Nitrogen-containing heterocyclic compound and preparation method thereof

Abstract

The invention discloses a nitrogen-containing heterocyclic compound and a preparation method thereof, which ingeniously combines visible light catalysis and metal complex catalysis functions, promotes N-aryl sulfonyl substituted conjugated diene and halogenated hydrocarbon to generate free radical addition cyclization reaction, and synthesizes a nitrogen-containing medium (large) ring skeleton heterocyclic molecular compound. The nitrogen-containing heterocyclic compound provided by the invention has cyclic systems with different sizes, and the preparation method adopts a visible light irradiation method, so that the reaction condition is mild, the yield is higher, the substrate range is large, and a target product is easy to obtain. Besides, the preparation method shows wide substrate compatibility, opens up a new way for synthesis of various nitrogen-containing heterocyclic compounds, and has a wide prospect in practical application.

Description

Technical Field

[0001] The present invention relates to the technical field of nitrogen-containing heterocyclic compounds, and in particular to a nitrogen-containing heterocyclic compound and a preparation method and application thereof. Background Art

[0002] In the field of organic synthetic chemistry, the catalytic synthesis of heterocyclic molecular compounds with nitrogen-containing medium (macro) ring skeletons has long been regarded as a challenging problem and cutting-edge research direction in the field of organic synthetic chemistry. Such structures are an indispensable part of many drugs and their core intermediates. Nitrogen-containing heterocyclic compounds have attracted much attention due to their unique physiological activities and pharmacological effects. Such compounds are widely distributed in natural products and various drugs, such as the antidepressant imipramine, the drug suovolexin for the treatment of insomnia, and the new HCV NS3 / 4A protease inhibitor Glecaprevir, all of which contain nitrogen heterocyclic structures. The wide application of these drugs further proves the important position of nitrogen-containing heterocyclic compounds in the medical field.

[0003] As an easily accessible free radical acceptor, conjugated dienes play an important role in free radical-mediated functionalization reactions. Chemists have developed a variety of chemical reactions around conjugated dienes, among which the free radical amination reaction of conjugated dienes is particularly eye-catching. This reaction has become an effective means to prepare various nitrogen-containing heterocyclic compounds, providing a new way to synthesize nitrogen-containing heterocyclic molecules with higher application value.

[0004] At present, the synthesis methods of nitrogen-containing heterocyclic (N-heterocyclic) compounds mainly include metal-catalyzed (such as palladium, cobalt, copper, etc.) cyclization reactions and light- and metal-catalyzed conjugated diene cyclization reactions. Through these metal-catalyzed reactions, five-membered and seven-membered N-heterocyclics containing allylamine structural units can be easily generated. These structural units can be further converted into a variety of high-value molecules after later modification and transformation, providing a rich source of raw materials for drug research and development.

[0005] However, for larger N-heterocycles (such as 8 to 14-membered rings), their synthesis still faces great difficulties due to the limitations of the synthesis method. Existing synthesis methods often have problems such as cumbersome steps, low yield, and serious environmental pollution, which are difficult to meet the needs of large-scale industrial production. Therefore, developing a more environmentally friendly and efficient synthesis process route for N-heterocyclic compounds to overcome the above-mentioned difficulties in the prior art has become a focus issue that many cutting-edge scholars in this field have paid extensive attention to and are committed to solving. Summary of the invention

[0006] In order to solve the above technical problems, the purpose of the present invention is to provide a nitrogen-containing heterocyclic compound and a preparation method thereof.

[0007] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0008] The present invention provides a method for preparing a nitrogen-containing heterocyclic compound, comprising the following steps:

[0009] (1) reacting substituted or unsubstituted 2-hydroxybenzonitrile with bromoalkyl alcohol to obtain substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile, wherein n is an integer of 3 to 9;

[0010] (2) subjecting substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile to an oxidation reaction to obtain substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile;

[0011] (3) subjecting substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile to a Wittig reaction with allyltriphenylphosphine bromide to obtain substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile;

[0012] (4) subjecting substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile to a reduction reaction to obtain substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methylamine;

[0013] (5) reacting substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methylamine with p-toluenesulfonyl chloride to obtain a sulfonyl-protected amino conjugated diene; the sulfonyl-protected amino conjugated diene has the structural formula Among them, R 1 is hydrogen or methoxy, m is an integer from 1 to 7, and m is equal to n-2;

[0014] (6) reacting a sulfonyl-protected amino conjugated diene with a halogenated hydrocarbon under a palladium catalyst and visible light irradiation to obtain the nitrogen-containing heterocyclic compound; the structural formula of the nitrogen-containing heterocyclic compound is Among them, R 1 is hydrogen or methoxy, R is tert-butyl or isopropyl, m is an integer from 1 to 7, and m is equal to n-2.

[0015] Furthermore, in step (1), the structural formula of the substituted or unsubstituted 2-hydroxybenzonitrile is Among them, R 1 It is hydrogen or methoxy.

[0016] Furthermore, in step (1), the substituted or unsubstituted 2-hydroxybenzonitrile is 2-hydroxybenzonitrile or 2-hydroxy-5-methoxybenzonitrile.

[0017] Furthermore, in step (1), the bromoalkyl alcohols may be bromoalkyl alcohols of different chain lengths.

[0018] Furthermore, in step (1), the structural formula of the bromoalkyl alcohol is Here, n is an integer from 3 to 9.

[0019] Furthermore, in step (1), the bromoalkyl alcohol is 3-bromopropanol, 4-bromopropanol, 5-bromopropanol, 6-bromopropanol, 7-bromopropanol, 8-bromopropanol or 9-bromopropanol.

[0020] Furthermore, in step (1), the structural formula of the substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile is Among them, R 1 is hydrogen or methoxy, and n is an integer of 3-9.

[0021] In a specific embodiment, in step (1), substituted or unsubstituted 2-hydroxybenzonitrile is reacted with bromoalkyl alcohol in the presence of a basic compound and a solvent to obtain substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile.

[0022] Further, the alkaline compound is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium carbonate, potassium carbonate (K2CO3), sodium hydroxide, potassium hydroxide, potassium phosphate, sodium phosphate, potassium benzoate, potassium pivalate, triethylamine (Et3N), N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably K2CO3.

[0023] Furthermore, the solvent is selected from one or more of dimethylacetamide (DMA), N,N-dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide and N-methylpyrrolidone, preferably DMF.

[0024] Furthermore, in step (2), the structural formula of the substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile is Among them, R 1 is hydrogen or methoxy, m is an integer from 1 to 7, and m is equal to n-2.

[0025] In a specific embodiment, in step (2), substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile is subjected to an oxidation reaction in the presence of an oxidant and a solvent to obtain substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile.

[0026] Furthermore, the oxidant is Dess-Martin periodinane (DMP).

[0027] Furthermore, the solvent is selected from one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), chloroform, methanol, and dichloromethane (DCM), preferably DCM.

