substituted or unsubstituted C₁～C₁₀An alkyl group;

or R₁And R₂Are linked to form R₃Substituted or unsubstituted 3-to 20-membered heteroaryl, R₃A substituted or unsubstituted 3-to 20-membered heterocycloalkyl group;

the R is₃Each independently selected from substituted or unsubstituted C₁～C₁₀Alkyl, substituted or unsubstituted C₆～C₂₀Aryl, substituted or unsubstituted siloxane, substituted or unsubstituted 3-20 membered heteroaryl, substituted or unsubstituted 3-20 membered heterocycloalkyl, or halogen; the substituent is selected from C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy, fluoro substituted C₁～C₄Alkyl radical, C₆～C₂₀Aryl, halogen, C₁～C₁₀An ester group or a tertiary amine group; the halogen is selected from F, Cl or Br.

3. A method of synthesis according to claim 2, characterized in that:

ar is selected from the group consisting of at least one R_Ar1Substituted or unsubstituted C₆～C₁₀Aryl radical, by at least one R_Ar1A substituted or unsubstituted 5-to 13-membered heteroaryl;

the R is_Ar1Each of which isIs independently selected from C₁～C₄Alkyl radical, C₁～C₂Alkoxy, methylthio, phenoxy, propyl substituted C₆Cycloalkyl, phenyl, halogen; the halogen is selected from F, Cl or Br;

or two R_Ar1Linked to form a phenyl-substituted 9-membered heteroaryl.

4. A method of synthesis according to claim 2, characterized in that:

the R is₁、R₂Each is independently selected from R₃Substituted or unsubstituted C₁～C₈An alkyl group;

or R₁And R₂Are linked to form R₃Substituted or unsubstituted 9-to 11-membered heteroaryl, R₃A substituted or unsubstituted 6-to 9-membered heterocycloalkyl group;

the R is₃Each independently selected from benzyl, substituted or unsubstituted C₆～C₁₀Aryl, heteroaryl, and heteroaryl,

The substituent is selected from halogen, trifluoromethyl and methoxy.

5. A synthesis process according to claim 1 or 2, characterized in that the sulphonamide compound is chosen from:

6. a method of synthesis according to claim 1, characterized in that:

the reaction is carried out under the combined action of a reagent A, a reagent B and a palladium catalyst, wherein the reagent A is selected from at least one of nitrogen-containing organic bases or inorganic bases, preferably the nitrogen-containing organic bases or inorganic bases are selected from DMAP, DABCO, KF and K₃PO₄And Cs₂CO₃Is selected from at least one of phosphine ligands or nitrogen ligands; preferably, the phosphine ligand or nitrogen ligand is selected from nBuPAD₂At least one of bipyridine, tricyclohexylphosphine, triphenylphosphine, 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, 4, 5-diazofluoren-9-one and 2,2':6', 2' -tripyridine, preferably, the palladium catalyst is selected from Pd (acac)₂、Pd(OAc)₂、Pd(dba)₂、Pd(PPh₃)₄And Pd (tBu)₃P)₂At least one of; preferably, the aryl iodide, amine, SO₂The dosage ratio of the gas to the reagent A is 1 (1.2-2.6): 3.0-7.0): 1.5-2.5), the dosage of the reagent B is 5.0-25.0 mol% of the dosage of the aryl iodide, and the dosage of the palladium catalyst is 2.5-12.5 mol% of the dosage of the aryl iodide.

And/or the concentration of the aryl iodide in the reaction system is 0.05-0.2 mmol/ml;

and/or, the reaction is carried out in the solvent DMSO;

and/or the reaction temperature of the reaction is 90-110 ℃, preferably 95 ℃.

7. The method of synthesis according to claim 6, wherein: the reagent A is DMAP, and the reagent B is nBuPAD₂The palladium catalyst is Pd (acac)₂。

8. A synthesis method according to any one of claims 1 to 7, characterized in that: the SO₂Gas channelProduced by the following reaction:

SO is generated by reacting the compound 1 with the compound 2₂A gas.

9. A method of synthesis according to claim 8, characterized in that:

the reaction of the compound 1 and the compound 2 is carried out in a saturated alkane solvent; preferably, the saturated alkane solvent is selected from at least one of n-hexane, n-heptane, octane, undecane, dodecane, tridecane or tetradecane;

and/or the temperature of the reaction of the compound 1 and the compound 2 is 90-110 ℃, preferably 95 ℃.

10. A method of synthesis according to claim 8, characterized in that: the synthesis is carried out in a reaction container A and a reaction container B which are communicated, the reaction of the compound 1 and the compound 2 is carried out in the reaction container A, and the SO is₂Gas enters the reaction vessel B through the communication part of the reaction vessel A and the reaction vessel B, and the mixture solution of the aryl iodide and the amine and SO₂The gas reacts in the reaction vessel B.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a sulfonamide compound.

Background

Sulfonamides have a wide range of important uses. For example, in the field of medicine, many important drug molecules and active intermediates are sulfonamides, such as quinolone antibacterial drug enoxacin, tricyclic antidepressant drug amoxapine, antihistamine desloratadine, dopamine D1 agonist fenoldopam intermediate, and the like. The artificially synthesized sulfanilamide medicine is used as an antibacterial medicine for nearly 50 years in clinic, and has the advantages of wide antibacterial spectrum, stable property, simple and convenient use, no grain consumption in production and the like. Particularly, after the discovery of Trimethoprim (TMP), an antibacterial synergist in 1969, the combined application of trimethoprim and sulfanilamide can enhance the antibacterial effect and enlarge the treatment range, so that the sulfanilamide is an important chemotherapeutic drug although a large number of antibiotics are available. In addition, in the agricultural field, sulfonamides such as Azisulfuron and azosulfuron are commonly used herbicides.

The traditional synthesis method of sulfanilamide compounds is generally that chlorosulfonic acid or sulfur-containing compounds such as thiophenol, mercaptan, thioether and the like are converted to generate sulfonyl chloride, and then the sulfonyl chloride and amine react to prepare the sulfanilamide compounds. Problems with this synthetic route include: long reaction route, multiple steps, low yield, need of strong acid in the reaction process, generation of organic sulfide with bad smell, and non-conformity with atom economy.

In order to overcome the defects of the traditional synthesis method of the sulfonamide compounds, a new synthesis route is proposed later: aryl halide catalyzed by palladium, DABCO-sulfur dioxide complex and hydrazine compounds are subjected to three-component series reaction to obtain aryl sulfonamide compounds. However, in the above reaction, the applicable range of the substrate for the amidosulfonylation of the aryl halide is limited to the hydrazine compounds, and only a specific kind of sulfonamide compounds can be synthesized.

Therefore, there is still a need for further improvement of the synthesis method of sulfonamides, so that sulfonamides can be produced more simply, economically and environmentally.

Disclosure of Invention

Aiming at the defects of the existing synthesis method of the sulfonamide compound, the invention provides a synthesis method of the sulfonamide compound, which aims to: provides a simple, economic and environment-friendly synthesis method of the sulfonamide compound, so that the sulfonamide compound is more suitable for industrial large-scale production.

A process for synthesizing sulfanilamide compound includes such steps as introducing SO to the mixture of aryl iodide and amine₂Reacting the gas to obtain the sulfonamide compound.

