CN106866670A - A kind of spiral shell [3,5` pyrroles [2,1 a] isoquinolin Oxoindole] class compound and preparation method thereof - Google Patents

A kind of spiral shell [3,5` pyrroles [2,1 a] isoquinolin Oxoindole] class compound and preparation method thereof Download PDF

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CN106866670A
CN106866670A CN201710297273.0A CN201710297273A CN106866670A CN 106866670 A CN106866670 A CN 106866670A CN 201710297273 A CN201710297273 A CN 201710297273A CN 106866670 A CN106866670 A CN 106866670A
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pyrroles
isoquinolin
oxoindole
spiral shell
class compound
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崔宝东
张廷磊
陈永正
韩文勇
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Zunyi Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

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Abstract

The invention discloses a kind of spiral shell [3,5' pyrroles [2,1 a] isoquinolin Oxoindole] class compound, including to adding 3 oxidizable pyrrole indoles and 2 bromomethyl aromatic bromides in organic solvent, metal palladium catalyst, Phosphine ligands and inorganic base are added, is chemically reacted in a heated condition, reaction completes to obtain the compounds of this invention sterling through treatment, and preparation method is as follows：Preparation method of the invention using 3 easily prepared oxidizable pyrrole indoles and the 2 bromomethyl aromatic bromides that are easy to get of business as raw material, by nucleophilic displacement of fluorine/C (sp2) H arylation one kettle ways cascade reaction obtains that a series of structures are novel and diversified spiral shell [3,5' pyrroles [2,1 a] isoquinolin Oxoindole] class compound, the features such as with wide application range of substrates, easy to operate, post processing simple and yield higher.

Description

A kind of spiral shell [3,5`- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound and its Preparation method
Technical field
The present invention relates to heterocyclic compound and organic chemical synthesis field, and in particular to a kind of spiral shell [3,5'- pyrroles [2,1- A] isoquinolin-Oxoindole] class compound and preparation method thereof.
Background technology
It is always the educational circles's concern that organises with the nitrogen-containing heterocycle compound of Material synthesis structure diversification simple and easy to get Focus.Indolizine skeleton containing pyrido pyrrole ring is the core texture unit for constituting natural alkaloid, contains this heterocycle The compound of skeleton often has good bioactivity and potential drug value.At present, the acquisition master of indolizine analog derivative To be separated or artificial synthesized method realization by being extracted from natural products.Wherein, artificial synthesized method becomes more and more important, main Will be including the series connection cyclization based on pyrroles or the intramolecular cyclization reaction, pyrroles or unsaturated amine of isoquinolin skeleton etc..
However, existing artificial synthesized technology still suffers from certain limitation, the indolizine analog derivative for such as synthesizing, except indolizine Outside basic framework, mainly some side chains or simultaneously ring structure, its structure type are not extensive enough.It is increasingly complex for space structure Indolizine analog derivative, the especially synthesis of the indolizine analog derivative containing spirane structure, are still a job for challenge.And from From the point of view of the design of medicine and structure-activity relationship, the compound containing spirane structure due to its unique three-dimensional conformation, in space It is upper to be easier and targeted integration, often with more preferable pharmaceutical activity.Therefore, develop easy, efficient synthetic technology and realize knot The synthesis of the novel volution indolizine analog derivative of structure is significant.
The content of the invention
It is an object of the invention to provide one kind with catalyzing by metal palladium 3- oxidizable pyrroles indoles and 2- bromomethyl aryl brominations The nucleophilic displacement of fluorine of thing/C (sp2)-H arylation one kettle way cascade reactions, it is novel and diversified that high yield synthesizes a series of structures The method of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound.