[0028] Furthermore, in step (3), the structural formula of the substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile is Among them, R 1 is hydrogen or methoxy, m is an integer from 1 to 7, and m is equal to n-2.

[0029] In a specific embodiment, in step (3), substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile is reacted with allyltriphenylphosphine bromide in the presence of a strong basic compound and a solvent to obtain substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile.

[0030] Furthermore, the strong alkaline compound is selected from n-butyl lithium (n-BuLi) and / or potassium tert-butoxide.

[0031] Furthermore, the solvent is tetrahydrofuran (THF).

[0032] Further, in step (4), the structural formula of the substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methylamine is Among them, R 1 is hydrogen or methoxy, m is an integer from 1 to 7, and m is equal to n-2.

[0033] In a specific embodiment, in step (4), substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile is subjected to a reduction reaction in the presence of a reducing agent and a solvent to obtain substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methanamine.

[0034] Furthermore, the reducing agent is one or more of borane tetrahydrofuran solution, borane dimethyl sulfide solution, sodium borohydride, and lithium aluminum tetrahydride (LiAlH4), preferably LiAlH4.

[0035] Furthermore, the solvent is tetrahydrofuran (THF), ether, or dichloromethane, preferably THF.

[0036] In a specific embodiment, in step (5), substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methanamine is reacted with p-toluenesulfonyl chloride (TsCl) in the presence of a basic compound and a solvent to obtain a sulfonyl-protected amino conjugated diene.

[0037] Furthermore, the alkaline compound is selected from one or more of sodium carbonate, sodium hydroxide, triethylamine (Et3N), diisopropylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably Et3N.

[0038] Furthermore, the solvent is selected from one or more of dimethylacetamide (DMA), N,N-dimethylformamide (DMF), and dichloromethane (DCM), preferably DCM.

[0039] Furthermore, in step (5), the sulfonyl-protected amino-conjugated diene is selected from one of the following structures:

[0040]

[0041] Furthermore, in step (6), the halogenated hydrocarbon is a bromohydrocarbon, an iodohydrocarbon, a fluorohydrocarbon or a chlorohydrocarbon, preferably a bromohydrocarbon.

[0042] Furthermore, the brominated hydrocarbon is tert-butyl bromide or isopropyl bromide.

[0043] Furthermore, in step (6), the molar ratio of the sulfonyl-protected amino conjugated diene to the halogenated hydrocarbon is 1:(1-5), preferably 1:4.

[0044] Furthermore, in step (6), the palladium catalyst is selected from one or more of tetrakistriphenylphosphine palladium (Pd(PPh3)4), palladium acetate, palladium trifluoroacetate, bistriphenylphosphine palladium dichloride, 1,1'-bisdiphenylphosphinoferrocene palladium dichloride, bisdibenzylideneacetone palladium, di(tri-tert-butylphosphine)palladium and bis[1,2-bis(diphenylphosphino)ethane]palladium, preferably Pd(PPh3)4.

[0045] In a specific embodiment, in step (6), a sulfonyl-protected amino conjugated diene is subjected to a free radical addition cyclization reaction with a halogenated hydrocarbon in the presence of a palladium catalyst, a ligand, a basic compound, a solvent and visible light to obtain the nitrogen-containing heterocyclic compound.

[0046] Further, the ligand is selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis(2-diphenylphosphinophenyl) ether (DPEPhos), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 1,2-bis(diphenylphosphino)ethane, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (R)-2,2′- One or more of bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,5-bis(diphenylphosphino)pentane, 2-dicyclohexylphosphino-2'-methylbiphenyl and 4,4'-bis(tert-butyl)-2,2'-bipyridine, preferably DPEPhos.

[0047] Furthermore, the alkaline compound is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium carbonate, potassium carbonate (K2CO3), sodium hydroxide, potassium hydroxide, potassium phosphate, sodium phosphate, potassium benzoate, potassium pivalate, triethylamine (Et3N), N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0048] Furthermore, in step (6), the molar ratio of the sulfonyl-protected amino conjugated diene to the basic compound is 1:(1-5), preferably 1:4.

[0049] Furthermore, the solvent is selected from one or more of dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,4-dioxane, trifluorotoluene, acetonitrile, toluene, chlorobenzene, dichloromethane (DCM), dimethyl sulfoxide and N-methylpyrrolidone.

[0050] Furthermore, in step (6), the nitrogen-containing heterocyclic compound is selected from one of the following structures:

[0051]

[0052] The present invention protects the nitrogen-containing heterocyclic compound prepared by the above method.

[0053] Beneficial effects of the present invention:

[0054] The present invention skillfully combines the catalytic functions of visible light and metal complexes to promote free radical addition cyclization reaction between N-arylsulfonyl-substituted conjugated dienes (sulfonyl-protected amino conjugated dienes) and halogenated hydrocarbons, thereby synthesizing nitrogen-containing heterocyclic compounds of various sizes, specifically nitrogen-containing medium (macro) ring skeleton heterocyclic molecular compounds (greater than 8-membered rings).

[0055] The significant beneficial effect of the preparation method provided by the present invention is its mild reaction conditions, which not only greatly simplifies the operation steps, but also significantly improves the synthesis efficiency. In addition, the preparation method shows a wide range of substrate compatibility, which opens up a new way for the synthesis of various nitrogen-containing heterocyclic compounds. Moreover, the various reagents used in the preparation method are easy to obtain from the market and are low in price, which further reduces the synthesis cost, the preparation process is simple, the yield is high, and it has broad prospects in practical applications. DETAILED DESCRIPTION

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0057] The present invention provides a method for preparing a nitrogen-containing heterocyclic compound, comprising the following steps:

[0058] (1) reacting substituted or unsubstituted 2-hydroxybenzonitrile with bromoalkyl alcohol to obtain substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile, wherein n is an integer of 3 to 9;

[0059] (2) subjecting substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile to an oxidation reaction to obtain substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile;

[0060] (3) subjecting substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile to a Wittig reaction with allyltriphenylphosphine bromide to obtain substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile;

[0061] (4) subjecting substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile to a reduction reaction to obtain substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methylamine;

[0062] (5) reacting substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methylamine with p-toluenesulfonyl chloride to obtain a sulfonyl-protected amino conjugated diene; the sulfonyl-protected amino conjugated diene has the structural formula Among them, R 1 is hydrogen or methoxy, m is an integer from 1 to 7, and m is equal to n-2;

[0063] (6) reacting a sulfonyl-protected amino conjugated diene with a halogenated hydrocarbon under a palladium catalyst and visible light irradiation to obtain the nitrogen-containing heterocyclic compound; the structural formula of the nitrogen-containing heterocyclic compound is Among them, R 1 is hydrogen or methoxy, R is tert-butyl or isopropyl, m is an integer from 1 to 7, and m is equal to n-2.

[0064] In a specific embodiment, the preparation method comprises the following steps:

[0065] (1) reacting the compound of formula VII with a brominated alkyl alcohol in the presence of K2CO3 and DMF to obtain a compound of formula VI, the reaction equation being as follows:

[0066] Among them, R 1 is hydrogen or methoxy, and n is an integer of 3-9.