Preferably, the reaction is carried out by the following reaction formula:

reacting the compound 3 with SO₂Reacting the gas with the compound 4 to obtain a sulfonamide compound;

wherein Ar is selected from at least oneR is_Ar1Substituted or unsubstituted C₆～C₂₀An aryl group;

the R is_Ar1Each independently selected from C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy radical, C₁～C₁₀Alkylthio radical, C₆～C₂₀Aryloxy radical, quilt R_Ar2Substituted or unsubstituted C₃-C₁₀Cycloalkyl radical, C₆～C₂₀Aryl, halogen, by R_Ar2A substituted or unsubstituted 3-to 20-membered heteroaryl; the halogen is selected from F, Cl or Br;

or two R_Ar1Are linked to form a quilt R_Ar2A substituted or unsubstituted 3-to 20-membered heteroaryl;

the R is_Ar2Each independently selected from halogen substituted or unsubstituted C₆～C₂₀Aryl, halogen substituted or unsubstituted C₁～C₁₀An alkyl group; the halogen is selected from F, Cl or Br;

the R is₁、R₂Each is independently selected from R₃Substituted or unsubstituted C₁～C₁₀An alkyl group;

or R₁And R₂Are linked to form R₃Substituted or unsubstituted 3-to 20-membered heteroaryl, R₃A substituted or unsubstituted 3-to 20-membered heterocycloalkyl group;

the R is₃Each independently selected from substituted or unsubstituted C₁～C₁₀Alkyl, substituted or unsubstituted C₆～C₂₀Aryl, substituted or unsubstituted siloxane, substituted or unsubstituted 3-20 membered heteroaryl, substituted or unsubstituted 3-20 membered heterocycloalkyl, or halogen; the substituent is selected from C₁～C₁₀Alkyl radical, C₁～C₁₀Alkoxy, fluoro substituted C₁～C₄Alkyl radical, C₆～C₂₀Aryl, halogen, C₁～C₁₀An ester group or a tertiary amine group; the halogen is selected from F, Cl or Br.

Preferably, Ar is selected from the group consisting of at least one R_Ar1Substituted or unsubstituted C₆～C₁₀Aryl radical, is at least oneR_Ar1A substituted or unsubstituted 5-to 13-membered heteroaryl;

the R is_Ar1Each independently selected from C₁～C₄Alkyl radical, C₁～C₂Alkoxy, methylthio, phenoxy, propyl substituted C₆Cycloalkyl, phenyl, halogen; the halogen is selected from F, Cl or Br;

or two R_Ar1Linked to form a phenyl-substituted 9-membered heteroaryl.

Preferably, said R is₁、R₂Each is independently selected from R₃Substituted or unsubstituted C₁～C₈An alkyl group;

or R₁And R₂Are linked to form R₃Substituted or unsubstituted 9-to 11-membered heteroaryl, R₃A substituted or unsubstituted 6-to 9-membered heterocycloalkyl group;

the R is₃Each independently selected from benzyl, substituted or unsubstituted C₆～C₁₀Aryl, heteroaryl, and heteroaryl,

The substituent is selected from halogen, trifluoromethyl and methoxy. Preferably, the sulfonamide compound is selected from:

preferably, the reaction is carried out in three reagents, reagent A, reagent B and palladium catalystUnder the combined action, the reagent A is selected from at least one of nitrogen-containing organic base or inorganic base, preferably, the nitrogen-containing organic base or inorganic base is selected from DMAP, DABCO, KF and K₃PO₄And Cs₂CO₃Is selected from at least one of phosphine ligands or nitrogen ligands; preferably, the phosphine ligand or nitrogen ligand is selected from nBuPAD₂At least one of bipyridine, tricyclohexylphosphine, triphenylphosphine, 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, 4, 5-diazofluoren-9-one and 2,2':6', 2' -tripyridine, preferably, the palladium catalyst is selected from Pd (acac)₂、Pd(OAc)₂、Pd(dba)₂、Pd(PPh₃)₄And Pd (tBu)₃P)₂At least one of; preferably, the aryl iodide, amine, SO₂The dosage ratio of the gas to the reagent A is 1 (1.2-2.6): 3.0-7.0): 1.5-2.5), the dosage of the reagent B is 5.0-25.0 mol% of the dosage of the aryl iodide, and the dosage of the palladium catalyst is 2.5-12.5 mol% of the dosage of the aryl iodide.

And/or the concentration of the aryl iodide in the reaction system is 0.05-0.2 mmol/ml;

and/or, the reaction is carried out in the solvent DMSO;

and/or the reaction temperature of the reaction is 90-110 ℃, preferably 95 ℃.

Preferably, the reagent A is DMAP and the reagent B is nBuPAD₂The palladium catalyst is Pd (acac)₂。

Preferably, the SO₂The gas is generated by the reaction:

SO is generated by reacting the compound 1 with the compound 2₂A gas.

Preferably, the reaction of the compound 1 and the compound 2 is carried out in a saturated alkane solvent; preferably, the saturated alkane solvent is selected from at least one of n-hexane, n-heptane, octane, undecane, dodecane, tridecane or tetradecane;

and/or the temperature of the reaction of the compound 1 and the compound 2 is 90-110 ℃, preferably 95 ℃.

Preferably, the synthesis is carried out in a reaction vessel A and a reaction vessel B which are communicated, the reaction of the compound 1 and the compound 2 is carried out in the reaction vessel A, and the SO is₂Gas enters the reaction vessel B through the communication part of the reaction vessel A and the reaction vessel B, and the mixture solution of the aryl iodide and the amine and SO₂The gas reacts in the reaction vessel B.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.

Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix C_a～C_bAlkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C₁～C₄The alkyl group means an alkyl group having 1 to 4 carbon atoms.

"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C₁-C₆Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, iso-pentyl)Pentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C₁-C₆An alkoxy group.

"alkoxy" refers to an alkyl group attached to an oxygen atom through which the molecule is substituted.

"alkylthio" refers to a group in which an alkyl group is attached to a sulfur atom, and the molecule is substituted by the sulfur atom.

"cycloalkyl" refers to a saturated or partially saturated cyclic group having from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.

"alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 10 carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least 1 site of vinyl unsaturation (> C ═ C <). For example, (Ca-Cb) alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like.

"alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6) alkynyl is intended to include ethynyl, propynyl, and the like.

"halogen" is fluorine, chlorine, bromine or iodine.

"heterocycle", "heterocycloalkyl" refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;

"heteroaryl" refers to an aromatic unsaturated cyclic group containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;

“R_aand R_bJoined to form a heterocyclic ring "means R_aAnd R_bAt least one atom in the structure is connected by chemical bonds, so that R in the general structure_aAnd R_bThe atoms or atom chains being jointly bound as part of a skeleton of a ring structure to R_aAnd R_bTogether form a heterocyclic ring.

