CN110627722A - Synthesis method of 7-alkynyl azepine derivative - Google Patents

Synthesis method of 7-alkynyl azepine derivative Download PDF

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CN110627722A
CN110627722A CN201910988563.9A CN201910988563A CN110627722A CN 110627722 A CN110627722 A CN 110627722A CN 201910988563 A CN201910988563 A CN 201910988563A CN 110627722 A CN110627722 A CN 110627722A
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azepine
group
allyl
derivative
alkynylazepine
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CN110627722B (en
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阳绪衡
黄坚
王芳
李玉姣
王建方
陶呈安
邹晓蓉
宋琛超
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National University of Defense Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 Table
    • 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
    • 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 Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond
    • 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 Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

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Abstract

The invention discloses a synthesis method of a 7-alkynyl azepine derivative, which comprises the steps of placing a halogenated alkynylamide compound, terminal alkyne and carbonate in an organic solvent under the catalytic action of copper salt and a nitrogen ligand, and carrying out serial cyclization reaction by using a one-pot method to obtain the 7-alkynyl azepine derivative. The catalyst of the method is cheap and easy to obtain, the reaction condition is simple, the reaction selectivity is good, the yield is high, the compatibility of the substrate functional group is excellent, and the method has high application value.

Description

Synthesis method of 7-alkynyl azepine derivative
Technical Field
The invention belongs to the technical field of synthesis of organic intermediates, and relates to a synthesis method of a 7-alkynyl azepine derivative, in particular to a method for synthesizing the 7-alkynyl azepine derivative by a multi-component one-pot reaction of a halogenated alkynylamide compound, terminal alkyne and carbonate under the action of a copper-containing catalytic system.
Background
Azepine is a high-value nitrogen-containing heterocyclic compound and plays an important role in the fields of drug research and development and the like. In the synthesis method of the nitrogen-containing heterocyclic compound, the traditional cycloaddition reaction can provide a very effective method for the construction of the cyclic compound, for example, a four-membered, five-membered and six-membered ring compound can be synthesized by the cycloaddition reaction of [2+2], [3+2] and [4+2], but the synthesis of a seven-membered ring compound such as an azepine derivative by using a similar method is very rare. The relevant literature is reported as follows:
in 2012, the Wender group reported a method of [3+2+2] cycloaddition of vinylcyclopropane and 1.2 times the chemical equivalent of alkyne in dichloroethane solution catalyzed by rhodium metal to produce a seven-membered cyclic compound (angelw. chem. int. ed.2012,51,2736, formula 1).
In 2016, Zjunliang et al also realized the formation of an azepine compound by the [3+2+2] cycloaddition of vinylazepine and 1.2 times the stoichiometric equivalent of alkyne in dichloroethane catalyzed by rhodium metal (J.Am.chem.Soc.2016,138,2178, formula 2).
The existing cycloaddition synthesis seven-membered ring reaction generally has the following defects:
most of the cycloaddition synthesis methods reported in the literature require noble metal catalysis, such as rhodium, ruthenium, palladium and other catalysts.
The cycloaddition synthesis method reported in the literature has strict requirements on the structure of raw materials, for example, the raw materials must have structures such as conjugated double bonds or double-bond conjugated rings.
The partial cycloaddition synthesis method reported in the literature has the defects that the product belongs to a pure carbon ring structure instead of nitrogen heterocycle and the like.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of the prior art, in particular to the defects of the existing synthesis method of azaheterocyclic compounds such as azepine and the like, and provides a synthesis method of a 7-alkynyl azepine derivative with specific reaction regioselectivity, high reaction yield, low cost and wide substrate adaptability.
In order to solve the technical problems, the invention adopts the following technical scheme.
A synthesis method of 7-alkynyl azepine derivatives comprises the steps of placing halogenated alkyne amide compounds, terminal alkyne and alkaline carbonate in an organic solvent under the catalysis of copper salt and nitrogen ligand, and performing serial cyclization reaction by using a one-pot method to obtain the 7-alkynyl azepine derivatives;
the halogenated alkynamide compound has a chemical structural formula shown in a formula (1):
the terminal alkyne has a chemical structural formula shown in formula (2) or formula (3):
wherein:
R1is one of alkyl, aryl and heterocyclic radical;
R2is one of alkyl, aryl and heterocyclic radical;
x is halogen;
R3is one of alkyl, aryl, heterocyclic radical, ester radical and silane radical.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably:
the R is1When it is an alkyl group, said alkyl group is selected from C1-C6Alkyl groups of (a);
the R is1When the aryl is the phenyl group, the aryl is the phenyl or the substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C6Alkyl radical, C1-C6One of alkoxy, halogen, aldehyde group, cyano, nitro, ester group and naphthyl;
the R is1When a heterocyclic group, the heterocyclic group is selected from three-to seven-membered cyclic compounds containing a heteroatom including oxygen, sulfur or nitrogen.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably:
x is chlorine, bromine or iodine;
the R is2When it is an alkyl group, said alkyl group is selected from C1-C3Alkyl groups of (a);
the R is2When the aryl is the phenyl group, the aryl is the phenyl or the substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C3Alkyl radical, C1-C3One of alkoxy, halogen, aldehyde group, cyano, nitro, ester group and naphthyl;
the R is2When it is a heterocyclic group, the heterocyclic group is selected from three-to six-membered cyclic compounds containing a heteroatom including oxygen, sulfur or nitrogen.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably:
the R is3When it is an alkyl group, said alkyl group is selected from C1-C6Alkyl groups of (a);
the R is3When the aryl is the phenyl group, the aryl is the phenyl or the substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C6Alkyl radical, C1-C6One of alkoxy, halogen, aldehyde group, cyano, nitro, ester group and naphthyl;
the R is3When heterocyclic, the heterocyclic is selected from three-to seven-membered cyclic compounds containing heteroatoms, including oxygen, sulfur, or nitrogen;
the R is3When an ester group is present, the ester group is selected from C1-C6An alkoxyacyl group of (a);
the R is3When it is a silane group, said silane group is selected from C1-C6A silane group of (a).
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably: the copper salt comprises at least one of copper acetate, copper sulfate, copper chloride, cuprous chloride and copper trifluoromethanesulfonate.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably: the nitrogen ligand comprises at least one of 1, 10-phenanthroline, 2' -bipyridine, pyridine, tetramethylethylenediamine and dimethylethylenediamine.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably: the carbonate includes at least one of sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably: the organic solvent comprises one or more of toluene, acetonitrile and tetrahydrofuran.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably: the molar ratio of the halogenated alkynylamide compound to the terminal alkyne, the copper salt, the nitrogen ligand and the carbonate is 1: 3-5: 0.03-0.10: 0.08-0.20: 2-3, preferably 1: 3-5: 0.05-0.10: 0.10-0.20: 2-3, and more preferably 1: 3: 0.05: 0.10: 2.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably: the conditions of the serial cyclization reaction are as follows: the heating temperature is 80-120 ℃, the reaction time is 8-12 h, the heating temperature is 100 ℃, and the reaction time is 12h is preferred.