[0067] (2) The compound of formula VI is subjected to an oxidation reaction in the presence of DMP and DCM to obtain a compound of formula V. The reaction equation is as follows:

[0068] Wherein, m is an integer from 1 to 7, and m is equal to n-2.

[0069] (3) The compound of formula V is reacted with allyl triphenylphosphine bromide in the presence of n-BuLi and THF to obtain the compound of formula IV. The reaction equation is as follows:

[0070]

[0071] (4) The compound of formula IV is subjected to a reduction reaction in the presence of LiAlH4 and THF to obtain a compound of formula III. The reaction equation is as follows:

[0072]

[0073] (5) The compound of formula III is reacted with TsCl in the presence of Et3N and DCM to obtain the compound of formula II. The reaction equation is as follows:

[0074]

[0075] (6) The compound of formula II is reacted with a halogenated hydrocarbon in the presence of Pd(PPh3)4, DPEpHos, K2CO3, DMA and visible light to undergo a free radical addition cyclization reaction to obtain a compound of formula I. The reaction equation is as follows:

[0076] Wherein, R is tert-butyl or isopropyl.

[0077] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0078] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods, and the materials, reagents, etc. used are all available from commercial sources unless otherwise specified.

[0079] Example 1

[0080] A method for preparing a nitrogen-containing heterocyclic compound comprises the following steps:

[0081] (1) Potassium carbonate (K2CO3, 2.0 equivalents) was added to a solution of 2-hydroxybenzonitrile (1.0 equivalents) in N,N-dimethylformamide (DMF) at room temperature. After 15 minutes, 3-bromopropanol was added to the above solution to obtain a slurry, which was heated to 60°C and maintained for 12 hours. Thereafter, the solid was filtered off, water was added to the solution, and it was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After removing the sodium sulfate, the organic solvent was concentrated using a rotary evaporator. The residue was then purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula VI-A

[0082]

[0083] (2) At 0°C, Dess-Martin periodinane (DMP, 1.1 equivalents) was added to a solution of the compound of formula VI-A (1.0 equivalents) in dichloromethane (DCM). The reaction was stirred at room temperature for 2 hours, and then the reaction was observed to be complete by thin layer chromatography. The reaction mixture was treated with saturated aqueous sodium thiosulfate solution and then partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was rinsed with saturated brine, dried over sodium sulfate, and carefully concentrated under vacuum, and separated by flash chromatography to obtain the compound of formula V-A

[0084]

[0085] (3) Under an inert atmosphere, a suspension of allyltriphenylphosphine bromide (1.2 equivalents) in dry tetrahydrofuran (THF) is cooled to 0°C, and then n-butyllithium (n-BuLi, 1.3 equivalents) is added dropwise. The reaction is stirred at 0°C for 30 minutes, and then the compound of formula V-A (1.0 equivalent) is added dropwise. The reaction is stirred at room temperature for 4 hours. Thereafter, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is collected, washed with saturated brine, and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel short column chromatography using petroleum ether-ethyl acetate as eluent to obtain a compound of formula IV-A.

[0086] (4) Under an inert atmosphere, lithium aluminum hydride (LiAlH4, 2.0 equivalents) is suspended in dry tetrahydrofuran (THF), cooled to 0°C, and then a solution of the compound of formula IV-A dissolved in dry tetrahydrofuran is added dropwise. The reaction is stirred at room temperature for 4 hours, and the reaction is observed to be complete by thin layer chromatography (TLC). Water (X grams of lithium aluminum hydride corresponds to X milliliters of water) is added dropwise at 0°C, and then X milliliters of 15% sodium hydroxide solution and 3X milliliters of water are slowly added to quench the reaction. Next, anhydrous sodium sulfate is added and stirred at room temperature for 15 minutes. The solid is filtered out and washed 3 times with dichloromethane. The solvent is removed under reduced pressure to obtain the compound of formula III-A It was used directly in the next step without further purification.

[0087] (5) To a solution of the compound of formula III-A (1.0 equivalent) and triethylamine (Et3N, 1.5 equivalent) in dichloromethane (DCM) at 0°C, p-toluenesulfonyl chloride (TsCl, 1.0 equivalent) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting solution was washed with 1.0 M hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution, and then the organic layer was dried over sodium sulfate. The filtrate was concentrated and the residue was purified by silica gel short column chromatography using a petroleum ether-ethyl acetate mixture as the eluent to obtain a clear viscous oil or white solid, i.e., the compound of formula II-A.

[0088] (6) In a dry 10 ml reaction bottle equipped with a magnetic stirrer, tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 23.1 mg, 0.02 mmol), DPEpHos (12.9 mg, 0.024 mmol), compound of formula II-A (71.5 mg, 0.2 mmol), tert-butyl bromide (109.7 mg, 0.8 mmol), K2CO3 (110.6 mg, 0.8 mmol) were added in sequence, followed by N,N-dimethylacetamide (DMA, 2.0 ml). The mixture was degassed and backfilled with argon, and then irradiated with a 22-watt blue light-emitting diode (LED) at 35°C for 48 hours. The reaction solution was extracted twice with ethyl acetate and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, compound of formula I-A. (46.3mg, 56%).

[0089] The compound of formula Ⅰ-A was characterized by NMR and mass spectrometry, and the results were:

[0090] (E)-4-(4,4-Dimethylpent-1-en-1-yl)-5-tosyl-3,4,5,6-tetrahydro-2H-benzo[b][1,5]Oxazocine(IA): 1H NMR(400MHz,Chloroform-d)δ7.65(d,J=8.3Hz,2H),7.47(dd,J=7.5,1.7Hz,1H),7.29(td,J=7.7,1.8Hz, 1H),7.22(d,J=8.1Hz,2H),7.12(td,J=7.5,1.2Hz,1H),7.04(d,J=7.9Hz,1H),5.73(dd,J=15.3,7.4Hz,1 H),5.47-5.39(m,1H),4.68(t,J=7.7Hz,1H),4.53-4.45(d,J=2.9Hz,2H),4.33(td,J=12.1,3.6Hz,1H),4 .03-3.98(m,1H),2.38(s,3H),1.97-1.88(m,1H),1.85(d,J=7.5Hz,2H),1.76-1.68(m,1H),0.79(s,9H). 13 C NMR(151MHz,cdcl3)δ156.3,142.8,138.5,133.0,132.4,131.1,129.7,129.5,127.1 ,126.8,124.7,121.9,71.4,57.1,46.9,42.6,33.7,30.8,29.2,21.4.IR(KBr):ν(cm -1 )2952,1490,1334,1157,1088,714,655.HRMS(ESI)calcd forC 24 H 32 NO3S + [M+H] + :414.2097,found:414.2105.