Compared with the synthesis method of the sulfonamide compound in the prior art, the synthesis method provided by the invention has the following advantages:

(1) the reaction is completed in one step, so that a long reaction step is avoided, the operation is simple, and the method is suitable for industrial large-scale production;

(2) the raw materials of the synthesis method are wide in source, cheap and easy to obtain;

(3) organic molecular wastes are not produced, the economic principle of atomic steps is reflected, and the method is economical and practical;

(4) compared with the traditional method, the method comprises the reaction step of converting sulfur-containing compounds such as chlorosulfonic acid or thiophenol, mercaptan, thioether and the like into sulfonyl chloride. The method avoids the use of organic sulfide with unpleasant smell and is environment-friendly;

(5) compared with the prior transition metal catalyzed arylsulfonyl reaction of aryl halide, the prior method has the advantages that the application range of a reaction substrate is limited to hydrazine compounds, the reaction substrate can use amine compounds, and the substrate universality is stronger;

(6) in the preferable scheme, gas sulfur dioxide generated in an efficient and controllable manner is used as a sulfur dioxide source and is combined with a two-chamber reaction system, and sulfur dioxide gas generated in situ is directly inserted into aryl iodide and amine to further generate a sulfonamide compound, so that the synthesis efficiency is further improved, and the operation steps are simplified.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 shows a reaction vessel used in an example of the present invention.

Detailed Description

The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.

The general synthetic routes for the compounds of examples 1-41 below are as follows:

through screening experiments, the first reaction is carried out in a saturated alkane solvent, and the sulfur dioxide gas is hardly dissolved in the saturated alkane solvent, so that the utilization rate of the sulfur dioxide gas can be improved. The second reaction described above is carried out in DMSO, but not in NMP, DMF, Anisole, Xylenes, etc.

The reaction is carried out in a two-chamber reaction device, the structure of which is shown in figure 1, the device comprises a tube A and a tube B, the tube A and the tube B are respectively provided with a bottle cap, and the upper parts of the tube A and the tube B are communicated.

As an example of the technical scheme of the present invention, the following compounds were prepared in the following examples 1 to 41:

EXAMPLE 1 preparation of Compound 5a

DMAP (61.0mg,2.5equiv), nBuPAD was placed in a glove box filled with high purity argon₂(14.4mg,20.0mol％),Pd(acac)₂(7.6mg,12.5 mol%), 4-iodo-1, 2-dimethoxybenzene 3a (0.2mmol,1.0equiv), N-methyl-2-phenylethane-1-amine 4a (0.52mmol,2.6equiv) were added in succession to tube B of the apparatus of FIG. 1 equipped with a magnetic stirrer, while 1ml of DMSO was added. Compound 1 was then quickly weighed into tube A equipped with a magnetic stirrer, 1ml tetradecane was added, and Compound 2 was added to tube A. And (2) quickly screwing the bottle caps of the A tube and the B tube, taking out the glove box, putting the graph loading device on a magnetic stirrer at 95 ℃ for stirring for 24 hours, after the reaction is finished, cooling to room temperature, extracting the reaction liquid in the B tube by using ethyl acetate and water (15ml multiplied by 3 times), combining ethyl acetate layers, drying by using anhydrous sodium sulfate, concentrating, adding 200-mesh and 300-mesh silica gel for stirring, and performing column chromatography to obtain the compound 5a shown in the formula 1, namely a light yellow liquid with the yield of 74%.

Compound 5 a:¹H NMR(400MHz,CDCl₃)δ7.40(dd,J＝8.4,2.0Hz,1H),7.34-7.28(m,2H),7.27-7.17(m,4H),6.95(d,J＝8.4Hz,1H),3.95(s,3H),3.92(s,3H),3.30-3.27(m,2H),2.90-2.86(m,2H),2.78(s,3H)；¹³C NMR(100MHz,CDCl₃)δ152.6,149.2,138.5,129.8,128.9,128.7,126.7,121.3,110.7,110.1,56.4,56.3,51.9,35.3,34.9；HRMS m/z calculated for C₁₇H₂₁NO₄S[M+Na]⁺:358.1083,found:358.1091.

EXAMPLE 2 preparation of Compound 5b

The preparation method can obtain the compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-ethoxy-4-iodobenzene to obtain the compound 5b as a white solid with a yield of 63%.

Compound 5 b:¹H NMR(400MHz,CDCl₃)δ7.70(d,J＝8.8Hz,2H),7.34-7.23(m,3H),7.21(d,J＝6.8Hz,2H),6.96(d,J＝8.8Hz,2H),4.10(q,J＝6.8Hz,2H),3.28-3.24(m,2H),2.90-2.86(m,2H),2.76(s,3H),1.46(t,J＝6.8Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ162.4,138.5,129.6,129.3,129.0,128.7,126.7,114.7,64.1,52.0,35.3,35.0,14.8；HRMS m/z calculated for C₁₇H₂₁NO₃S[M+H]⁺:320.1315,found:320.1316.

EXAMPLE 3 preparation of Compound 5c

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-iodo-4-phenoxybenzene to obtain compound 5c as yellow liquid with yield of 62%.

Compound 5 c:¹H NMR(400MHz,CDCl₃)δ7.70(d,J＝8.8Hz,2H),7.43-7.39(m,2H),7.32-7.28(m,2H),7.23-7.18(m,4H),7.07(d,J＝7.6Hz,2H),7.02(d,J＝8.8Hz,2H),3.29-3.25(m,2H),2.89-2.86(m,2H),2.77(s,3H)；¹³C NMR(100MHz,CDCl₃)δ161.6,155.3,138.4,131.6,130.3,129.6,128.9,128.7,126.7,125.0,120.4,117.7,51.9,35.3,35.0；HRMS m/z calculated for C₂₁H₂₁NO₃S[M+Na]⁺:390.1134,found:390.1136.

EXAMPLE 4 preparation of Compound 5d

The preparation method can obtain the compound 5a by only changing 4-iodine-1, 2-dimethoxybenzene into 1-iodine-2-methoxybenzene to obtain the compound 5d as white solid with the yield of 56%.

Compound 5 d:¹H NMR(400MHz,CDCl₃)δ7.89(dd,J＝7.8,1.8Hz,1H),7.48-7.44(m,1H),7.26-7.21(m,2H),7.19-7.11(m,3H),7.01-6.93(m,2H),3.85(s,3H),3.40-3.35(m,2H),2.86-2.82(m,5H)；¹³C NMR(100MHz,CDCl₃)δ156.8,138.8,134.4,131.8,128.9,128.6,127.6,126.6,120.4,112.2,56.0,52.0,35.40,35.38；HRMS m/z calculated for C₁₆H₁₉NO₃S[M+Na]⁺:328.0978,found:328.0979.

EXAMPLE 5 preparation of Compound 5e

The preparation method can obtain compound 5a by only changing 4-iodine-1, 2-dimethoxybenzene into 1-iodine-3-methoxybenzene to obtain compound 5e as light yellow liquid with yield of 56%.

Compound 5 e:¹H NMR(400MHz,CDCl₃)δ7.36-7.29(m,1H),7.28-7.18(m,4H),7.15(d,J＝7.2Hz,1H),7.11(d,J＝7.0Hz,2H),7.01(dd,J＝8.2,1.6Hz,1H),3.76(s,3H),3.24-3.16(m,2H),2.83-2.75(m,2H),2.69(s,3H)；¹³C NMR(100MHz,CDCl₃)δ160.0,139.1,138.4,130.3,128.9,128.7,126.7,119.5,118.8,112.4,55.8,52.0,35.4,35.0；HRMS m/z calculated for C₁₆H₁₉NO₃S[M+Na]⁺:328.0978,found:328.0977.

EXAMPLE 6 preparation of Compound 5f

The preparation method can obtain the compound 5f as a light yellow liquid with the yield of 65 percent by only replacing 4-iodine-1, 2-dimethoxybenzene with 6-iodine-2, 3-dihydrobenzo [ b ] [1,4] dioxazole.