The technical scheme is that, a kind of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound, knot Structure formula is,
In formula：R1It is each independently selected from 5-Me, 5-OMe, 5-F, 5-OCF3、5-Cl、5-Br、7-F、7-Cl、7-CF3Or 7-OCF3；
R2Be each independently selected from H, Me, Et,nPr、nBu、iPr, allyl, Ph or Bn；
Ar is each independently selected from phenyl, methoxy substitution phenyl, [1,3] dioxolane and phenyl, fluorine substituted-phenyl, three Methyl fluoride substituted-phenyl, chlorine substituted-phenyl, naphthyl or thienyl.Wherein, nPr, nBu, iPr are represented respectively：N-propyl, normal-butyl And isopropyl.
The preparation method of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound, comprises the following steps system It is standby：Using 3- oxidizable pyrroles indoles, 2- bromomethyls aromatic bromide as substrate, by metal palladium catalyst, Phosphine ligands and inorganic base It is added sequentially in organic solvent, spiral shell [3,5'- is obtained after being processed through extraction, dry, column chromatography or recrystallization after completion of the reaction Pyrroles [2,1-a] isoquinolin-Oxoindole] class compound, synthetic route is as follows：
Compared with prior art, the present invention has the advantages that：The present invention is with catalyzing by metal palladium 3- oxidizable pyrroles Yin The nucleophilic displacement of fluorine of diindyl and 2- bromomethyl aromatic bromides/C (sp2)-H arylation one kettle way cascade reactions, composite structure it is novel and Diversified spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound, is to new indolizine analog derivative and spiral shell The important supplement of epoxidation Benzazole compounds synthetic method, the new cascade reaction participated in design 3- oxidizable pyrroles indoles, There is spiroheterocyclic compound for synthesizing other new constructions important enlightenment to act on, and the technology has the substrate scope of application Extensively, simple to operate, product is more single, the generation of basic no coupling product, the advantages of easy purification.
Preferably, described metal palladium catalyst is zero valent palladium catalyst or divalence palladium catalyst, the zeroth order palladium chtalyst Agent be tetrakis triphenylphosphine palladium or three (dibenzalacetone) two palladium, the divalence palladium catalyst be palladium, palladium trifluoroacetate, Pivalic acid palladium or palladium bichloride.From these metal palladium catalysts, the yield of product is higher, reaches as high as 92%.
Preferably, the organic solvent is toluene, chlorobenzene, fluorobenzene, benzotrifluoride, mesitylene, dimethyl sulfoxide (DMSO), special penta Alcohol, DMF, Isosorbide-5-Nitrae-dioxane or acetonitrile, reach as high as 92%.
Preferably, the inorganic base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, pivalic acid sodium, potassium phosphate, the tert-butyl alcohol Sodium or potassium tert-butoxide.After these inorganic bases, the yield of product is higher, reaches as high as 92%.
Preferably, the reaction temperature is 120~160 DEG C, and the reaction time is 24~48h.Product under the reaction conditions Produce rate highest.
Preferably, the Phosphine ligands be triphenylphosphine, Isosorbide-5-Nitrae-bis- diphenylphosphine butane, 2,2'- it is double-(diphenyl phosphine) -1, 1'- dinaphthalenes or the double diphenylphosphine -9,9- dimethyl xanthenes of 4,5-.
It is further preferred that the processing method is column chromatography separation method.In the product of generation, part is not solid Body is more practical by column chromatographic isolation and purification.
Brief description of the drawings
Fig. 1 is chipal compounds 3a of the present invention1H NMR spectras；
Fig. 2 is chipal compounds 3a of the present invention13C NMR spectras；
Fig. 3 is chipal compounds 3b of the present invention1H NMR spectras；
Fig. 4 is chipal compounds 3b of the present invention13C NMR spectras；
Fig. 5 is chipal compounds 3c of the present invention1H NMR spectras；
Fig. 6 is chipal compounds 3c of the present invention13C NMR spectras.
Specific embodiment
The present invention is further explained with reference to specific embodiment, but specific embodiment is not to the present invention It is limited in any way.Unless stated otherwise, reagent involved in embodiment, method are reagent and method commonly used in the art.