[0091] Example 2

[0092] (1) Potassium carbonate (2.0 equivalents) was added to a solution of 2-hydroxy-5-methoxybenzonitrile (1.0 equivalents) in N,N-dimethylformamide at room temperature. After 15 minutes, 4-bromopropanol was added to the above solution to obtain a slurry, which was heated to 60°C and maintained for 12 hours. Thereafter, the solid was filtered off, water was added to the solution, and it was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After removing the sodium sulfate, the organic solvent was concentrated using a rotary evaporator. The residue was then purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula VI-B.

[0093] (2) Dess-Martin periodinane (1.1 equivalents) was added to a dichloromethane solution of the compound of formula VI-B (1.0 equivalents) at 0°C. The reaction was stirred at room temperature for 2 hours, and then the reaction was observed to be complete by thin layer chromatography. The reaction mixture was treated with a saturated aqueous sodium thiosulfate solution and then partitioned between an aqueous sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and carefully concentrated under vacuum. The compound of formula V-B was isolated by flash chromatography.

[0094] (3) Under an inert atmosphere, a suspension of allyltriphenylphosphine bromide (1.2 equivalents) in dry tetrahydrofuran is cooled to 0°C, and then n-butyllithium (n-BuLi, 1.3 equivalents) is added dropwise. The reaction is stirred at 0°C for 30 minutes, and then the compound of formula V-B (1.0 equivalents) is added dropwise. The reaction is stirred at room temperature for 4 hours. Thereafter, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is collected, washed with saturated brine, and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula IV-B.

[0095] (4) Under an inert atmosphere, lithium aluminum hydride (2.0 equivalents) is suspended in dry tetrahydrofuran, cooled to 0°C, and then a solution of the compound of formula IV-B dissolved in dry tetrahydrofuran is added dropwise. The reaction is stirred at room temperature for 4 hours, and the reaction is observed to be complete by thin layer chromatography (TLC). Water (X grams of lithium aluminum hydride corresponds to X milliliters of water) is added dropwise at 0°C, and then X milliliters of 15% sodium hydroxide solution and 3X milliliters of water are slowly added to quench the reaction. Next, anhydrous sodium sulfate is added and stirred at room temperature for 15 minutes. The solid is filtered out and washed 3 times with dichloromethane. The solvent is removed under reduced pressure to obtain the compound of formula III-B It was used directly in the next step without further purification.

[0096] (5) To a solution of the compound of formula III-B (1.0 equivalent) and triethylamine (1.5 equivalent) in dichloromethane at 0°C, p-toluenesulfonyl chloride (1.0 equivalent) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting solution was washed with 1.0 M hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution, and then the organic layer was dried over sodium sulfate. The filtrate was concentrated and the residue was purified by silica gel short column chromatography using a petroleum ether-ethyl acetate mixture as the eluent to obtain a clear viscous oil or a white solid, i.e., the compound of formula II-B.

[0097] (6) In a dry 10 ml reaction bottle equipped with a magnetic stirrer, tetrakis(triphenylphosphine)palladium (23.1 mg, 0.02 mmol), DPEPhos (12.9 mg, 0.024 mmol), compound of formula II-B (80.3 mg, 0.2 mmol), tert-butyl bromide (109.7 mg, 0.8 mmol), K2CO3 (110.6 mg, 0.8 mmol) were added in sequence, followed by N,N-dimethylacetamide (2.0 ml). The mixture was degassed and backfilled with argon, and then irradiated with a 22-watt blue light-emitting diode (LED) at 35°C for 48 hours. The reaction solution was extracted twice with ethyl acetate and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, compound of formula I-B. (47.6mg, 52%).

[0098] The compound of formula I-B was characterized by NMR and mass spectrometry, and the results were:

[0099] (E)-5-(4,4-Dimethylpent-1-en-1-yl)-9-methoxy-6-tosyl-2,3,4,5,6,7-hexahydrobenzo[b][1,5]oxazonine(IB): 1 H NMR(600MHz,Chloroform-d)δ7.60(d,J=7.9Hz,2H),7.20(d,J=7.9Hz,2H),6.92(d,J=8.7Hz, 1H),6.87(d,J=3.1Hz,1H),6.80(dd,J=8.8,3.1Hz,1H),5.62-5.55(m,2H),4.50-4.46(m,1H), 4.25(d,J=15.1Hz,1H),4.17-4.15(m,1H),4.08(d,J=15.1Hz,1H),3.97(t,J=10.8Hz,1H),3. 79(s,3H),2.38(s,3H),1.86-1.80(m,3H),1.70-1.64(m,2H),1.49-1.42(m,1H),0.84(s,9H). 13 C NMR(151MHz,Chloroform-d)δ155.1,151.4,142.8,138.1,132.6,131.8,130.2,129.2,1 27.5,121.6,117.3,114.4,74.4,55.6,46.8,30.9,29.7,29.3,24.2,21.4.IR(KBr):ν(cm-1 )2925,1501,1331,1170,803,654.HRMS(ESI)calcd for C 26 H 36 NO4S + [M+H] + :458.2360,found:458.2359.

[0100] Example 3

[0101] (1) Potassium carbonate (2.0 equivalents) was added to a solution of 2-hydroxybenzonitrile (1.0 equivalents) in N,N-dimethylformamide at room temperature. After 15 minutes, 5-bromopropanol was added to the above solution to obtain a slurry, which was heated to 60°C and maintained for 12 hours. Thereafter, the solid was filtered off, water was added to the solution, and it was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After removing the sodium sulfate, the organic solvent was concentrated using a rotary evaporator. The residue was then purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain compound VI-C

[0102] (2) At 0°C, Dess-Martin periodinane (1.1 equivalents) was added to a solution of compound VI-C (1.0 equivalents) in dichloromethane. The reaction was stirred at room temperature for 2 hours, and then the reaction was observed to be complete by thin layer chromatography. The reaction mixture was treated with saturated aqueous sodium thiosulfate solution and then partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and carefully concentrated under vacuum. Compound V-C was isolated by flash chromatography.

[0103] (3) Under an inert atmosphere, a suspension of allyltriphenylphosphine bromide (1.2 equivalents) in dry tetrahydrofuran is cooled to 0°C, and then n-butyllithium (n-BuLi, 1.3 equivalents) is added dropwise. The reaction is stirred at 0°C for 30 minutes, and then the compound of formula V-C (1.0 equivalent) is added dropwise. The reaction is stirred at room temperature for 4 hours. Thereafter, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is collected, washed with saturated brine, and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula IV-C.

[0104] (4) Under an inert atmosphere, lithium aluminum hydride (2.0 equivalents) is suspended in dry tetrahydrofuran, cooled to 0°C, and then a solution of the compound of formula IV-C dissolved in dry tetrahydrofuran is added dropwise. The reaction is stirred at room temperature for 4 hours, and the reaction is observed to be complete by thin layer chromatography (TLC). Water (X grams of lithium aluminum hydride corresponds to X milliliters of water) is added dropwise at 0°C, and then X milliliters of 15% sodium hydroxide solution and 3X milliliters of water are slowly added to quench the reaction. Next, anhydrous sodium sulfate is added and stirred at room temperature for 15 minutes. The solid is filtered out and washed 3 times with dichloromethane. The solvent is removed under reduced pressure to obtain the compound of formula III-C It was used directly in the next step without further purification.