Compound 5 f:¹H NMR(400MHz,CDCl₃)δ7.24-7.13(m,5H),7.12-7.10(m,2H),6.85(d,J＝8.4Hz,1H),4.23-4.19(m,4H),3.18-3.14(m,2H),2.80-2.76(m,2H),2.67(s,3H)；¹³C NMR(100MHz,CDCl₃)δ147.4,143.7,138.5,130.4,128.9,128.7,126.7,121.1,117.8,117.0,64.6,64.3,52.0,35.4,35.0；HRMS m/z calculated for C₁₇H₁₉NO₄S[M+Na]⁺:356.0927,found:356.0931.

EXAMPLE 7 preparation of 5g Compound

The preparation method can be used for preparing compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into (4-iodophenyl) (methyl) sulfane to obtain compound 5g, yellow liquid, and yield of 66%.

Compound 5 g:¹H NMR(400MHz,CDCl₃)δ7.56(d,J＝8.4Hz,2H),7.23-7.19(m,4H),7.15(d,J＝7.2Hz,1H),7.10(d,J＝7.2Hz,2H),3.19-3.15(m,2H),2.80-2.76(m,2H),2.67(s,3H),2.43(s,3H)；¹³C NMR(100MHz,CDCl₃)δ145.5,138.4,133.6,128.9,128.7,127.8,126.7,125.5,51.9,35.2,34.9,14.9；HRMS m/z calculated for C₁₆H₁₉NO₂S₂[M+Na]⁺:344.0749,found:344.0754.

EXAMPLE 8 preparation of Compound 5h

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-iodo-4-methylbenzene, and the compound is 5h in light yellow liquid with yield of 59%.

Compound 5 h:¹H NMR(400MHz,CDCl₃)δ7.57(d,J＝8.4Hz,2H),7.24-7.14(m,5H),7.10(d,J＝7.2Hz,2H),3.19-3.15(m,2H),2.79-2.76(m,2H),2.67(s,3H),2.34(s,3H)；¹³C NMR(100MHz,CDCl₃)δ143.4,138.5,134.9,129.8,128.9,128.7,127.5,126.7,52.0,35.3,35.0,21.6；HRMS m/z calculated for C₁₆H₁₉NO₂S[M+Na]⁺:312.1029,found:312.1028.

example 9 preparation of Compound 5i

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-ethyl-4-iodobenzene to obtain compound 5i as yellow liquid with yield of 65%.

Compound 5 i:¹H NMR(400MHz,CDCl₃)δ7.59(d,J＝8.4Hz,2H),7.24-7.21(m,3H),7.20-7.10(m,4H),3.20-3.16(m,2H),2.80-2.76(m,2H),2.67(s,3H),2.63(q,J＝7.6Hz,2H),1.18(t,J＝7.6Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ149.5,138.5,135.1,128.9,128.7,128.6,127.6,126.7,52.0,35.3,35.0,28.9,15.2；HRMS m/z calculated for C₁₇H₂₁NO₂S[M+Na]⁺:326.1185,found:326.1185.

EXAMPLE 10 preparation of Compound 5j

The preparation method can obtain the compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1- (tert-butyl) -4-iodobenzene to obtain the compound 5j in yellow liquid with the yield of 66%.

Compound 5 j:¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.23-7.18(m,2H),7.16-7.10(m,3H),3.21-3.17(m,2H),2.81-2.77(m,2H),2.69(s,3H),1.26(s,9H)；¹³C NMR(100MHz,CDCl₃)δ156.3,138.5,134.9,128.9,128.7,127.3,126.7,126.1,52.0,35.4,35.2,35.0,31.2；HRMS m/z calculated for C₁₉H₂₅NO₂S[M+Na]⁺:354.1498,found:354.1507.

EXAMPLE 11 preparation of Compound 5k

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 4-iodo-1, 2-dimethylbenzene to obtain compound 5k in light yellow liquid with yield of 80%.

Compound 5 k:¹H NMR(400MHz,CDCl₃)δ7.44-7.40(m,2H),7.23-7.19(m,2H),7.18-7.14(m,2H),7.11(d,J＝7.2Hz,2H),3.19-3.15(m,2H),2.80-2.76(m,2H),2.67(s,3H),2.23(s,6H)；¹³C NMR(100MHz,CDCl₃)δ142.1,138.5,137.9,135.1,130.3,128.9,128.7,128.3,126.7,125.1,51.9,35.3,35.0,19.98,19.97；HRMS m/z calculated for C₁₇H₂₁NO₂S[M+Na]⁺:326.1185,found:326.1183.

EXAMPLE 12 preparation of Compound 5l

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-iodo-4- ((1s,4r) -4-propylcyclohexyl) benzene to obtain compound 5l as light yellow solid with yield of 64%.

Compound 5 l:¹H NMR(400MHz,CDCl₃)δ7.69(d,J＝8.4Hz,2H),7.35-7.28(m,4H),7.26-7.20(m,3H),3.29(t,J＝8.0Hz,2H),2.89(t,J＝8.0Hz,2H),2.78(s,3H),2.60-2.55(m,1H),1.91(d,J＝11.6Hz,4H),1.56-1.43(m,2H),1.43-1.31(m,3H),1.28-1.20(m,2H),1.12-1.03(m,2H),0.93(t,J＝7.6Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ153.1,138.5,135.2,128.9,128.7,127.6,127.5,126.7,52.0,44.7,39.7,37.0,35.3,35.0,34.1,33.4,20.1,14.5；HRMS m/z calculated for C₂₄H₃₃NO₂S[M+Na]⁺:422.2124,found:422.2122.

EXAMPLE 13 preparation of Compound 5m

The preparation method can obtain the compound 5a by only changing 4-iodine-1, 2-dimethoxybenzene into 4-iodine-1, 1' -biphenyl, i.e. the compound 5m is light yellow solid with the yield of 57%.

Compound 5 m:¹H NMR(400MHz,CDCl₃)δ7.76(d,J＝8.4Hz,2H),7.64(d,J＝8.4Hz,2H),7.54(d,J＝7.2Hz,2H),7.44-7.40(m,2H),7.37-7.34(m,1H),7.26-7.22(m,2H),7.20-7.14(m,3H),3.28-3.24(m,2H),2.85-2.82(m,2H),2.75(s,3H)；¹³C NMR(100MHz,CDCl₃)δ145.5,139.4,138.4,136.5,129.2,128.9,128.7,128.6,128.0,127.8,127.4,126.7,52.0,35.3,35.0；HRMS m/z calculated for C₂₁H₂₁NO₂S[M+Na]⁺:374.1185,found:374.1188.

EXAMPLE 14 preparation of Compound 5n

The preparation method can obtain compound 5a by converting 4-iodo-1, 2-dimethoxybenzene into iodobenzene to obtain compound 5n in yellow liquid with yield of 59%.

Compound 5 n:¹H NMR(400MHz,CDCl₃)δ7.69(d,J＝7.2Hz,2H),7.51-7.48(m,1H),7.45-7.39(m,2H),7.23-7.18(m,2H),7.16-7.10(m,3H),3.21-3.17(m,2H),2.80-2.76(m,2H),2.69(s,3H)；¹³C NMR(100MHz,CDCl₃)δ138.4,138.0,132.7,129.2,128.9,128.7,127.4,126.7,52.0,35.3,35.0；HRMS m/z calculated for C₁₅H₁₇NO₂S[M+Na]⁺:298.0872,found:298.0874.