The above-mentioned synthesis method of 7-alkynylazepine derivatives is preferably: after the completion of the tandem cyclization reaction by the one-pot method, the crude product of the 7-alkynylazepine derivative was separated by filtration to obtain a crude product, and the crude product of the 7-alkynylazepine derivative was purified by silica gel column chromatography (preferably, petroleum ether: ethyl acetate ═ 20: 1) to obtain a pure product of the 7-alkynylazepine derivative.
In the scheme of the invention, the main considerations for selecting functional groups or components are as follows:
in the halogenated alkynamide compound of the invention, R1Selected from a wide range of groups such as alkyl, aryl, heterocyclic, etc., R1When an alkyl group is selected, an azepine derivative can be produced, and when a short chain is used, the production efficiency is higher. R1When the aryl is aryl, the aryl is selected from phenyl or substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C6Alkyl radical, C1-C6Alkoxy, halogen such as fluorine, chlorine, bromine or iodine, and electron withdrawing substituent such as aldehyde group, cyano, nitro, ester group, naphthyl, etc., wherein the position of the substituent on the benzene ring is not limited. R1When a heterocyclic group is selected, the heterocyclic group is preferably selected from small-ring heterocyclic groups such as furan, imidazole, thiophene, pyridine, dioxane, etc., and the position, number and kind of the hetero atom on the ring are not limited.
In the halogenated alkynamide compound of the invention, R2The range of choice is relatively modest, e.g., alkyl, aryl, heterocyclic, etc., R2When alkyl is selected, the alkyl is preferably selected from short chain alkyl groups, such as C1-C3Such as methyl, ethyl, propyl, and the like. R2When aryl is used, the aryl is selected from phenyl or substituted phenyl, the substituent group on the benzene ring of the substituted phenyl is not too sterically hindered, and comprises C1-C3Alkyl radical, C1-C3Alkoxy, halogen such as fluorine, chlorine, bromine or iodine, and electron withdrawing substituent such as aldehyde group, cyano, nitro, ester group, naphthyl, etc., wherein the position of the substituent on the benzene ring is not limited. R2When a heterocyclic group is selected, the heterocyclic group is preferably selected from small-ring heterocyclic groups such as furan, imidazole, thiophene, pyridine, dioxane, etc., and the position, number and kind of the hetero atom on the ring are not limited.
In the haloalkynoamide compound of the present invention, X is preferably chlorine, bromine or iodine.
In the halogenated alkynamide compound of the invention, R3A wide range of choices, such as alkyl, aryl, heterocyclic, ester, silyl, etc., R3When alkyl is selected, the alkyl is preferably selected from short chain alkyl groups, such as C1-C6Such as butyl, pentyl, hexyl, and the like. R3When the aryl is aryl, the aryl is selected from phenyl or substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C6Alkyl radical, C1-C6Alkoxy, halogen such as fluorine, chlorine, bromine or iodine, and electron withdrawing substituent such as aldehyde group, cyano, nitro, ester group, naphthyl, etc., wherein the position of the substituent on the benzene ring is not limited. R3When heterocyclic group is selected, heterocyclic group can be selected from various heterocyclic ring groups, such as furan, imidazole, thiophene, pyridine, dioxane, etc., and the position, number and type of heteroatoms on the ring are not limited. R3When it is an ester group, the ester group is C1-C6Such as methoxyacyl group, ethoxyacyl group and the like. R3In the case of silyl radicals, the alkylsilyl radicals are short-chain alkylsilyl radicals, e.g. C1-C6Alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, etc.
In a preferred embodiment, the copper salt is mainly used as a catalyst, and theoretically, any copper salt capable of catalyzing the series reaction is suitable for the present invention, and is preferably at least one of copper acetate, copper sulfate, copper chloride, cuprous chloride and copper trifluoromethanesulfonate, and most preferably copper acetate.
In a preferred scheme, a nitrogen ligand is mainly used as an additive, theoretically, as long as the nitrogen ligand contributing to catalyzing the series reaction is suitable for the invention, at least one of 1, 10-phenanthroline, 2' -bipyridine, pyridine, tetramethylethylenediamine and dimethylethylenediamine is preferred; most preferably 1, 10-phenanthroline.
In the preferred embodiment, the carbonate mainly serves as a base, and in theory, the carbonate that contributes to the elimination reaction is suitable for the present invention, and is preferably at least one of sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate; most preferred is potassium carbonate.
In a preferred scheme, the organic reagent is mainly used as a solvent, theoretically, the solvent which is helpful for dissolving and dispersing the raw materials is suitable for the invention, and at least one of toluene, acetonitrile and tetrahydrofuran is preferably used; toluene is most preferred.
The method is implemented by a one-pot method through the serial cyclization reaction of halogenated alkyne amide compounds and terminal alkyne in a copper-containing catalytic system. It is known that the construction of seven-membered nitrogen heterocyclic compounds such as azepine is very difficult. The reason for this phenomenon is mainly two-fold, on one hand, because when the seven-membered cyclic compound is synthesized, the bond-forming interaction is low due to the large ring tension, which causes the compound to have disadvantages in both entropy effect and enthalpy effect; on the other hand, when the compound is synthesized, the regioselectivity and the stereoselectivity are difficult to control. Under the catalysis condition of the copper salt and the nitrogen ligand, the halogenated alkyne amide compound and terminal alkyne synthesize the azepine compound with wide application value by a one-step method through a series cyclization reaction (comprising a claisen rearrangement reaction, a nucleophilic addition reaction and an intramolecular coupling reaction). Therefore, the azepine compound and the derivative are synthesized by the series reaction of the halogenated alkynylamide compound and the terminal alkyne, on one hand, the separation and purification of an intermediate are avoided, thereby simplifying the operation steps, simultaneously reducing the dosage of a solvent and an eluent and the generation of byproducts, and being beneficial to environmental protection; on the other hand, the catalyst system adopts copper salt as the catalyst, so that the cost can be effectively reduced.
The synthetic route of the invention is exemplified as follows:
the invention takes N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide and phenylacetylene as substrate raw materials, copper acetate as a catalyst, 1, 10-phenanthroline (Phen) as a nitrogen ligand, potassium carbonate as an alkali salt and toluene as a solvent, and the route of synthesizing the 7-alkynyl azepine derivative by a series cyclization reaction at 100 ℃ is as follows:
compared with the prior art, the invention has the advantages that:
the synthetic method of the invention adopts copper salt to replace the traditional precious metal as the catalyst, the copper salt has rich and easily obtained sources and much lower price than the corresponding catalysts of rhodium, ruthenium, palladium and the like, and the production cost can be effectively reduced. The invention adopts the tandem cyclization reaction to synthesize the 7-alkynyl azepine derivative, successfully connects the claisen reaction, the nucleophilic addition reaction and the intramolecular coupling reaction in series, avoids the separation of intermediates, thereby simplifying the operation steps, not only reducing the reaction cost, but also avoiding the use of a large amount of solvent and eluant, and having good reaction selectivity and high yield. On the other hand, the 7-alkynyl azepine derivative belongs to a seven-membered nitrogen heterocyclic compound which is difficult to synthesize, and the report of constructing the seven-membered medium-sized nitrogen heterocyclic compound by a halogenated alkynylamide one-step method is not seen.
Drawings
FIG. 1 is a single crystal diffractogram of 6-allyl-7-phenylethynyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine compound prepared in example 1 of the present invention.
Detailed Description
The invention is further described below with reference to the drawings and specific preferred embodiments of the description, without thereby limiting the scope of protection of the invention.