[0105] (5) To a solution of the compound of formula III-C (1.0 equivalent) and triethylamine (1.5 equivalent) in dichloromethane at 0°C, p-toluenesulfonyl chloride (1.0 equivalent) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting solution was washed with 1.0 M hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution, and then the organic layer was dried over sodium sulfate. The filtrate was concentrated and the residue was purified by short column chromatography on silica gel using a petroleum ether-ethyl acetate mixture as the eluent to obtain a clear viscous oil or a white solid, i.e., the compound of formula II-C.

[0106] (6) In a dry 10 ml reaction bottle equipped with a magnetic stirrer, tetrakis(triphenylphosphine)palladium (23.1 mg, 0.02 mmol), DPEPhos (12.9 mg, 0.024 mmol), compound of formula Ⅱ-C (77.1 mg, 0.2 mmol), tert-butyl bromide (109.7 mg, 0.8 mmol), K2CO3 (110.6 mg, 0.8 mmol) were added in sequence, followed by N,N-dimethylacetamide (2.0 ml). The mixture was degassed and backfilled with argon, and then irradiated with a 22-watt blue light-emitting diode (LED) at 35°C for 48 hours. The reaction solution was extracted twice with ethyl acetate and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, compound of formula Ⅰ-C. (40.6mg, 46%).

[0107] The compound of formula Ⅰ-C was characterized by NMR and mass spectrometry, and the results were:

[0108] (E)-6-(4,4-Dimethylpent-1-en-1-yl)-7-tosyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,5]Oxazecine(IC): 1H NMR(400MHz,Chloroform-d)δ7.40(dd,J=7.5,1.7Hz,1H),7.28-7.24(m,3H),7.06(d,J=8.0Hz,2H),6.97(td, J=7.5,1.2Hz,1H),6.77(d,J=8.0Hz,1H),5.65-5.57(m,1H),5.44(dd,J=15.6,5.9Hz,1H),4.42-4.37(m,1H), 4.32-4.29(m,1H),4.26(d,J=14.3Hz,1H),4.03(d,J=14.2Hz,1H),3.47(t,J=7.9Hz,1H),2.33(s,3H),2.20-2 .11(m,1H),1.85(d,J=7.4,1.0Hz,2H),1.82-1.73(m,1H),1.71-1.59(m,3H),1.12-1.12(m,1H),0.85(s,9H). 13 C NMR(151MHz,Chloroform-d)δ158.9,142.3,138.8,133.0,131.7,130.3,129.3,128.9,127.3, 127.1,121.1,114.4,73.0,62.5,47.0,32.0,30.9,30.2,29.3,27.9,23.8,21.4.IR(KBr):ν(cm -1 )2925,1493,1454,1329,1158,742,651.HRMS(ESI)calcd for C 26 H 35 NO3SNa + [M+Na] + :464.2230,found:464.2238.

[0109] Example 4

[0110] (1) Potassium carbonate (2.0 equivalents) was added to a solution of 2-hydroxybenzonitrile (1.0 equivalents) in N,N-dimethylformamide at room temperature. After 15 minutes, 6-bromopropanol was added to the above solution to obtain a slurry, which was heated to 60°C and maintained for 12 hours. Thereafter, the solid was filtered off, water was added to the solution, and it was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After removing the sodium sulfate, the organic solvent was concentrated using a rotary evaporator. The residue was then purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain compound VI-D.

[0111] (2) At 0°C, Dess-Martin periodinane (1.1 equivalents) was added to a solution of compound VI-D (1.0 equivalents) in dichloromethane. The reaction was stirred at room temperature for 2 hours, and then the reaction was observed to be complete by thin layer chromatography. The reaction mixture was treated with saturated aqueous sodium thiosulfate solution and then partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and carefully concentrated under vacuum to obtain compound V-D by flash chromatography.

[0112] (3) Under an inert atmosphere, a suspension of allyltriphenylphosphine bromide (1.2 equivalents) in dry tetrahydrofuran is cooled to 0°C, and then n-butyllithium (n-BuLi, 1.3 equivalents) is added dropwise. The reaction is stirred at 0°C for 30 minutes, and then the compound of formula V-D (1.0 equivalents) is added dropwise. The reaction is stirred at room temperature for 4 hours. Thereafter, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is collected, washed with saturated brine, and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain the compound of formula IV-D.

[0113] (4) Under an inert atmosphere, lithium aluminum hydride (2.0 equivalents) is suspended in dry tetrahydrofuran, cooled to 0°C, and then a solution of the compound of formula IV-D dissolved in dry tetrahydrofuran is added dropwise. The reaction is stirred at room temperature for 4 hours, and the reaction is observed to be complete by thin layer chromatography (TLC). Water (X grams of lithium aluminum hydride corresponds to X milliliters of water) is added dropwise at 0°C, and then X milliliters of 15% sodium hydroxide solution and 3X milliliters of water are slowly added to quench the reaction. Next, anhydrous sodium sulfate is added and stirred at room temperature for 15 minutes. The solid is filtered out and washed 3 times with dichloromethane. The solvent is removed under reduced pressure to obtain the compound of formula III-D It was used directly in the next step without further purification.

[0114] (5) To a solution of the compound of formula III-D (1.0 equivalent) and triethylamine (1.5 equivalent) in dichloromethane at 0°C, p-toluenesulfonyl chloride (1.0 equivalent) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting solution was washed with 1.0 M hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution, and then the organic layer was dried over sodium sulfate. The filtrate was concentrated and the residue was purified by short column chromatography on silica gel using a petroleum ether-ethyl acetate mixture as the eluent to obtain a clear viscous oil or a white solid, i.e., the compound of formula II-D.

[0115] (6) In a dry 10 ml reaction bottle equipped with a magnetic stirrer, tetrakis(triphenylphosphine)palladium (23.1 mg, 0.02 mmol), DPEpHos (12.9 mg, 0.024 mmol), the compound of formula II-D (79.9 mg, 0.2 mmol), tert-butyl bromide (109.7 mg, 0.8 mmol), K2CO3 (110.6 mg, 0.8 mmol) were added in sequence, followed by N,N-dimethylacetamide (2.0 ml). The mixture was degassed and backfilled with argon, and then irradiated with a 22-watt blue light-emitting diode (LED) at 35°C for 48 hours. The reaction solution was extracted twice with ethyl acetate and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, compound of formula I-D. (47.4mg, 52%).