EXAMPLE 15 preparation of Compound 5o

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 2-iodonaphthalene to obtain compound 5o in light yellow liquid with yield of 56%.

Compound 5 o:¹H NMR(400MHz,CDCl₃)δ8.26(s,1H),7.90-7.80(m,3H),7.65(dd,J＝8.6,1.8Hz,1H),7.58-7.50(m,2H),7.22-7.18(m,2H),7.15-7.06(m,3H),3.28-3.24(m,2H),2.82-2.77(m,2H),2.73(s,3H)；¹³C NMR(100MHz,CDCl₃)δ138.4,135.0,134.9,132.3,129.4,129.3,128.9,128.8,128.72,128.69,128.0,127.6,126.7,122.8,52.0,35.3,35.0；HRMS m/z calculated for C₁₉H₁₉NO₂S[M+Na]⁺:348.1029,found:348.1029.

EXAMPLE 16 preparation of Compound 5p

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-fluoro-4-iodobenzene to obtain compound 5p as yellow liquid with yield of 47%.

Compound 5 p:¹H NMR(400MHz,CDCl₃)δ7.68(dd,J＝8.8,5.2Hz,2H),7.24-7.20(m,2H),7.19-7.15(m,1H),7.14-7.07(m,4H),3.19(t,J＝7.6Hz,2H),2.79(t,J＝7.6Hz,2H),2.68(s,3H)；¹³C NMR(100MHz,CDCl₃)δ165.1(d,J_C-F＝253.0Hz),138.3,134.1(d,J_C-F＝3.0Hz),130.1(d,J_C-F＝9.0Hz),128.9,128.8,126.8,116.4(d,J_C-F＝22.0Hz),51.9,35.2,34.9；¹⁹F NMR(376MHz,CDCl₃)δ-105.58；HRMS m/z calculated for C₁₅H₁₆FNO₂S[M+Na]⁺:316.0778,found:316.0787.

EXAMPLE 17 preparation of Compound 5q

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-chloro-4-iodobenzene to obtain compound 5q as yellow liquid with yield of 52%.

Compound 5 q:¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝8.6Hz,2H),7.39(d,J＝8.6Hz,2H),7.25-7.19(m,2H),7.19-7.14(m,1H),7.10(d,J＝6.8Hz,2H),3.24-3.16(m,2H),2.83-2.74(m,2H),2.69(s,3H)；¹³C NMR(100MHz,CDCl₃)δ139.2,138.2,136.6,129.5,128.9,128.84,128.78,126.8,51.9,35.2,34.9；HRMS m/z calculated for C₁₅H₁₆ClNO₂S[M+Na]⁺:332.0482,found:332.0487.

EXAMPLE 18 preparation of Compound 5r

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into 1-bromo-4-iodobenzene to obtain compound 5r as yellow solid with yield of 48%.

Compound 5 r:¹H NMR(400MHz,CDCl₃)δ7.58-7.51(m,4H),7.24-7.16(m,3H),7.10(d,J＝7.0Hz,2H),3.20(t,J＝7.6Hz,2H),2.79(t,J＝7.6Hz,2H),2.68(s,3H)；¹³C NMR(100MHz,CDCl₃)δ138.2,137.1,132.5,129.0,128.9,128.8,127.6,126.8,51.9,35.2,34.9；HRMS m/z calculated for C₁₅H₁₆BrNO₂S[M+H]⁺:354.0158,found:354.0158.

EXAMPLE 19 preparation of Compound 5s

The preparation method can obtain compound 5a by only changing 4-iodo-1, 2-dimethoxybenzene into methyl 4-iodobenzoate to obtain compound 5s as yellow liquid with yield of 41%.

Compound 5 s:¹H NMR(400MHz,CDCl₃)δ8.08(d,J＝8.4Hz,2H),7.74(d,J＝8.4Hz,2H),7.24-7.16(m,3H),7.10(d,J＝6.8Hz,2H),3.88(s,3H),3.22(t,J＝8.0Hz,2H),2.79(t,J＝8.0Hz,2H),2.71(s,3H)；¹³C NMR(100MHz,CDCl₃)δ165.8,142.1,138.1,133.8,130.4,128.9,128.8,127.4,126.8,52.8,52.0,35.3,35.0；HRMS m/z calculated for C₁₇H₁₉NO₄S[M+H]⁺:334.1108,found:334.1111.

EXAMPLE 20 preparation of Compound 5t

The preparation method can obtain compound 5t as yellow liquid with yield of 45% by only replacing 4-iodo-1, 2-dimethoxybenzene with 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene.

Compound 5 t:¹H NMR(400MHz,CDCl₃)δ7.46-7.45(m,2H),7.41-7.40(m,1H),7.22-7.14(m,3H),7.07(d,J＝7.2Hz,2H),6.98(d,J＝8.4Hz,2H),6.71(d,J＝8.4Hz,2H),3.98(s,2H),3.90(q,J＝7.0Hz,2H),3.13(t,J＝8.0Hz,2H),2.73(t,J＝8.0Hz,2H),2.62(s,3H),1.32(t,J＝7.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ157.9,140.9,139.0,138.2,136.6,130.4,130.1,130.0,129.5,128.9,128.8,126.8,126.4,114.8,63.5,51.9,38.5,35.3,34.9,15.0；HRMS m/z calculated for C₂₄H₂₆ClNO₃S[M+Na]⁺:466.1214,found:466.1220.

example 21 preparation of Compound 5u

The preparation method can obtain the compound 5a by only changing 4-iodine-1, 2-dimethoxybenzene into 3-iodine-9-phenyl-9H-carbazole to obtain the compound 5u as yellow liquid with the yield of 69%.

Compound 5 u:¹H NMR(400MHz,CDCl₃)δ8.51(d,J＝1.6Hz,1H),8.10(d,J＝7.6Hz,1H),7.70(dd,J＝8.8,2.0Hz,1H),7.58-7.54(m,2H),7.46-7.42(m,3H),7.40-7.38(m,1H),7.35-7.26(m,3H),7.22-7.16(m,2H),7.13-7.10(m,3H),3.24(t,J＝8.0Hz,2H),2.80(t,J＝8.4Hz,2H),2.73(s,3H)；¹³C NMR(100MHz,CDCl₃)δ142.9,141.9,138.6,136.8,130.3,129.0,128.71,128.69,128.5,127.4,127.3,126.6,125.1,123.3,122.9,121.2,121.0,120.9,110.5,110.1,52.0,35.4,35.0；HRMS m/z calculated for C₂₇H₂₄N₂O₂S[M+Na]⁺:463.1451,found:463.1452.

EXAMPLE 22 preparation of Compound 5v

The preparation method can obtain the compound 5a by only changing 4-iodine-1, 2-dimethoxybenzene into 4- (4-fluorophenyl) -2- (4-iodine-2-methylbenzyl) thiophene, namely the compound 5v which is a light yellow liquid with the yield of 64 percent.