The starting materials and equipment used in the following examples are commercially available.
Example 1:
a method for synthesizing a 7-alkynylazepine derivative of the present invention, specifically a 6-allyl-7-phenylethynyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine compound, comprises the steps of:
adding 9mg (0.05mmol) of copper acetate, 18mg (0.10mmol) of 1, 10-phenanthroline, 276mg (2.00mmol) of potassium carbonate, 325mg (1.00mmol) of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 306mg (3.00mmol) of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, and filtering to obtain a crude product of 6-allyl-7-phenylacetylene-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, wherein the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate 20: 1) to obtain a pure product 243mg of the 7-alkynyl azepine derivative, and the yield is 62%.
In the above synthesis, the structural formula of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide is as follows:
the structural formula of phenylacetylene is as follows:
the chemical structural formula of the 6-allyl-7-phenylethynyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine compound prepared by the invention is as follows:
the specific chemical reaction equation is as follows:
the product characterization results were as follows:
as shown in FIG. 1, it is a single crystal diffraction pattern of the product produced in this example.
The product nuclear magnetic data are as follows:
1H NMR(400MHz,CDCl3)δ:7.87(d,J＝8.4Hz,2H),7.29-7.26(m,3H),7.21-7.18(m,4H),5.82-5.72(m,1H),5.19-5.08(m,2H),3.44-3.42(m,2H),3.18(d,J＝6.8Hz,2H),2.43-2.41(m,2H),2.36(s,3H),1.94-1.89(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:150.5,142.8,138.2,133.8,131.3,129.2,128.2,128.1,127.5,122.8,120.4,117.4,93.6,84.8,49.7,40.6,32.1,31.0,23.7,21.4。
the product high resolution data is as follows:
HRMS(ESI)for C24H25NO2S[M+H]+calcd.392.1679,found.392.1682。
in combination with the above characterization, this example indeed yielded 6-allyl-7-phenylethynyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine compounds.
Example 2:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: the copper acetate is replaced by copper sulfate for catalytic reaction, the copper sulfate is 8mg, and 148mg of the pure 6-allyl-7-phenylethynyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine compound is obtained, and the yield is 38%.
Example 3:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: replacing copper acetate with copper chloride for catalyzing reaction: copper chloride (7 mg) gave 172mg of pure 6-allyl-7-phenylethynyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine compound in 44% yield.
Example 4:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: copper trifluoromethanesulfonate is used for replacing copper acetate to perform catalytic reaction, 11mg of copper trifluoromethanesulfonate is used for obtaining 199mg of a pure 6-allyl-7-phenylethynyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine compound, and the yield is 51%.
Example 5:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: replacing 1, 10-phenanthroline with 2,2 '-bipyridine for auxiliary catalytic reaction, wherein the amount of 2,2' -bipyridine is 16mg, and the crude product is analyzed by thin layer chromatography (the liquid of developing solution is petroleum ether: ethyl acetate: 20: 1) to find no product.
Example 6:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: pyridine is used for replacing 1, 10-phenanthroline for auxiliary reaction, the content of pyridine is 18mg, and the crude product is analyzed by adopting a thin layer chromatography (petroleum ether and ethyl acetate are 20: 1 in developing solution liquid) to find that no product exists.
Example 7:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: replacing 1, 10-phenanthroline with tetramethyl ethylenediamine for auxiliary reaction, wherein the amount of tetramethyl ethylenediamine is 12mg, and the crude product is analyzed by thin-layer chromatography (the liquid of developing solution is petroleum ether and ethyl acetate is 20: 1) to find no product.
Example 8:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: replacing 1, 10-phenanthroline with dimethyl ethylenediamine for auxiliary reaction, wherein the amount of the dimethyl ethylenediamine is 9mg, and analyzing a crude product by using a thin layer chromatography (petroleum ether and ethyl acetate are 20: 1 as developing solution liquid) to find that no product is generated.
Example 9:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: sodium carbonate was used as an alkaline carbonate in place of potassium carbonate, and the amount of sodium carbonate was 212mg, whereby 145mg of a pure 7-alkynylazepine derivative was obtained in a 37% yield.
Example 10:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: potassium carbonate was replaced with cesium carbonate of 652mg to give 168mg of a pure 7-alkynylazepine derivative in 43% yield.
Example 11:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: acetonitrile is used as a solvent instead of toluene to obtain 223mg of a pure 7-alkynyl azepine derivative with a yield of 57%.
Example 12:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: tetrahydrofuran was used as a solvent instead of toluene as a solvent to obtain 152mg of a pure 7-alkynylazepine derivative in 39% yield.
Example 13:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: the 5 mol% of chemical equivalent of copper acetate was replaced by 10 mol% of chemical equivalent of copper acetate to obtain 254mg of a pure 7-alkynylazepine derivative in 65% yield.
Example 14:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: replacing 10 mol% of 1, 10-phenanthroline with 20 mol% of 1, 10-phenanthroline with chemical equivalent, and taking 1, 10-phenanthroline as 36mg to obtain a 7-alkynyl azepine derivative pure product of 238mg with a yield of 61%.
Example 15:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: phenylacetylene with 5 times of chemical equivalent replaces phenylacetylene with 3 times of chemical equivalent, and the phenylacetylene accounts for 510mg, so that a pure product of the 7-alkynyl azepine derivative with 258mg can be obtained, and the yield is 66%.
Example 16:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: 3 times of chemical equivalent of potassium carbonate was used instead of 2 times of chemical equivalent of potassium carbonate, which was 414mg, to obtain 219mg of a pure product of 7-alkynylazepine derivative, in 56% yield.
Example 17:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: the reaction temperature of 100 ℃ was replaced by the reaction temperature of 80 ℃ to obtain 168mg of a pure 7-alkynylazepine derivative in 43% yield.
Example 18:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: the reaction temperature of 120 ℃ was used instead of the reaction temperature of 100 ℃ to obtain 215mg of a pure 7-alkynylazepine derivative in a yield of 55%.
Example 19:
a synthesis method of a 7-alkynylazepine derivative of the present invention is substantially the same as the procedure of example 1 except that: the reaction time was changed to 8 hours instead of 12 hours, whereby 199mg of a pure 7-alkynylazepine derivative was obtained in 51% yield.
Example 20:
a method for synthesizing a 7-alkynylazepine derivative of the present invention, specifically, a 7-alkynylazepine derivative which is 6-allyl-7-p-methylphenyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, comprises the steps of:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 348mg of p-methylbenzene acetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7-p-methylphenyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a pure product 275mg of 6-allyl-7-p-methylphenyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 68%.
The chemical structure of 6-allyl-7-p-methylphenyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.87(d,J＝8.4Hz,2H),7.20(d,J＝8.0Hz,2H),7.14(d,J＝8.8Hz,2H),6.81(d,J＝8.8Hz,2H),5.82-5.72(m,1H),5.18-5.07(m,2H),3.82(s,3H),3.43-3.41(m,2H),3.16(d,J＝6.8Hz,2H),2.42-2.39(m,2H),2.38(s,3H),1.94-1.88(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:159.6,149.5,142.8,138.3,134.0,132.8,129.2,127.5,120.6,117.3,115.0,113.8,93.6,83.5,55.3,49.7,40.6,32.0,31.1,23.8,21.5；
high resolution data:
HRMS(ESI)for C25H27NO2S[M+H]+calcd.406.1835,found.406.1831.
as is clear from the above-mentioned characteristics, the present invention indeed provides 6-allyl-7-p-methylphenyl-1-p-methylsulfonyl-2, 3,4, 5-tetrahydro-1H-azepine.