[0116] The compound of formula I-D was characterized by NMR and mass spectrometry, and the results were:

[0117] (E)-7-(4,4-Dimethylpent-1-en-1-yl)-8-tosyl-2,3,4,5,6,7,8,9-octahydrobenzo[b][1]oxa[5]azacycloundecine(ID): 1 H NMR(400MHz,Chloroform-d)δ7.47(dd,J=7.5,1.8Hz,1H),7.25-7.21(m,1H),7.19(d,J=8.3Hz,2H),7.01( d,J=8.1Hz,2H),6.90(td,J=7.4,1.1Hz,1H),6.62(d,J=8.1Hz,1H),5.73-5.65(m,1H),5.46(dd,J=15.6,5 .3Hz,1H),4.47-4.43(m,1H),4.14(d,J=13.9Hz,2H),4.05(d,J=14.0Hz,1H),3.49(dd,J=11.5,8.9Hz,1H) ,2.31(s,3H),2.10-1.99(m,1H),1.88(d,J=7.7Hz,2H),1.72-1.51(m,3H),1.51-1.15(m,4H),0.87(s,9H). 13C NMR(151MHz,Chloroform-d)δ157.0,142.0,138.7,134.2,131.8,130.2,129.3,128.7,127.1,124 .6,119.6,109.6,67.8,61.0,47.1,44.5,30.9,29.3,28.1,26.4,24.4,24.0,21.4.IR(KBr):ν(cm -1 )2935,1494,1454,1335,1158,784,693,649.HRMS(ESI)calcd for C 26 H 35 NO3SNa + [M+Na] + :478.2386,found:478.2380.

[0118] Example 5

[0119] (1) Potassium carbonate (2.0 equivalents) was added to a solution of 2-hydroxy-5-methoxybenzonitrile (1.0 equivalents) in N,N-dimethylformamide at room temperature. After 15 minutes, 7-bromopropanol was added to the above solution to obtain a slurry, which was heated to 60°C and maintained for 12 hours. Thereafter, the solid was filtered off, water was added to the solution, and it was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After removing the sodium sulfate, the organic solvent was concentrated using a rotary evaporator. The residue was then purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula VI-E.

[0120]

[0121] (2) At 0°C, Dess-Martin periodinane (1.1 equivalents) was added to a solution of compound VI-E (1.0 equivalents) in dichloromethane. The reaction was stirred at room temperature for 2 hours, and then the reaction was observed to be complete by thin layer chromatography. The reaction mixture was treated with saturated aqueous sodium thiosulfate solution and then partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and carefully concentrated under vacuum, and separated by flash chromatography to obtain compound V-E.

[0122]

[0123] (3) Under an inert atmosphere, a suspension of allyltriphenylphosphine bromide (1.2 equivalents) in dry tetrahydrofuran is cooled to 0°C, and then n-butyllithium (n-BuLi, 1.3 equivalents) is added dropwise. The reaction is stirred at 0°C for 30 minutes, and then the compound of formula V-E (1.0 equivalent) is added dropwise. The reaction is stirred at room temperature for 4 hours. Thereafter, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is collected, washed with saturated brine, and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula IV-E.

[0124] (4) Under an inert atmosphere, lithium aluminum hydride (2.0 equivalents) is suspended in dry tetrahydrofuran, cooled to 0°C, and then a solution of the compound of formula IV-E dissolved in dry tetrahydrofuran is added dropwise. The reaction is stirred at room temperature for 4 hours, and the reaction is observed to be complete by thin layer chromatography (TLC). Water (X grams of lithium aluminum hydride corresponds to X milliliters of water) is added dropwise at 0°C, and then X milliliters of 15% sodium hydroxide solution and 3X milliliters of water are slowly added to quench the reaction. Next, anhydrous sodium sulfate is added and stirred at room temperature for 15 minutes. The solid is filtered out and washed 3 times with dichloromethane. The solvent is removed under reduced pressure to obtain the compound of formula III-E It was used directly in the next step without further purification.

[0125] (5) To a solution of the compound of formula III-E (1.0 equivalent) and triethylamine (1.5 equivalent) in dichloromethane at 0°C, p-toluenesulfonyl chloride (1.0 equivalent) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting solution was washed with 1.0 M hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution, and then the organic layer was dried over sodium sulfate. The filtrate was concentrated and the residue was purified by short column chromatography on silica gel using a petroleum ether-ethyl acetate mixture as the eluent to obtain a clear viscous oil or a white solid, i.e., the compound of formula II-E.

[0126] (6) In a dry 10 ml reaction bottle equipped with a magnetic stirrer, tetrakis(triphenylphosphine)palladium (23.1 mg, 0.02 mmol), DPEpHos (12.9 mg, 0.024 mmol), the compound of formula II-E (88.7 mg, 0.2 mmol), tert-butyl bromide (109.7 mg, 0.8 mmol), K2CO3 (110.6 mg, 0.8 mmol) were added in sequence, followed by N,N-dimethylacetamide (2.0 ml). The mixture was degassed and backfilled with argon, and then irradiated with a 22-watt blue light-emitting diode (LED) at 35°C for 48 hours. The reaction solution was extracted twice with ethyl acetate and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, compound of formula I-E. (45.0mg, 45%).

[0127] The compound of formula Ⅰ-E was characterized by NMR and mass spectrometry, and the results were:

[0128] (E)-8-(4,4-Dimethylpent-1-en-1-yl)-12-methoxy-9-tosyl-3,4,5,6,7,8,9,10-octahydro-2H-benzo[b][1]oxa[5]azacyclododecine(IE): 1 H NMR(600MHz,Chloroform-d)δ7.68(d,J=8.0Hz,2H),7.21(d,J=7.9Hz,2H),6.73-6.69(m,2H ),6.41(d,J=2.9Hz,1H),5.68(dd,J=15.3,8.2Hz,1H),5.01-4.96(m,1H),4.42(d,J=13.8Hz ,1H),4.09-4.06(m,1H),4.00(d,J=13.7Hz,1H),3.78-3.74(m,2H),3.58(s,3H),2.39(s,3H ),2.05-1.97(m,2H),1.94-1.79(m,4H),1.58-1.52(m,2H),1.49-1.33(m,4H),0.77(s,9H). 13CNMR(151MHz,Chloroform-d)δ153.3,151.9,142.5,139.1,131.8,131.2,129.1,127.7,125.3,116.3,1 15.2,112.7,66.3,59.4,55.4,46.6,45.1,30.8,29.7,29.2,28.7,26.7,22.7,21.4,20.1.IR(KBr):ν(cm -1 )2925,1501,1331,1170,803,654.HRMS(ESI)calcd forC 29 H 42 NO4S + [M+H] + :500.2829,found:500.2835.

[0129] Example 6

[0130] (1) Potassium carbonate (2.0 equivalents) was added to a solution of 2-hydroxybenzonitrile (1.0 equivalents) in N,N-dimethylformamide at room temperature. After 15 minutes, 8-bromopropanol was added to the above solution to obtain a slurry, which was heated to 60°C and maintained for 12 hours. Thereafter, the solid was filtered off, water was added to the solution, and it was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After removing the sodium sulfate, the organic solvent was concentrated using a rotary evaporator. The residue was then purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula VI-F.