Compound 5 v:¹H NMR(400MHz,CDCl₃)δ7.56(d,J＝1.6Hz,1H),7.50(dd,J＝8.0,1.6Hz,1H),7.36-7.33(m,2H),7.23-7.16(m,3H),7.14(d,J＝7.2Hz,1H),7.11-7.08(m,2H),6.96-6.92(m,3H),6.59(d,J＝3.6Hz,1H),4.09(s,2H),3.20-3.16(m,2H),2.78-2.74(m,2H),2.68(s,3H),2.31(s,3H)；¹³C NMR(100MHz,CDCl₃)δ162.3(d,J_C-F＝246.0Hz),142.1,142.0,141.8,139.6,138.4,135.7,131.3,130.7(d,J_C-F＝3.0Hz),128.9,128.7,128.3,127.3(d,J_C-F＝8.0Hz),126.7,126.5,126.1,122.9,115.9(d,J_C-F＝21.0Hz),52.0,35.4,34.9,34.2,19.7；¹⁹F NMR(376MHz,CDCl₃)δ-114.80；HRMS m/z calculated for C₂₇H₂₆FNO₂S₂[M+Na]⁺:502.1281,found:502.1288.

EXAMPLE 23 preparation of Compound 5w

The preparation method can be used for preparing the compound 5a by only changing N-methyl-2-phenyl ethane-1-amine into N-methyl-1-phenyl methylamine to obtain the compound 5w which is yellow liquid with the yield of 63%.

Compound 5 w:¹H NMR(400MHz,CDCl₃)δ7.46(dd,J＝8.4,2.4Hz,1H),7.37-7.26(m,6H),6.99(d,J＝8.4Hz,1H),4.14(s,2H),3.96(s,3H),3.94(s,3H),2.60(s,3H)；¹³C NMR(100MHz,CDCl₃)δ152.7,149.3,135.8,129.3,128.8,128.5,128.1,121.5,110.8,110.2,56.4,56.3,54.3,34.5；HRMS m/z calculated for C₁₆H₁₉NO₄S[M+Na]⁺:344.0927,found:344.0930.

EXAMPLE 24 preparation of Compound 5x

The preparation method can obtain the compound 5x, yellow solid with the yield of 62 percent, by only changing N-methyl-2-phenyl ethane-1-amine into 1- (4-fluorophenyl) -N-methyl methylamine.

Compound 5 x:¹H NMR(400MHz,CDCl₃)δ7.38(dd,J＝8.4,2.2Hz,1H),7.24-7.18(m,3H),6.99-6.89(m,3H),4.03(s,2H),3.89(s,3H),3.87(s,3H),2.52(s,3H)；¹³C NMR(100MHz,CDCl₃)δ162.6(d,J_C-F＝245.0Hz),152.8,149.3,131.6(d,J_C-F＝3.0Hz),130.2(d,J_C-F＝9.0Hz),129.2,121.5,115.7(d,J_C-F＝22.0Hz)110.9,110.2,56.4,56.3,53.6,34.5；¹⁹F NMR(376MHz,CDCl₃)δ-114.36；HRMS m/z calculated for C₁₆H₁₈FNO₄S[M+Na]⁺:362.0833,found:362.0832.

EXAMPLE 25 preparation of Compound 5y

The preparation method can obtain the compound 5y with yellow solid and yield of 68% by only replacing N-methyl-2-phenyl ethane-1-amine with 1- (4-chlorphenyl) -N-methyl methylamine.

Compound 5 y:¹H NMR(400MHz,CDCl₃)δ7.37(dd,J＝8.4,2.2Hz,1H),7.24(d,J＝8.4Hz,2H),7.21(d,J＝2.0Hz,1H),7.18(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,1H),4.03(s,2H),3.89(s,3H),3.87(s,3H),2.52(s,3H)；¹³C NMR(100MHz,CDCl₃)δ152.8,149.3,134.4,133.9,129.8,129.1,129.0,121.5,110.9,110.1,56.4,56.3,53.7,34.6；HRMS m/z calculated for C₁₆H₁₈ClNO₄S[M+Na]⁺:378.0537,found:378.0540.

EXAMPLE 26 preparation of Compound 5z

The preparation method is similar to that of the compound 5a, and only needs to replace N-methyl-2-phenyl ethane-1-amine with 1- (3-bromophenyl) -N-methyl methylamine, so that the compound 5z is obtained and is yellow solid, and the yield is 71%.

Compound 5 z:¹H NMR(400MHz,CDCl₃)δ7.40-7.32(m,3H),7.22-7.10(m,3H),6.92(d,J＝8.4Hz,1H),4.04(s,2H),3.89(s,3H),3.86(s,3H),2.54(s,3H)；¹³C NMR(100MHz,CDCl₃)δ152.8,149.3,138.3,131.3,131.1,130.3,129.0,127.0,122.8,121.4,110.9,110.1,56.4,56.3,53.7,34.7；HRMS m/z calculated for C₁₆H₁₈BrNO₄S[M+Na]⁺:422.0032,found:422.0035.

example 27 preparation of Compound 5aa

The preparation method can obtain the compound 5aa by only changing N-methyl-2-phenyl ethane-1-amine into N-methyl-1- (4- (trifluoromethyl) phenyl) methylamine, namely the compound 5aa is light yellow solid with the yield of 67 percent.

Compound 5 aa:¹H NMR(400MHz,CDCl₃)δ7.60(d,J＝8.0Hz,2H),7.46-7.42(m,3H),7.29(d,J＝2.0Hz,1H),6.99(d,J＝8.4Hz,1H),4.19(s,2H),3.96(s,3H),3.94(s,3H),2.62(s,3H)；¹³C NMR(100MHz,CDCl₃)δ152.9,149.3,140.2,130.4(q,J_C-F＝32.0Hz),129.1,128.7,125.8(q,J_C-F＝4.0Hz),124.1(q,J_C-F＝270.0Hz),121.5,110.9,110.1,56.4,56.3,53.9,34.8；¹⁹F NMR(376MHz,CDCl₃)δ-62.57；HRMS m/z calculated for C₁₇H₁₈F₃NO₄S[M+Na]⁺:412.0801,found:412.0800.

example 28 preparation of Compound 5ab

The preparation method can obtain compound 5ab as yellow solid with yield of 66% by only replacing N-methyl-2-phenyl ethane-1-amine with N-methyl-1- (naphthalene-1-yl) methylamine.

Compound 5 ab:¹H NMR(400MHz,CDCl₃)δ8.42(d,J＝8.4Hz,1H),7.88-7.82(m,2H),7.63-7.57(m,1H),7.56-7.50(m,2H),7.42-7.35(m,2H),7.30(d,J＝6.8Hz,1H),7.03(d,J＝8.4Hz,1H),4.55(s,2H),3.99(s,3H),3.95(s,3H),2.52(s,3H)；¹³C NMR(100MHz,CDCl₃)δ152.9,149.3,134.1,132.1,130.8,129.4,128.7,128.3,128.1,126.9,126.3,125.1,124.4,121.8,110.9,110.4,56.5,56.4,52.9,34.4；HRMS m/z calculated for C₂₀H₂₁NO₄S[M+Na]⁺:394.1083,found:394.1084.

EXAMPLE 29 preparation of Compound 5ac

The preparation method can obtain the compound 5a by only changing N-methyl-2-phenyl ethane-1-amine into N-methyl octane-1-amine, namely the compound 5ac is yellow solid with the yield of 72 percent.