Example 21:
the invention relates to a synthesis method of 7-alkynyl azepine derivatives, in particular to 6-allyl-7- (p-methoxyphenylethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, which comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 396mg of p-methoxybenzene acetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- (p-methoxybenzene ethynyl) -1-p-methylbenzene sulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to obtain a pure product of 6-allyl-7- ((p-methoxybenzene ethynyl) -1-p-methylbenzene sulfonyl-2, 3,4, 5-tetrahydro-1H-azepine of 320mg, the yield was 76%.
The chemical structure of 6-allyl-7- ((p-methoxyphenylethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.87(d,J＝8.4Hz,2H),7.20(d,J＝8.0Hz,2H),7.14(d,J＝8.8Hz,2H),6.81(d,J＝8.8Hz,2H),5.82-5.72(m,1H),5.18-5.07(m,2H),3.82(s,3H),3.43-3.41(m,2H),3.16(d,J＝6.8Hz,2H),2.42-2.39(m,2H),2.38(s,3H),1.94-1.88(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:159.6,149.5,142.8,138.3,134.0,132.8,129.2,127.5,120.6,117.3,115.0,113.8,93.6,83.5,55.3,49.7,40.6,32.0,31.1,23.8,21.5；
high resolution data:
HRMS(ESI)for C25H27NO3S[M+H]+calcd.422.1784,found.422.1788.
example 22:
a synthesis method of 7-alkynyl azepine derivative, specifically 6-allyl-7- ((p-chlorophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 408mg of p-chlorobenzeneacetylene and 5mL of toluene in sequence into a 25mL round-bottom flask, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((p-chlorophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to obtain 272mg of a pure product of 6-allyl-7- ((p-chlorophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 64%.
The chemical structure of 6-allyl-7- ((p-chlorophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.84(d,J＝8.0Hz,2H),7.25(d,J＝8.4Hz,2H),7.20(d,J＝8.0Hz,2H),7.11(d,J＝8.4Hz,2H),5.81-5.71(m,1H),5.18-5.08(m,2H),3.44-3.42(m,2H),3.16(d,J＝7.2Hz,2H),2.45-2.39(m,2H),2.37(s,3H),1.93-1.87(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:151.0,142.9,138.2,134.2,133.6,132.4,129.2,128.4,127.4,121.3,120.1,117.5,92.4,85.8,49.7,40.6,32.1,31.0,23.6,21.4；
high resolution data:
HRMS(ESI)for C24H24ClNO2S[M+H]+calcd.426.1289,found.426.1293.
example 23:
the invention relates to a synthesis method of 7-alkynyl azepine derivative, in particular to a synthesis method of 7-alkynyl azepine derivative, which is 6-allyl-7- ((p-fluorophenyl) ethynyl) -1-p-methyl benzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine,
the method comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 360mg of p-fluoroacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((p-fluorophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to obtain a pure product 217mg of 6-allyl-7- ((p-fluorophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 53%.
Nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.85(d,J＝8.0Hz,2H),7.21-7.16(m,4H),6.97(t,J＝8.8Hz,2H),5.81-5.71(m,1H),5.18-5.08(m,2H),3.44-3.42(m,2H),3.16(d,J＝6.8Hz,2H),2.42-2.39(m,2H),2.37(s,3H),1.92-1.88(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:163.7,161.2,150.6,142.9,138.3,133.8,133.2,133.1,129.2,127.5,120.3,118.9,117.4,115.6,115.3,92.5,84.5,84.5,49.7,40.7,32.1,31.0,23.7,21.5；19FNMR(376MHz,CDCl3)δ:-110.8；
high resolution data:
HRMS(ESI)for C24H24FNO2S[M+H]+calcd.410.1585,found.410.1591。
example 24:
a synthesis method of 7-alkynyl azepine derivative, specifically 6-allyl-7- ((p-cyanophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 381mg of p-cyanobenzene acetylene and 5mL of toluene in sequence into a 25mL round-bottom flask, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((p-cyanophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 10: 1) to obtain 175mg of a pure product of 6-allyl-7- ((p-cyanophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 42%.
The chemical structure of 6-allyl-7- ((p-cyanophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.83(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),7.22(d,J＝8.0Hz,2H),5.80-5.70(m,1H),5.19-5.11(m,2H),3.47-3.45(m,2H),3.17(d,J＝6.8Hz,2H),2.40-2.38(m,2H),2.39(s,3H),1.93-1.87(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:152.9,143.1,138.3,133.3,131.8,131.7,129.3,127.7,127.4,119.9,118.4,117.8,111.4,91.8,89.4,49.8,40.7,32.2,30.8,23.5,21.5；
high resolution data:
HRMS(ESI)for C25H24N2O2S[M+H]+calcd.417.1631,found.417.1626.
example 25:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-7- ((p-nitrophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 441mg of p-nitroacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((p-nitrophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 10: 1) to obtain 148mg of a pure product of 6-allyl-7- ((p-nitrophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 34%.
The chemical structure of 6-allyl-7- ((p-nitrophenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:8.15(d,J＝8.8Hz,2H),7.84(d,J＝8.4Hz,2H),7.32(d,J＝8.8Hz,2H),7.24(d,J＝7.6Hz,2H),5.81-5.71(m,1H),5.20-5.12(m,2H),3.48-3.46(m,2H),3.18(d,J＝6.8Hz,2H),2.41-2.38(m,2H),2.40(s,3H),1.93-1.88(m,2H),1.52-1.50(m,2H)；
13C NMR(100MHz,CDCl3)δ:153.4,146.9,143.2,138.3,133.3,131.8,129.7,129.3,127.4,123.4,119.8,117.8,91.6,90.3,49.8,40.8,32.3,30.8,23.5,21.5；
high resolution data:
HRMS(ESI)for C24H24N2O4S[M+H]+calcd.437.1530,found.437.1539.
example 26:
a synthesis method of 7-alkynyl azepine derivative, specifically 6-allyl-7- ((m-methoxyphenyl) ethynyl) -1-p-toluenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 396mg of m-methoxybenzene acetylene and 5mL of toluene in sequence into a 25mL round-bottom flask, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((m-methoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to obtain 303mg of a pure product of 6-allyl-7- ((m-methoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 72%.
The chemical structure of 6-allyl-7- ((m-methoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.86(d,J＝8.4Hz,2H),7.22-7.17(m,3H),6.87-6.79(m,2H),6.78-6.72(m,1H),5.82-5.72(m,1H),5.19-5.08(m,2H),3.79(s,3H),3.44-3.42(m,2H),3.18(d,J＝6.8Hz,2H),2.44-2.40(m,2H),2.37(s,3H),1.94-1.88(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:159.1,150.6,142.9,138.2,133.8,129.2,129.2,127.5,123.9,123.8,120.3,117.4,116.3,114.5,93.5,84.5,55.2,49.7,40.6,32.1,31.0,23.7,21.4；
high resolution data:
HRMS(ESI)for C25H27NO3S[M+H]+calcd.422.1784,found.422.1786.
example 27:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-7- ((o-methoxyphenyl) ethynyl) -1-p-methyl benzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 396mg of o-methoxybenzene acetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((o-methoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to obtain 253mg of a pure product of 6-allyl-7- ((o-methoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 60%.