[0131] (2) At 0°C, Dess-Martin periodinane (1.1 equivalents) was added to a dichloromethane solution of the compound of formula VI-F (1.0 equivalents). The reaction was stirred at room temperature for 2 hours, and then the reaction was observed to be complete by thin layer chromatography. The reaction mixture was treated with a saturated aqueous sodium thiosulfate solution and then partitioned between an aqueous sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and carefully concentrated under vacuum. The compound of formula V-F was isolated by flash chromatography.

[0132]

[0133] (3) Under an inert atmosphere, a suspension of allyltriphenylphosphine bromide (1.2 equivalents) in dry tetrahydrofuran is cooled to 0°C, and then n-butyllithium (n-BuLi, 1.3 equivalents) is added dropwise. The reaction is stirred at 0°C for 30 minutes, and then the compound of formula V-F (1.0 equivalents) is added dropwise. The reaction is stirred at room temperature for 4 hours. Thereafter, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is collected, washed with saturated brine, and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain a compound of formula IV-F.

[0134] (4) Under an inert atmosphere, lithium aluminum hydride (2.0 equivalents) is suspended in dry tetrahydrofuran, cooled to 0°C, and then a solution of the compound of formula IV-F dissolved in dry tetrahydrofuran is added dropwise. The reaction is stirred at room temperature for 4 hours, and the reaction is observed to be complete by thin layer chromatography (TLC). Water (X grams of lithium aluminum hydride corresponds to X milliliters of water) is added dropwise at 0°C, and then X milliliters of 15% sodium hydroxide solution and 3X milliliters of water are slowly added to quench the reaction. Next, anhydrous sodium sulfate is added and stirred at room temperature for 15 minutes. The solid is filtered out and washed 3 times with dichloromethane. The solvent is removed under reduced pressure to obtain the compound of formula III-F It was used directly in the next step without further purification.

[0135] (5) To a solution of the compound of formula III-F (1.0 equivalent) and triethylamine (1.5 equivalent) in dichloromethane at 0°C, p-toluenesulfonyl chloride (1.0 equivalent) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting solution was washed with 1.0 M hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution, and then the organic layer was dried over sodium sulfate. The filtrate was concentrated and the residue was purified by silica gel short column chromatography using a petroleum ether-ethyl acetate mixture as the eluent to obtain a clear viscous oil or a white solid, i.e., the compound of formula II-F.

[0136] (6) In a dry 10 ml reaction bottle equipped with a magnetic stirrer, tetrakis(triphenylphosphine)palladium (23.1 mg, 0.02 mmol), DPEPhos (12.9 mg, 0.024 mmol), compound of formula II-F (85.5 mg, 0.2 mmol), isopropyl bromide (98.4 mg, 0.8 mmol), K2CO3 (110.6 mg, 0.8 mmol), and then N,N-dimethylacetamide (2.0 ml) are added in sequence. The mixture is degassed and backfilled with argon, and then irradiated with a 22-watt blue light-emitting diode (LED) at 35°C for 48 hours. The reaction solution is extracted twice with ethyl acetate and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate. The solvent is removed under vacuum, and the residue is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, compound of formula I-F. (60.1mg, 64%).

[0137] The compound of formula I-F was characterized by NMR and mass spectrometry, and the results were:

[0138] (E)-9-(4-Methylpent-1-en-1-yl)-10-tosyl-2,3,4,5,6,7,8,9,10,11-decahydrobenzo[b][1]oxa[5]azacyclotridecine(IF): 1 H NMR(600MHz,Chloroform-d)δ7.77(d,J=8.2Hz,2H),7.72-7.68(m,1H),7.31(d,J=8.0Hz,2H),7.20-7.17(m,1 H),6.97(t,J=7.5Hz,1H),6.81(d,J=8.2Hz,1H),5.18-5.13(m,1H),4.98(dd,J=15.6,6.6Hz,1H),4.53-4.35(m ,2H),4.28(q,J=7.1Hz,1H),4.01-3.98(m,1H),3.96-3.92(m,1H),2.43(s,3H),1.94-1.88(m,1H),1.85-1.73 (m,3H),1.58–1.41(m,4H),1.41-1.32(m,3H),1.29-1.19(m,4H),0.81(d,J=6.6Hz,3H),0.60(d,J=6.6Hz,3H). 13C NMR(151MHz,Chloroform-d)δ155.8,142.9,137.9,134.8,132.2,129.7,129.5,128.1,127.9,127.4,120. 7,111.5,67.7,58.7,42.9,41.9,31.0,28.2,27.0,26.9,26.7,25.9,24.3,22.4,22.0,21.5.IR(KBr):ν(cm -1 )2931,1455,1335,1160,1091,745,655.HRMS(EI)calcd for C 28 H 39 NO3S:469.2651,found:469.2644.

[0139] Example 7

[0140] (1) Potassium carbonate (2.0 equivalents) was added to a solution of 2-hydroxybenzonitrile (1.0 equivalents) in N,N-dimethylformamide at room temperature. After 15 minutes, 9-bromopropanol was added to the above solution to obtain a slurry, which was heated to 60°C and maintained for 12 hours. Thereafter, the solid was filtered off, water was added to the solution, and it was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After removing the sodium sulfate, the organic solvent was concentrated using a rotary evaporator. The residue was then purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain compound VI-G.

[0141] (2) Dess-Martin periodinane (1.1 equivalents) was added to a solution of compound VI-G (1.0 equivalents) in dichloromethane at 0°C. The reaction was stirred at room temperature for 2 hours, and then the reaction was observed to be complete by thin layer chromatography. The reaction mixture was treated with saturated aqueous sodium thiosulfate solution and then partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and carefully concentrated under vacuum to obtain compound V-G by flash chromatography.

[0142]

[0143] (3) Under an inert atmosphere, a suspension of allyltriphenylphosphine bromide (1.2 equivalents) in dry tetrahydrofuran is cooled to 0°C, and then n-butyllithium (n-BuLi, 1.3 equivalents) is added dropwise. The reaction is stirred at 0°C for 30 minutes, and then the compound of formula V-G (1.0 equivalents) is added dropwise. The reaction is stirred at room temperature for 4 hours. Thereafter, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is collected, washed with saturated brine, and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by silica gel short column chromatography using petroleum ether-ethyl acetate as an eluent to obtain the compound of formula IV-G.

[0144] (4) Under an inert atmosphere, lithium aluminum hydride (2.0 equivalents) is suspended in dry tetrahydrofuran, cooled to 0°C, and then a solution of the compound of formula IV-G dissolved in dry tetrahydrofuran is added dropwise. The reaction is stirred at room temperature for 4 hours, and the reaction is observed to be complete by thin layer chromatography (TLC). Water (X grams of lithium aluminum hydride corresponds to X milliliters of water) is added dropwise at 0°C, and then X milliliters of 15% sodium hydroxide solution and 3X milliliters of water are slowly added to quench the reaction. Next, anhydrous sodium sulfate is added and stirred at room temperature for 15 minutes. The solid is filtered out and washed 3 times with dichloromethane. The solvent is removed under reduced pressure to obtain the compound of formula III-G It was used directly in the next step without further purification.