A kind of novel spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] the class compound of structure of the present invention and its system Preparation Method, the compound 3a~x of synthesis, structural formula is as follows：
Preparation method is comprised the following steps that：
The operating procedure of synthesis representative compound 3a：
Embodiment 1：
Weigh 3- oxidizable pyrrole indoles 1a (59.4mg, 0.3mmol), 2- bromobenzyl bromines 2a (90.0mg, 0.36mmol), Na2CO3(0.75mmol,79.5mg)、Pd(TFA)2(10mol%, 10.0mg) and PPh3(20mol%, 15.7mg) is anti-in hard Ying Guanzhong, is subsequently adding 2.5mL DMF, reaction solution stirring reaction 24h at 140 DEG C.After TLC monitoring reactions are carried out completely, to 10.0mL water is added in reaction solution, and is extracted with ethyl acetate (6 × 6mL).The saline solution of the organic phase saturation obtained by merging Washing, anhydrous sodium sulfate drying, filtering and concentration.The residue of last gained is through column chromatography (petrol ether/ethyl acetate=5:1) Isolate and purify to obtain target compound 3a (yield 72%).
Embodiment 2：
Weigh 3- oxidizable pyrrole indoles 1a (39.6mg, 0.2mmol), 2- bromobenzyl bromines 2a (50.0mg, 0.2mmol), Na2CO3 (0.5mmol,53.0mg)、Pd2(dba)3(10mol%, 18.3mg) and PPh3(20mol%, 10.5mg) is in hard reaction pipe In, it is subsequently adding 2.0mL DMF, reaction solution stirring reaction 10h at 140 DEG C.After TLC monitoring reactions are carried out completely, to reaction 10.0mL water is added in liquid, and is extracted with ethyl acetate (6 × 6mL).The brine It of the organic phase saturation obtained by merging, Anhydrous sodium sulfate drying, filtering and concentration.The residue of last gained is through column chromatography (petrol ether/ethyl acetate=5:1) separate Purify to obtain target compound 3a (yield 53%).
Embodiment 3：
Weigh 3- oxidizable pyrrole indoles 1a (39.6mg, 0.2mmol), 2- bromobenzyl bromines 2a (50.0mg, 0.2mmol), Na2CO3 (0.5mmol,53.0mg)、Pd(TFA)2(10mol%, 6.7mg) and PPh3(20mol%, 10.5mg) in hard reaction pipe, It is subsequently adding 2.0mL DMF, reaction solution stirring reaction 10h at 160 DEG C.After TLC monitoring reactions are carried out completely, in reaction solution 10.0mL water is added, and is extracted with ethyl acetate (6 × 6mL).It is the brine It of the organic phase saturation obtained by merging, anhydrous Sodium sulphate is dried, filters and concentrated.The residue of last gained is through column chromatography (petrol ether/ethyl acetate=5:1) isolate and purify Obtain target compound 3a (yield 48%).
Embodiment 4：
Weigh 3- oxidizable pyrrole indoles 1a (39.6mg, 0.2mmol), 2- bromobenzyl bromines 2a (50.0mg, 0.2mmol), NaOPiv(0.5mmol,71.1mg)、Pd(TFA)2(10mol%, 6.7mg) and PPh3(20mol%, 10.5mg) is in hard reaction Guan Zhong, is subsequently adding 2.0mL DMF, reaction solution stirring reaction 10h at 140 DEG C.After TLC monitoring reactions are carried out completely, to anti- Addition 10.0mL water in liquid is answered, and is extracted with ethyl acetate (6 × 6mL).The salt washing of the organic phase saturation obtained by merging Wash, anhydrous sodium sulfate drying, filtering and concentration.The residue of last gained is through column chromatography (petrol ether/ethyl acetate=5:1) divide From purifying to obtain target compound 3a (yield 62%).