The chemical structure of 6-allyl-7- ((o-methoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.92(d,J＝8.4Hz,2H),7.28-7.20(m,3H),7.07-7.05(m,1H),6.88-6.83(m,2H),5.86-5.76(m,1H),5.21-5.06(m,2H),3.82(s,3H),3.40-3.38(m,2H),3.25(d,J＝6.8Hz,2H),2.44-2.41(m,2H),2.38(s,3H),1.94-1.88(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:159.9,150.4,142.7,138.1,134.2,132.7,129.6,129.2,127.7,120.6,120.2,117.1,112.3,110.5,90.1,89.0,55.6,49.5,40.7,32.1,31.0,23.8,21.5；
high resolution data:
HRMS(ESI)for C25H27NO3S[M+H]+calcd.422.1784,found.422.1781.
example 28:
a synthesis method of 7-alkynyl azepine derivative, specifically 6-allyl-7- ((3, 5-dimethoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, comprises the following steps:
sequentially adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 486mg of 3, 5-dimethoxyphenylacetylene and 5mL of methylbenzene into a 25mL round-bottom flask, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((3, 5-dimethoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to obtain 6-allyl-7- ((3, 5-dimethoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, pure 3,4, 5-tetrahydro-1H-azepine (302 mg) was obtained in 67% yield.
The chemical structure of 6-allyl-7- ((3, 5-dimethoxyphenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.86(d,J＝8.4Hz,2H),7.21(d,J＝8.0Hz,2H),6.42(t,J＝2.4Hz,1H),6.36(d,J＝2.4Hz,2H),5.82-5.72(m,1H),5.19-5.09(m,2H),3.77(s,6H),3.43-3.41(m,2H),3.17(d,J＝6.8Hz,2H),2.43-2.40(m,2H),2.37(s,3H),1.94-1.88(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:160.4,150.7,142.9,138.2,133.8,129.2,127.5,124.1,120.3,117.4,109.2,101.4,93.6,84.3,55.4,49.7,40.6,32.1,31.0,23.7,21.4；
high resolution data:
HRMS(ESI)for C26H29NO4S[M+H]+calcd.452.1890,found.452.1895.
example 29:
a synthesis method of 7-alkynyl azepine derivative of the invention, the 7-alkynyl azepine derivative is specifically 6-allyl-7- ((2-naphthyl) ethynyl) -1-p-methyl benzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
sequentially adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 456mg of 2-naphthylacetylene and 5mL of toluene into a 25mL round-bottom flask, heating to 100 ℃ to react for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((2-naphthyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (oil ether: ethyl acetate ═ 20: 1) to obtain a pure product 229mg of 6-allyl-7- ((2-naphthyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 52%.
The chemical structure of 6-allyl-7- ((2-naphthyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.90(d,J＝8.4Hz,2H),7.81-7.79(m,1H),7.75-7.72(m,2H),7.68(s,1H),7.50-7.47(m,2H),7.25-7.20(m,3H),5.86-5.75(m,1H),5.22-5.10(m,2H),3.48-3.46(m,2H),3.23(d,J＝6.8Hz,2H),2.46-2.43(m,2H),2.35(s,3H),1.96-1.91(m,2H),1.53-1.51(m,2H)；
13C NMR(100MHz,CDCl3)δ:150.6,142.9,138.4,133.9,132.8,132.7,131.2,129.3,128.0,127.7,127.6,127.5,126.7,126.6,120.4,120.1,117.4,110.0,94.0,85.1,49.8,40.7,32.1,31.1,23.7,21.5；
high resolution data:
HRMS(ESI)for C28H27NO2S[M+H]+calcd.442.1835,found.442.1833.
example 30:
a synthesis method of 7-alkynylazepine derivatives of the present invention, specifically, 7-alkynylazepine derivatives are 6-allyl-7- ((2-pyridyl) ethynyl) -1-p-toluenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, comprising the steps of:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 309mg of 2-ethynylpyridine and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((2-pyridyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to obtain 6-allyl-7- ((2-pyridyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3, 188mg of pure 4, 5-tetrahydro-1H-azepine (purity: yield: 48%).
The chemical structure of 6-allyl-7- ((2-pyridinyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:8.58-8.57(m,1H),7.91(d,J＝8.4Hz,2H),7.64-7.60(m,1H),7.22-7.19(m,4H),5.81-5.71(m,1H),5.19-5.09(m,2H),3.41-3.39(m,2H),3.22(d,J＝6.8Hz,2H),2.40-2.37(m,2H),2.35(s,3H),1.92-1.87(m,2H),1.49-1.47(m,2H)；
13C NMR(100MHz,CDCl3)δ:152.8,149.9,143.1,143.0,137.8,135.9,133.6,129.3,127.7,127.1,122.7,119.8,117.6,92.5,84.7,49.5,40.7,32.1,30.8,23.6,21.4；
high resolution data:
HRMS(ESI)for C23H24N2O2S[M+H]+calcd.393.1631,found.393.1627.
example 31:
a synthesis method of 7-alkynyl azepine derivative, specifically 6-allyl-7- ((2-thienyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 324mg of 2-thiopheneacetylene and 5mL of toluene in a 25mL round-bottom flask in turn, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((2-thienyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a 7-alkynyl azepine derivative 6-allyl-7- ((2-thienyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 278mg of pure 3,4, 5-tetrahydro-1H-azepine was obtained in 70% yield.
The chemical structure of 6-allyl-7- ((2-thienyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.86(d,J＝8.4Hz,2H),7.27-7.25(m,1H),7.22(d,J＝8.0Hz,2H),7.04-7.03(m,1H),6.98-6.95(m,1H),5.81-5.71(m,1H),5.19-5.08(m,2H),3.40-3.38(m,2H),3.15(d,J＝6.8Hz,2H),2.44-2.41(m,2H),2.38(s,3H),1.94-1.89(m,2H),1.51-1.49(m,2H)；
13C NMR(100MHz,CDCl3)δ:150.9,143.0,138.0,133.7,131.8,129.3,127.5,127.4,126.9,122.8,120.2,117.5,88.3,86.8,49.6,40.7,32.2,31.0,23.7,21.5；
high resolution data:
HRMS(ESI)for C22H23NO2S2[M+H]+calcd.398.1243,found.398.1238.
example 32:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-7- (octynyl) -1-p-methyl benzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 330mg of N-octyne and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- (octynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a pure product of 6-allyl-7- (octynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine 211mg, the yield was 53%.