Compound 5 ac:¹H NMR(400MHz,CDCl₃)δ7.38(d,J＝8.4Hz,1H),7.23(d,J＝2.0Hz,1H),6.94(d,J＝8.4Hz,1H),3.93(s,3H),3.92(s,3H),3.03-2.92(m,2H),2.70(s,3H),1.54-1.47(m,2H),1.32-1.25(m,10H),0.87(t,J＝6.4Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ152.5,149.1,129.6,121.3,110.7,110.1,56.4,56.3,50.3,34.67,34.65,31.9,29.3,27.7,26.7,22.7,14.2；HRMS m/z calculated for C₁₇H₂₉NO₄S[M+Na]⁺:366.1710,found:366.1712.

EXAMPLE 30 preparation of Compound 5ad

The preparation method comprises the step of replacing N-methyl-2-phenyl ethane-1-amine with (3aR,7aS) -octahydro-1H-isoindole to obtain a compound 5ad which is light yellow liquid and has the yield of 82 percent.

Compound 5 ad:¹H NMR(400MHz,CDCl₃)δ7.44(dd,J＝8.4,2.0Hz,1H),7.30(d,J＝2.0Hz,1H),6.95(d,J＝8.4Hz,1H),3.94(s,3H),3.92(s,3H),3.27(dd,J＝9.2,6.8Hz,2H),3.15(dd,J＝9.2,5.2Hz,2H),2.10-2.05(m,2H),1.51-1.33(m,4H),1.31-1.19(m,4H)；¹³C NMR(100MHz,CDCl₃)δ152.5,149.1,129.5,121.2,110.7,110.1,56.4,56.3,51.7,37.5,25.6,22.7；HRMS m/z calculated for C₁₆H₂₃NO₄S[M+Na]⁺:348.1240,found:348.1241.

EXAMPLE 31 preparation of Compound 5ae

The preparation method of the compound 5a only needs to change 4-iodine-1, 2-dimethoxybenzene into 1-iodine-4- ((1s,4r) -4-propylcyclohexyl) benzene and change N-methyl-2-phenylethane-1-amine into (3aR,7aS) -octahydro-1H-isoindole to obtain the compound 5ae aS yellow solid with the yield of 66%.

Compound 5 ae:¹H NMR(400MHz,CDCl₃)δ7.73(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H),3.26(dd,J＝9.6,6.8Hz,2H),3.15(dd,J＝9.6,5.6Hz,2H),2.57-2.50(m,1H),2.10-2.02(m,2H),1.89-1.87(m,4H),1.52-1.15(m,15H),1.11-0.98(m,2H),0.90(t,J＝7.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ153.0,134.9,127.5,51.7,44.7,39.7,37.5,37.0,34.2,33.5,25.5,22.7,20.1,14.5；HRMS m/z calculated for C₂₃H₃₅NO₂S[M+Na]⁺:412.2281,found:412.2285.

EXAMPLE 32 preparation of Compound 5af

The preparation method can be used for preparing the compound 5a by only changing N-methyl-2-phenyl ethane-1-amine into 4-benzyl piperidine to obtain the compound 5af in yellow liquid with the yield of 63%.

Compound 5 af:¹H NMR(400MHz,CDCl₃)δ7.27(dd,J＝8.4,2.0Hz,1H),7.21-7.15(m,2H),7.14-7.07(m,2H),7.02-6.97(m,2H),6.86(d,J＝8.4Hz,1H),3.86(s,3H),3.83(s,3H),3.67(d,J＝12.0Hz,2H),2.43(d,J＝6.8Hz,2H),2.13(t,J＝11.6Hz,2H),1.61(d,J＝12.4Hz,2H),1.39-1.23(m,3H)；¹³C NMR(100MHz,CDCl₃)δ152.6,149.0,139.9,129.1,128.4,128.0,126.2,121.6,110.6,110.3,56.34,56.26,46.6,42.7,37.5,31.4；HRMS m/z calculated for C₂₀H₂₅NO₄S[M+Na]⁺:398.1397,found:398.1400.

EXAMPLE 33 preparation of Compound 5ag

The preparation method comprises converting N-methyl-2-phenylethane-1-amine to 2- ((tert-butyldimethylsilyl) oxo) -N-methylethane-1-amine to obtain compound 5ag as yellow liquid with a yield of 47%.

Compound 5 ag:¹H NMR(400MHz,CDCl₃)δ7.39(dd,J＝8.4,2.0Hz,1H),7.24(d,J＝2.0Hz,1H),6.94(d,J＝8.4Hz,1H),3.93(s,3H),3.92(s,3H),3.77(t,J＝6.0Hz,2H),3.13(t,J＝6.0Hz,2H),2.85(s,3H),0.87(s,9H),0.04(s,6H)；¹³C NMR(100MHz,CDCl₃)δ152.6,149.2,129.9,121.2,110.8,110.1,62.6,56.4,56.3,52.5,36.9,26.0,18.3,-5.3；HRMS m/z calculated for C₁₇H₃₁NO₅SSi[M+Na]⁺:412.1584,found:412.1591.

example 34 preparation of Compound 5ah

The preparation method can obtain the compound 5a by only changing N-methyl-2-phenyl ethane-1-amine into indoline, namely the compound 5ah which is yellow liquid and has the yield of 55 percent.

Compound 5 ah:¹H NMR(400MHz,CDCl₃)δ7.68(d,J＝8.4Hz,1H),7.43(dd,J＝8.4,2.0Hz,1H),7.22-7.18(m,1H),7.11(d,J＝2.0Hz,1H),7.09-7.05(m,1H),7.02-6.94(m,1H),6.86(d,J＝8.4Hz,1H),3.93-3.85(m,5H),3.73(s,3H),2.83(t,J＝8.4Hz,2H)；¹³C NMR(100MHz,CDCl₃)δ153.1,149.0,142.4,132.4,128.7,127.7,125.3,124.1,121.4,115.7,110.6,109.8,56.3,56.2,50.2,28.1；HRMS m/z calculated for C₁₆H₁₇NO₄S[M+Na]⁺:342.0770,found:342.0768.

EXAMPLE 35 preparation of Compound 5ai

The preparation method of the compound 5a only needs to change 4-iodo-1, 2-dimethoxybenzene into 4-iodo-4-methoxybenzene and change N-methyl-2-phenylethane-1-amine into N, 4-dimethyl-N- (piperidine-4-ylmethyl) benzenesulfonamide to obtain the compound 5ai as a light yellow solid with the yield of 50%.

Compound 5 ai:¹H NMR(400MHz,CDCl₃)δ7.69(d,J＝8.8Hz,2H),7.62(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,2H),6.99(d,J＝8.8Hz,2H),3.87(s,3H),3.77(d,J＝11.6Hz,2H),2.77(d,J＝7.2Hz,2H),2.66(s,3H),2.42(s,3H),2.28-2.21(m,2H),1.79(d,J＝11.6Hz,2H),1.55-1.48(m,1H),1.37-1.30(m,2H)；¹³C NMR(100MHz,CDCl₃)δ163.1,143.6,134.3,129.9,129.8,127.9,127.5,114.3,55.8,55.6,46.1,36.2,34.5,29.3,21.6；HRMS m/z calculated for C₂₁H₂₈N₂O₅S₂[M+Na]⁺:475.1332,found:475.1331.