[0145] (5) To a solution of the compound of formula III-G (1.0 equivalent) and triethylamine (1.5 equivalent) in dichloromethane at 0°C, p-toluenesulfonyl chloride (1.0 equivalent) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting solution was washed with 1.0 M hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution, and then the organic layer was dried over sodium sulfate. The filtrate was concentrated and the residue was purified by silica gel short column chromatography using a petroleum ether-ethyl acetate mixture as the eluent to obtain a clear viscous oil or a white solid, i.e., the compound of formula II-G.

[0146] (6) In a dry 10 ml reaction bottle equipped with a magnetic stirrer, tetrakis(triphenylphosphine)palladium (23.1 mg, 0.02 mmol), DPEpHos (12.9 mg, 0.024 mmol), compound of formula II-G (88.3 mg, 0.2 mmol), isopropyl bromide (98.4 mg, 0.8 mmol), K2CO3 (110.6 mg, 0.8 mmol), and then N,N-dimethylacetamide (2.0 ml) are added in sequence. The mixture is degassed and backfilled with argon, and then irradiated with a 22-watt blue light-emitting diode (LED) at 35°C for 48 hours. The reaction solution is extracted twice with ethyl acetate and saturated sodium chloride solution, and the organic phase is dried over sodium sulfate. The solvent is removed under vacuum, and the residue is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, compound of formula I-G. (59.0mg, 61%).

[0147] The compound of formula I-G was characterized by NMR and mass spectrometry, and the results were:

[0148] (E)-10-(4-Methylpent-1-en-1-yl)-11-tosyl-3,4,5,6,7,8,9,10,11,12-decahydro-2H-benzo[b][1]oxa[5]azacyclotetradecine(IG): 1 H NMR(600MHz,Chloroform-d)δ7.77(d,J=8.2Hz,2H),7.69(dd,J=7.4,1.7Hz,1H),7.29(d,J=8.0Hz,2H),7.18-7.15(m, 1H),6.94(t,J=7.5Hz,1H),6.77(dd,J=8.2,1.1Hz,1H),5.16-5.11(m,1H),5.02(dd,J=15.8,5.7Hz,1H),4.47-4.35(m ,3H),4.00-3.91(m,2H),2.42(s,3H),1.98-1.93(m,1H),1.76-1.70(m,2H),1.70-1.61(m,2H),1.61-1.52(m,1H),1.5 2-1.37(m,3H),1.36-1.31(m,2H),1.29-1.15(m,4H),1.14-1.05(m,2H),0.84(d,J=6.5Hz,3H),0.54(d,J=6.7Hz,3H). 13C NMR(151MHz,Chloroform-d)δ155.6,143.0,138.2,133.7,129.5,129.1,128.5,127.7,127.5,127.3,120.3,1 10.2,67.5,58.0,41.8,41.7,31.5,28.1,26.9,26.7,26.2,24.9,24.2,23.9,22.4,22.1,21.5.IR(KBr):ν(cm -1 )2922,1492,1453,1334,1154,750,655.HRMS(EI)calcd for C 29 H 41 NO3S:483.2807,found:483.2804.

[0149] The nitrogen-containing heterocyclic compound provided by the present invention has ring systems of different sizes. The preparation method thereof adopts a visible light irradiation method, has mild reaction conditions, high yield, a large substrate range, and is easy to obtain the target product.

[0150] Obviously, the above embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Those skilled in the art should understand that other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing a nitrogen-containing heterocyclic compound, characterized in that: The following steps are involved: (1) reacting substituted or unsubstituted 2-hydroxybenzonitrile with bromoalkyl alcohol to obtain substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile, wherein n is an integer of 3 to 9; (2) subjecting substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile to an oxidation reaction to obtain substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile; (3) subjecting substituted or unsubstituted 2-(n-oxoalkoxy)benzonitrile to a Wittig reaction with allyltriphenylphosphine bromide to obtain substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile; (4) subjecting substituted or unsubstituted 2-(n,n+2-diene-1-oxy)benzonitrile to a reduction reaction to obtain substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methylamine; (5) reacting substituted or unsubstituted (2-(n,n+2-diene-1-oxy)phenyl)methylamine with p-toluenesulfonyl chloride to obtain a sulfonyl-protected amino conjugated diene; the sulfonyl-protected amino conjugated diene has the structural formula Among them, R 1 is hydrogen or methoxy, m is an integer from 1 to 7, and m is equal to n-2; (6) reacting a sulfonyl-protected amino conjugated diene with a halogenated hydrocarbon under a palladium catalyst and visible light irradiation to obtain the nitrogen-containing heterocyclic compound; the structural formula of the nitrogen-containing heterocyclic compound is Among them, R 1 is hydrogen or methoxy, R is tert-butyl or isopropyl, m is an integer from 1 to 7, and m is equal to n-2.

2. The preparation method according to claim 1, characterized in that: In step (1), substituted or unsubstituted 2-hydroxybenzonitrile is reacted with bromoalkyl alcohol in the presence of a basic compound and a solvent to obtain substituted or unsubstituted 2-(n-hydroxyalkoxy)benzonitrile.

3. The preparation method according to claim 2, characterized in that: The alkaline compound is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate, sodium phosphate, potassium benzoate, potassium pivalate, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

4. The preparation method according to claim 2, characterized in that: The solvent is selected from one or more of dimethylacetamide, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide and N-methylpyrrolidone.

5. The preparation method according to claim 1, characterized in that: In step (5), the sulfonyl-protected amino-conjugated diene is selected from one of the following structures:

6. The preparation method according to claim 1, characterized in that: In step (6), the palladium catalyst is selected from one or more of tetrakistriphenylphosphine palladium, palladium acetate, palladium trifluoroacetate, bistriphenylphosphine palladium dichloride, 1,1'-bisdiphenylphosphinoferrocene palladium dichloride, bisdibenzylideneacetone palladium, di(tri-tert-butylphosphine)palladium and bis[1,2-bis(diphenylphosphino)ethane]palladium.

7. The preparation method according to claim 1, characterized in that: In step (6), a sulfonyl-protected amino conjugated diene is subjected to a free radical addition cyclization reaction with a halogenated hydrocarbon in the presence of a palladium catalyst, a ligand, a basic compound, a solvent and visible light irradiation to obtain the nitrogen-containing heterocyclic compound.

8. The preparation method according to claim 7, characterized in that: The ligand is selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis(2-diphenylphosphinophenyl)ether, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 1,2-bis(diphenylphosphino)ethane, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (R)-2,2′-bisphosphino-1,1′-binaphthyl, One or more of (diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,5-bis(diphenylphosphino)pentane, 2-dicyclohexylphosphino-2'-methylbiphenyl and 4,4'-bis(tert-butyl)-2,2'-bipyridine.

9. The preparation method according to claim 1, characterized in that: In step (6), the nitrogen-containing heterocyclic compound is selected from one of the following structures:

10. A nitrogen-containing heterocyclic compound prepared by the method according to any one of claims 1 to 9.

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