The chemical structure of 6-allyl-7- (octynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.84(d,J＝8.4Hz,2H),7.25(d,J＝8.0Hz,2H),5.77-5.67(m,1H),5.14-5.04(m,2H),3.34-3.32(m,2H),3.06(d,J＝6.8Hz,2H),2.41(s,3H),2.34-2.31(m,2H),2.17(t,J＝7.2Hz,2H),1.89-1.83(m,2H),1.45-1.38(m,4H),1.34-1.23(m,6H),0.88(t,J＝6.8Hz,3H)；
13C NMR(100MHz,CDCl3)δ:148.0,142.7,138.3,134.2,129.0,127.6,120.7,116.9,94.9,75.8,49.5,40.4,31.7,31.3,31.0,28.6,28.4,23.7,22.5,21.5,19.5,14.0；
high resolution data:
HRMS(ESI)for C24H33NO2S[M+H]+calcd.400.2305,found.400.2299.
example 33:
the invention relates to a synthesis method of 7-alkynyl azepine derivatives, in particular to 6-allyl-7- (cyclopropylethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, which comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 198mg of cyclopropylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- (cyclopropylethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a pure product of 6-allyl-7- (cyclopropylethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine of 156mg, the yield was 44%.
The chemical structure of 6-allyl-7- (cyclopropylethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.84(d,J＝8.4Hz,2H),7.27(d,J＝8.0Hz,2H),5.76-5.66(m,1H),5.13-5.04(m,2H),3.33-3.31(m,2H),3.05(d,J＝6.8Hz,2H),2.42(s,3H),2.33-2.30(m,2H),1.88-1.82(m,2H),1.45-1.43(m,2H),1.28-1.21(m,1H),0.78-0.73(m,2H),0.59-0.55(m,2H)；
13C NMR(100MHz,CDCl3)δ:148.4,142.8,138.3,134.2,129.1,127.6,120.6,117.0,97.8,71.2,49.5,40.4,31.8,30.9,23.7,21.5,8.4,0.1；
high resolution data:
HRMS(ESI)for C21H25NO2S[M+H]+calcd.356.1679,found.356.1680.
example 34:
the invention relates to a synthesis method of a 7-alkynyl azepine derivative, in particular to a 7-alkynyl azepine derivative which is 6-allyl-7- ((1-cyclohexenyl) ethynyl) -1-p-methyl benzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 318mg of cyclohexenyl acetylene and 5mL of toluene in sequence into a 25mL round-bottom flask, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7- ((1-cyclohexenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by silica gel column chromatography, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain 6-allyl-7- ((1-cyclohexenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 217mg of pure 5-tetrahydro-1H-azepine was obtained in 55% yield.
The chemical structure of 6-allyl-7- ((1-cyclohexenyl) ethynyl) -1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.86(d,J＝8.4Hz,2H),7.25(d,J＝8.0Hz,2H),5.91-5.89(m,1H),5.78-5.68(m,1H),5.15-5.05(m,2H),3.35-3.33(m,2H),3.09(d,J＝6.8Hz,2H),2.41(s,3H),2.37-2.35(m,2H),2.10-2.07(m,2H),2.01-1.98(m,2H),1.90-1.84(m,2H),1.63-1.55(m,4H),1.47-1.45(m,2H)；
13C NMR(100MHz,CDCl3)δ:149.0,142.7,138.2,134.9,134.0,129.1,127.5,120.6,120.4,117.1,95.5,82.2,49.5,40.6,31.9,30.9,28.8,25.7,23.7,22.2,21.4,21.4；
high resolution data:
HRMS(ESI)for C24H29NO2S[M+H]+calcd.396.1992,found.396.1988.
example 35:
the invention relates to a synthesis method of a 7-alkynyl azepine derivative, wherein the 7-alkynyl azepine derivative is specifically 6-allyl-1-p-toluenesulfonyl-7- ((trimethylsilyl) ethynyl) -2,3,4, 5-tetrahydro-1H-azepine, and the synthesis method comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 325mg of N-allyl-N- (6-chlorohexynyl) p-methylbenzenesulfonamide, 294mg of trimethylsilylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-1-p-methylbenzenesulfonyl-7- ((trimethylsilyl) ethynyl) -2,3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain 174mg of a pure product of 6-allyl-1-p-methylbenzenesulfonyl-7- ((trimethylsilyl) ethynyl) -2,3,4, 5-tetrahydro-1H-azepine, the yield was 45%.
The chemical structure of 6-allyl-1-p-methylbenzenesulfonyl-7- ((trimethylsilyl) ethynyl) -2,3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.88(d,J＝8.4Hz,2H),7.26(d,J＝8.0Hz,2H),5.79-5.69(m,1H),5.16-5.06(m,2H),3.31-3.29(m,2H),3.11(d,J＝6.8Hz,2H),2.42(s,3H),2.40-2.38(m,2H),1.91-1.85(m,2H),1.48-1.46(m,2H),0.13(s,9H)；
13C NMR(100MHz,CDCl3)δ:151.7,142.9,138.0,133.7,129.1,127.7,120.4,117.3,99.7,98.8,49.3,40.8,32.1,30.9,23.7,21.5,-0.2；
high resolution data:
HRMS(ESI)for C21H29NO2SSi[M+H]+calcd.388.1761,found.388.1768.
example 36:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6- (2-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 339mg of N- (6-chlorohexynyl) -N- (2-methylallyl) p-methylbenzenesulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in turn, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6- (2-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain 6- (2-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine (243 mg) pure in 60% yield.
The chemical structural formula of the N- (6-chlorohexynyl) -N- (2-methylallyl) p-methylbenzenesulfonamide is as follows:
the chemical structure of 6- (2-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.87(d,J＝8.4Hz,2H),7.29-7.26(m,3H),7.21-7.17(m,4H),4.83(d,J＝6.0Hz,2H),3.45-3.43(m,2H),3.13(s,2H),2.41-2.38(m,2H),2.36(s,3H),1.96-1.90(m,2H),1.75(s,3H),1.49-1.47(m,2H)；
13C NMR(100MHz,CDCl3)δ:150.5,142.8,142.0,138.3,131.2,129.2,128.2,128.1,127.5,122.8,121.0,113.1,93.3,85.1,49.7,44.6,31.8,31.2,23.7,22.0,21.4；
high resolution data:
HRMS(ESI)for C25H27NO2S[M+H]+calcd.406.1835,found.406.1830.
example 37:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6- (3-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 339mg of N- (6-chlorohexynyl) -N- (3-methylallyl) p-methylbenzenesulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in turn, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6- (3-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain 6- (3-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 211mg of pure 5-tetrahydro-1H-azepine (FIG. 52%) was obtained.
The chemical structural formula of the N- (6-chlorohexynyl) -N- (3-methylallyl) p-methylbenzenesulfonamide is as follows:
the chemical structure of 6- (3-methylallyl) -7-phenylethynyl-1-p-methylbenzenesulfonyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.86(d,J＝8.4Hz,2H),7.29-7.26(m,3H),7.22-7.18(m,4H),5.86-5.78(m,1H),5.15-5.08(m,2H),3.88-3.82(m,1H),3.44-3.42(m,2H),2.36(s,3H),2.30-2.38(m,2H),1.90(t,J＝6.0Hz,2H),1.48-1.42(m,2H),1.17(d,J＝6.8Hz,3H)；
13C NMR(100MHz,CDCl3)δ:155.0,142.8,139.3,138.2,131.3,129.2,128.2,128.1,127.5,122.8,119.6,114.9,93.6,84.6,49.5,41.2,31.0,27.4,24.4,21.4,16.2；
HRMS(ESI)for C25H27NO2S[M+H]+calcd.406.1835,found.406.1828.
example 38:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-1-methylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 249mg of N-allyl-N- (6-chlorohexynyl) methylsulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-1-methylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, and purifying the crude product by silica gel column chromatography, wherein the ratio of petroleum ether to ethyl acetate is 20: 1, so as to obtain 233mg of a pure 6-allyl-1-methylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine product with the yield of 74%.