EXAMPLE 36 preparation of Compound 5aj

The preparation method can obtain the compound 5aj as a white solid with the yield of 70 percent by only changing N-methyl-2-phenyl ethane-1-amine into 1-phenyl piperazine.

Compound 5 aj:¹H NMR(400MHz,CDCl₃)δ7.39(dd,J＝8.4,2.0Hz,1H),7.25-7.19(m,3H),6.96(d,J＝8.4Hz,1H),6.92-6.83(m,3H),3.93(s,3H),3.93(s,3H),3.31-3.08(m,8H)；¹³C NMR(100MHz,CDCl₃)δ153.0,149.3,129.4,127.2,121.9,117.1,110.8,110.5,56.5,56.4,49.4,46.2；HRMS m/z calculated for C₁₈H₂₂N₂O₄S[M+Na]⁺:385.1192,found:385.1195.

EXAMPLE 37 preparation of Compound 5ak

The preparation method can obtain the compound 5a by only changing N-methyl-2-phenyl ethane-1-amine into morpholine, namely the compound 5ak which is a light yellow solid with the yield of 60 percent.

Compound 5 ak:¹H NMR(400MHz,CDCl₃)δ7.37(dd,J＝8.4,2.0Hz,1H),7.20(d,J＝2.4Hz,1H),6.97(d,J＝8.4Hz,1H),3.95(s,3H),3.93(s,3H),3.78-3.71(m,4H),3.02-2.95(m,4H)；¹³C NMR(100MHz,CDCl₃)δ153.1,149.3,127.0,122.0,110.8,110.4,66.3,56.44,56.36,46.2；HRMS m/z calculated for C₁₂H₁₇NO₅S[M+Na]⁺:310.0720,found:310.0719.

EXAMPLE 38 preparation of Compound 5al

The preparation method of the compound 5a only needs to change 4-iodine-1, 2-dimethoxybenzene into 4-iodine-1, 2-dimethylbenzene and change N-methyl-2-phenylethane-1-amine into methyl 1-ethyl-6-fluoro-4-carbonyl-7- (piperazine-1-yl) -1, 4-dihydro-1, 8-naphthyridine-3-carboxylic ester to obtain the compound 5al as a light yellow solid with the yield of 60%.

Compound 5 al:¹H NMR(400MHz,CDCl₃)δ8.41(s,1H),8.07(d,J＝13.2Hz,1H),7.48-7.39(m,2H),7.20(d,J＝3.2Hz,1H),4.21(q,J＝6.8Hz,2H),3.84(s,3H),3.81-3.71(m,4H),3.14-3.02(m,4H),2.29(s,3H),2.28(s,3H),1.36(t,J＝6.8Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ173.5,166.4,149.6(d,J_C-F＝9.4Hz),147.9,147.2(d,J_C-F＝255.4Hz),144.2,143.0,138.1,132.4,130.4,128.6,125.5,122.1(d,J_C-F＝21.6Hz),117.5(d,J_C-F＝2.7Hz),111.6,52.3,47.1,46.6,46.5,45.9,20.0,15.1；¹⁹F NMR(376MHz,CDCl₃)δ-130.13；HRMS m/z calculated for C₂₄H₂₉FN₄O₅S[M+Na]⁺:525.1578,found:525.1575.

example 39 preparation of Compound 5am

Preparation method of compound 5a by changing N-methyl-2-phenylethane-1-amine into 2-chloro-11- (piperazine-1-yl) dibenzo [ b, f][1,4]Oxa nitrogenCompound 5am was obtained as a pale yellow solid with a yield of 62%.

Compound 5 am:¹H NMR(400MHz,CDCl₃)δ7.43-7.36(m,2H),7.22(d,J＝2.0Hz,1H),7.20(d,J＝2.5Hz,1H),7.18(d,J＝8.7Hz,1H),7.15-7.05(m,3H),7.02(d,J＝8.3Hz,1H),6.98(d,J＝8.5Hz,1H),3.95(s,3H),3.94(s,3H),3.65(s,4H),3.15(s,4H)；¹³C NMR(100MHz,CDCl₃)δ159.5,158.5,153.1,152.1,149.3,133.5,130.7,129.1,127.3,127.1,126.1,125.7,124.0,123.1,121.8,120.3,111.0,110.3,56.4,56.3,47.5,45.9；HRMS m/z calculated for C₂₅H₂₄ClN₃O₅S[M+Na]⁺:536.1017,found:536.1021.

EXAMPLE 40 preparation of Compound 5an

The preparation method of the compound 5a only needs to change 4-iodo-1, 2-dimethoxybenzene into 4-iodo-1, 2-dimethylbenzene and change N-methyl-2-phenylethane-1-amine into 8-chloro-11- (piperidine-4-ylidene) -6, 11-dihydro-5H-benzo [5,6] cycloheptatriene [1,2-b ] pyridine to obtain the compound 5an as a yellow solid with the yield of 38%.

Compound 5 an:¹H NMR(400MHz,CDCl₃)δ8.38(d,J＝4.4Hz,1H),7.55-7.43(m,3H),7.30-7.26(m,1H),7.17-7.09(m,3H),7.04(d,J＝8.0Hz,1H),3.36-3.24(m,3H),3.23-3.15(m,1H),3.06-2.95(m,2H),2.88-2.70(m,2H),2.68-2.59(m,1H),2.57-2.46(m,1H),2.41-2.28(m,8H)；¹³C NMR(100MHz,CDCl₃)δ156.2,146.0,142.5,139.5,138.6,138.0,137.2,136.8,133.9,133.7,133.3,130.6,130.3,129.2,128.5,126.4,125.3,122.7,47.3,31.6,31.5,30.3,30.1,20.1；HRMS m/z calculated for C₂₇H₂₇ClN₂O₂S[M+Na]⁺:501.1374,found:501.1378.

EXAMPLE 41 preparation of Compound 5ao

The preparation method is characterized in that the compound 5a is prepared by only changing N-methyl-2-phenyl ethane-1-amine into 6-chlorine-7, 8-dimethoxy-1- (4-methoxyphenyl) -2,3,4, 5-tetrahydro-1H-benzo [ d]Aza derivativesThe compound 5ao is obtained as a light yellow liquid with the yield of 60 percent.

Compound 5 ao:¹H NMR(400MHz,CDCl₃)δ7.31(dd,J＝8.4,2.0Hz,1H),7.16(d,J＝2.0Hz,1H),7.04(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,3H),6.33(s,1H),4.28(dd,J＝7.8,3.6Hz,1H),3.91(s,3H),3.86(s,3H),3.82(s,3H),3.80-3.77(m,4H),3.70(d,J＝9.0Hz,1H),3.67(s,3H),3.35-3.28(m,2H),3.27-3.19(m,1H),3.06-2.98(m,1H)；¹³C NMR(100MHz,CDCl₃)δ158.5,152.6,151.7,149.1,144.0,139.1,132.7,130.2,129.4,129.0,128.8,121.1,114.2,112.9,110.7,109.9,60.6,56.4,56.2,56.0,55.4,51.1,50.1,47.5,29.2；HRMS m/z calculated for C₂₇H₃₀ClNO₇S[M+Na]⁺:570.1324,found:570.1329.

as can be seen from the examples 1 to 41, the synthesis method provided by the invention has the advantages of simple reaction operation, strong substrate universality and economic and practical synthesis process. Therefore, the invention has strong practical value and wide application prospect.