The chemical structural formula of the N-allyl-N- (6-chlorohexynyl) methylsulfonamide is as follows:
the chemical structure of 6-allyl-1-methylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.44-7.42(m,2H),7.35-7.32(m,3H),5.84-5.74(m,1H),5.21-5.10(m,2H),3.41-3.39(m,2H),3.18(d,J＝6.8Hz,2H),3.14(s,3H),2.46-2.43(m,2H),1.92-1.86(m,2H),1.53-1.51(m,2H)；
13C NMR(100MHz,CDCl3)δ:149.9,133.8,131.2,128.6,128.4,122.5,120.1,117.5,93.9,84.2,49.5,40.6,39.6,32.2,31.5,23.7；
HRMS(ESI)for C18H21NO2S[M+H]+calcd.316.1366,found.316.1363.
example 39:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-1-ethylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 263mg of N-allyl-N- (6-chlorohexynyl) ethyl sulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12H, filtering to obtain a crude product of 6-allyl-1-ethylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, and purifying the crude product by silica gel column chromatography, wherein the ratio of petroleum ether to ethyl acetate is 20: 1, so as to obtain a pure product of 6-allyl-1-ethylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine of 224mg with a yield of 68%.
The chemical structural formula of the N-allyl-N- (6-chlorohexynyl) ethyl sulfonamide is as follows:
the chemical structure of 6-allyl-1-ethylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.42-7.38(m,2H),7.35-7.31(m,3H),5.84-5.74(m,1H),5.21-5.10(m,2H),3.47-3.45(m,2H),3.38-3.32(m,2H),3.19(d,J＝6.8Hz,2H),2.48-2.45(m,2H),1.92-1.87(m,2H),1.53-1.51(m,2H),1.45(t,J＝7.2Hz,3H)；
13C NMR(100MHz,CDCl3)δ:150.8,133.7,131.2,128.6,128.4,122.6,120.0,117.4,93.3,84.6,50.5,47.7,40.8,32.3,31.9,23.7,8.2；
HRMS(ESI)for C19H23NO2S[M+H]+calcd.330.1522,found.330.1527.
example 40:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-7-phenylethynyl-1- (2-thienylsulfonyl) -2,3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 317mg of N-allyl-N- (6-chlorohexynyl) -2-thiophenesulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-7-phenylethynyl-1- (2-thienylsulfonyl) -2,3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a pure product of 6-allyl-7-phenylethynyl-1- (2-thienylsulfonyl) -2,3,4, 5-tetrahydro-1H-azepine 249mg, the yield was 65%.
The chemical structural formula of the N-allyl-N- (6-chlorohexynyl) -2-thiophene sulfonamide is as follows:
the chemical structure of 6-allyl-7-phenylethynyl-1- (2-thienylsulfonyl) -2,3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.71-7.70(m,1H),7.53-7.52(m,1H),7.31-7.29(m,5H),7.01-6.99(m,1H),5.83-5.73(m,1H),5.20-5.09(m,2H),3.45-3.43(m,2H),3.19(d,J＝6.8Hz,2H),2.43-2.40(m,2H),1.96-1.90(m,2H),1.52-1.50(m,2H)；
13C NMR(100MHz,CDCl3)δ:150.5,142.8,138.2,133.8,131.3,129.2,128.2,128.1,127.5,122.8,120.4,117.4,93.6,84.8,49.7,40.6,32.1,31.0,23.7,21.4；
high resolution data:
HRMS(ESI)for C21H21NO2S2[M+H]+calcd.384.1086,found.384.1084.
example 41:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-1- (2-naphthylsulfonyl) -7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 361mg of N-allyl-N- (6-chlorohexynyl) -2-naphthylsulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12H, filtering to obtain a crude product of 6-allyl-1- (2-naphthylsulfonyl) -7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a pure product 239mg of 6-allyl-1- (2-naphthylsulfonyl) -7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 56%.
The chemical structural formula of the N-allyl-N- (6-chlorohexynyl) -2-naphthyl sulfonamide is as follows:
the chemical structure of 6-allyl-1- (2-naphthylsulfonyl) -7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:8.51(s,1H),8.02-7.99(m,1H),7.87-7.83(m,2H),7.76-7.74(m,1H),7.60-7.56(m,1H),7.50-7.46(m,1H),7.22-7.18(m,1H),7.13-7.09(m,2H),6.97-6.95(m,2H),5.82-5.72(m,1H),5.20-5.08(m,2H),3.50-3.49(m,2H),3.19(d,J＝6.8Hz,2H),2.46-2.44(m,2H),1.98-1.94(m,2H),1.52-1.50(m,2H)；
13C NMR(100MHz,CDCl3)δ:150.6,137.9,134.6,133.7,132.0,131.1,129.2,128.8,128.7,128.4,128.1,128.0,127.6,127.0,122.8,122.4,120.2,117.4,93.7,84.4,49.8,40.6,32.1,31.1,23.6；
high resolution data:
HRMS(ESI)for C27H25NO2S[M+H]+calcd.428.1679,found.428.1686.
example 42:
the invention relates to a synthesis method of a 7-alkynyl azepine derivative, wherein the 7-alkynyl azepine derivative is specifically 6-allyl-1-o-chlorophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 345mg of N-allyl-N- (6-chlorohexynyl) -o-chlorobenzenesulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-1-o-chlorophenyl sulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a pure product of 6-allyl-1-o-chlorophenyl sulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine of 201mg, the yield was 49%.
The chemical structural formula of the N-allyl-N- (6-chlorohexynyl) -o-chlorobenzenesulfonamide is as follows:
the chemical structure of 6-allyl-1-o-chlorophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:8.12-8.09(m,1H),7.44-7.42(m,1H),7.29-7.15(m,5H),6.95-6.93(m,2H),5.81-5.71(m,1H),5.19-5.09(m,2H),3.78-3.76(m,2H),3.14(d,J＝6.8Hz,2H),2.56-2.53(m,2H),2.01-1.96(m,2H),1.59-1.54(m,2H)；
13C NMR(100MHz,CDCl3)δ:152.2,139.0,133.5,133.0,132.2,132.0,131.5,131.1,128.2,127.9,126.6,122.3,119.4,117.5,93.5,83.8,51.2,40.8,32.4,32.1,23.6；
high resolution data:
HRMS(ESI)for C23H22ClNO2S[M+H]+calcd.412.1133,found.412.1136.
example 43:
the invention relates to a synthesis method of 7-alkynyl azepine derivatives, and the 7-alkynyl azepine derivatives are specifically 6-allyl-1-p-chlorophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine and comprise the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 345mg of N-allyl-N- (6-chlorohexynyl) -p-chlorobenzenesulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-1-p-chlorophenyl sulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain a pure product of 6-allyl-1-p-chlorophenyl sulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine of 222mg, the yield was 54%.
The chemical structural formula of the N-allyl-N- (6-chlorohexynyl) -p-chlorobenzenesulfonamide is as follows:
the chemical structure of 6-allyl-1-p-chlorophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:7.91(d,J＝8.8Hz,2H),7.38-7.34(m,2H),7.32-7.29(m,3H),7.18-7.16(m,2H),5.82-5.72(m,1H),5.20-5.09(m,2H),3.44-3.42(m,2H),3.18(d,J＝6.8Hz,2H),2.45-2.42(m,2H),1.96-1.91(m,2H),1.53-1.51(m,2H)；
13C NMR(100MHz,CDCl3)δ:151.0,139.5,138.6,133.6,131.2,128.9,128.8,128.5,128.3,122.4,120.0,117.5,93.9,84.4,49.8,40.6,32.1,31.2,23.6；
high resolution data:
HRMS(ESI)for C23H22ClNO2S[M+H]+calcd.412.1133,found.412.1132.
example 44:
a synthetic method of 7-alkynyl azepine derivative, 7-alkynyl azepine derivative is specifically 6-allyl-1-p-cyanophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, and comprises the following steps:
adding 9mg of copper acetate, 18mg of 1, 10-phenanthroline, 276mg of potassium carbonate, 336mg of N-allyl-N- (6-chlorohexynyl) -p-cyanobenzenesulfonamide, 306mg of phenylacetylene and 5mL of toluene in a 25mL round-bottom flask in sequence, heating to 100 ℃ for reaction for 12 hours, filtering to obtain a crude product of 6-allyl-1-p-cyanophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, purifying the crude product by a silica gel column chromatography method, wherein the ratio of petroleum ether to ethyl acetate is 20: 1 to obtain 165mg of a pure product of 6-allyl-1-p-cyanophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine, the yield was 41%.
The chemical structural formula of the N-allyl-N- (6-chlorohexynyl) -p-cyanobenzenesulfonamide is as follows:
the chemical structure of 6-allyl-1-p-cyanophenylsulfonyl-7-phenylethynyl-2, 3,4, 5-tetrahydro-1H-azepine is as follows:
nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ8.07(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,2H),7.37-7.32(m,3H),7.14-7.12(m,2H),5.81-5.71(m,1H),5.20-5.10(m,2H),3.48-3.46(m,2H),3.17(d,J＝6.8Hz,2H),2.47-2.44(m,2H),1.99-1.93(m,2H),1.55-1.53(m,2H)；
13C NMR(100MHz,CDCl3)δ:151.4,145.1,133.3,132.4,131.1,128.8,128.4,128.0,122.1,119.6,117.7,117.4,115.7,94.1,84.0,50.1,40.5,32.0,31.3,23.5；
high resolution data:
HRMS(ESI)for C24H22N2O2S[M+H]+calcd.403.1475,found.403.1473.
the foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make many possible variations and modifications to the disclosed embodiments, or equivalent modifications, without departing from the spirit and scope of the invention, using the methods and techniques disclosed above. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention are still within the scope of the protection of the technical solution of the present invention.

Claims (10)

1. A method for synthesizing a 7-alkynylazepine derivative, characterized by: the synthesis method comprises the steps of placing halogenated alkynylamide compounds, terminal alkyne and alkaline carbonate in an organic solvent under the catalytic action of copper salt and nitrogen ligand, and carrying out serial cyclization reaction by using a one-pot method to obtain the 7-alkynyl azepine derivative;
the halogenated alkynamide compound has a chemical structural formula shown in a formula (1):
the terminal alkyne has a chemical structural formula shown in formula (2) or formula (3):
wherein:
R1is one of alkyl, aryl and heterocyclic radical;
R2is one of alkyl, aryl and heterocyclic radical;
x is halogen;
R3is one of alkyl, aryl, heterocyclic radical, ester radical and silane radical.
2. A method of synthesizing a 7-alkynylazepine derivative according to claim 1, characterized in that:
the R is1When it is an alkyl group, said alkyl group is selected from C1-C6Alkyl groups of (a);
the R is1When the aryl is the phenyl group, the aryl is the phenyl or the substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C6Alkyl radical, C1-C6One of alkoxy, halogen, aldehyde group, cyano, nitro, ester group and naphthyl;
the R is1When a heterocyclic group, the heterocyclic group is selected from three-to seven-membered cyclic compounds containing a heteroatom including oxygen, sulfur or nitrogen.
3. A method of synthesizing a 7-alkynylazepine derivative according to claim 1, characterized in that:
x is chlorine, bromine or iodine;
the R is2When it is an alkyl group, said alkyl group is selected from C1-C3Alkyl groups of (a);
the R is2When the aryl is the phenyl group, the aryl is the phenyl or the substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C3Alkyl radical, C1-C3One of alkoxy, halogen, aldehyde group, cyano, nitro, ester group and naphthyl;
the R is2When it is a heterocyclic group, the heterocyclic group is selected from three-to six-membered cyclic compounds containing a heteroatom including oxygen, sulfur or nitrogen.
4. A method of synthesizing a 7-alkynylazepine derivative according to claim 1, characterized in that:
the R is3When it is an alkyl group, said alkyl group is selected from C1-C6Alkyl groups of (a);
the R is3When the aryl is the phenyl group, the aryl is the phenyl or the substituted phenyl, and the benzene ring of the substituted phenyl at least comprises C1-C6Alkyl radical, C1-C6One of alkoxy, halogen, aldehyde group, cyano, nitro, ester group and naphthyl;
the R is3When heterocyclic, the heterocyclic is selected from three-to seven-membered cyclic compounds containing heteroatoms, including oxygen, sulfur, or nitrogen;
the R is3When an ester group is present, the ester group is selected from C1-C6An alkoxyacyl group of (a);
the R is3When it is a silane group, said silane group is selected from C1-C6Silane group (b) of。
5. A method of synthesizing a 7-alkynylazepine derivative according to any one of claims 1 to 4, characterized in that: the copper salt comprises at least one of copper acetate, copper sulfate, copper chloride, cuprous chloride and copper trifluoromethanesulfonate.
6. A method of synthesizing a 7-alkynylazepine derivative according to any one of claims 1 to 4, characterized in that: the nitrogen ligand comprises at least one of 1, 10-phenanthroline, 2' -bipyridine, pyridine, tetramethylethylenediamine and dimethylethylenediamine.
7. A method of synthesizing a 7-alkynylazepine derivative according to any one of claims 1 to 4, characterized in that: the carbonate includes at least one of sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate.
8. A method of synthesizing a 7-alkynylazepine derivative according to any one of claims 1 to 4, characterized in that: the organic solvent comprises one or more of toluene, acetonitrile and tetrahydrofuran.
9. A method of synthesizing a 7-alkynylazepine derivative according to any one of claims 1 to 4, characterized in that: the molar ratio of the halogenated alkynylamide compound to the terminal alkyne, the copper salt to the nitrogen ligand to the carbonate is 1: 3-5: 0.03-0.10: 0.08-0.20: 2-3;
and/or the conditions of the serial cyclization reaction are as follows: the heating temperature is 80-120 ℃, and the reaction time is 8-12 h.
10. A method of synthesizing a 7-alkynylazepine derivative according to any one of claims 1 to 4, characterized in that: after the cascade cyclization reaction is completed by a one-pot method, filtering and separating to obtain a crude product of the 7-alkynyl azepine derivative, and purifying the crude product of the 7-alkynyl azepine derivative by a silica gel column chromatography to obtain a pure product of the 7-alkynyl azepine derivative.
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