Embodiment 5：
Weigh 3- oxidizable pyrrole indoles 1a (39.6mg, 0.2mmol), 2- bromobenzyl bromines 2a (50.0mg, 0.2mmol), Na2CO3 (0.5mmol,53.0mg)、Pd(TFA)2(10mol%, 6.7mg) and PPh3(20mol%, 10.5mg) in hard reaction pipe, It is subsequently adding 2.0mL mesitylene, reaction solution stirring reaction 10h at 140 DEG C.After TLC monitoring reactions are carried out completely, to reaction 10.0mL water is added in liquid, and is extracted with ethyl acetate (6 × 6mL).The brine It of the organic phase saturation obtained by merging, Anhydrous sodium sulfate drying, filtering and concentration.The residue of last gained is through column chromatography (petrol ether/ethyl acetate=5:1) separate Purify to obtain target compound 3a (yield 60%).
The preparation of compound 3b~x：Using with the prepare compound 3a identical reaction conditions of embodiment 1, can respectively obtain Compound 3b~x.
Extracting compound 3a, 3b, 3c carries out spectrum analysis, and NMR spectra is as shown in Fig. 1~Fig. 6.
The data characterization of compound 3a~x is as follows：
3a:Yellow solid；61.8mg, yield 72%；mp 260.5-261.5℃；1H NMR(400MHz, CDCl3), δ 9.17 (s, 1H), 7.68 (d, J=7.6Hz, 1H), 7.36-7.32 (m, 1H), 7.23-7.19 (m, 1H), 7.15- 7.13(m,2H),6.92-6.89(m,1H),6.84-6.79(m,2H),6.72-6.71(m,1H),6.43-6.42(m,1H), 6.25-6.23 (m, 1H), 3.51 (d, J=15.6Hz, 1H), 3.21 (d, J=15.6Hz, 1H)；13C NMR(100MHz, CDCl3),δ177.2,139.6,130.4,129.9,129.2,128.6,127.7,127.3,126.0,124.2,123.4, 122.4,119.0,111.1,110.5,105.6,63.6,39.2.HRMS(ESI)calcd.for C19H14N2NaO[M+Na]+: 309.0998；found:309.0999.
3b:Light yellow solid；61.3mg, yield68%；mp202.6-204.1℃；1H NMR(400MHz, CDCl3), δ 8.68 (s, 1H), 7.66 (d, J=7.7Hz, 1H), 7.35-7.31 (m, 1H), 7.16-7.12 (m, 2H), 7.02 (d, J=7.9Hz, 1H), 6.74 (d, J=7.9Hz, 1H), 6.70 (d, J=3.3Hz, 1H), 6.65 (s, 1H), 6.41 (s, 1H), 6.23 (s, 1H), 3.48 (d, J=15.7Hz, 1H), 3.20 (d, J=15.7Hz, 1H), 2.16 (s, 3H)；13C NMR (100MHz,CDCl3),δ177.0,137.0,133.1,130.4,130.3,130.0,129.1,128.5,127.7,127.3, 126.0,124.9,122.4,119.0,110.6,110.5,105.5,63.6,39.2,21.2.HRMS(ESI)calcd.for C20H17N2O[M+H]+:301.1335；found:301.1323.
3c:Light yellow solid；63.6mg, yield67%；mp176.2-177.2℃；1H NMR(400MHz, CDCl3), δ 8.66 (s, 1H), 7.66 (d, J=7.6Hz, 1H), 7.34-7.30 (m, 1H), 7.13 (d, J=3.9Hz, 2H), 6.79-6.73(m,2H),6.70-6.69(m,1H),6.45(s,1H),6.41(s,1H),6.24(s,1H),3.60(s,3H), 3.53 (d, J=15.6Hz, 1H), 3.18 (d, J=15.6Hz, 1H)；13C NMR(100MHz,CDCl3),δ176.9,156.2, 132.6,131.2,130.3,129.1,128.6,127.8,127.2,126.1,122.4,119.0,114.5,111.3, 111.2,110.6,105.6,63.9,55.7,39.3.HRMS(ESI)calcd.for C20H17N2O2[M+H]+:317.1285； found:317.1301.
3d:Yellow solid；65.7mg, yield72%；mp254.3-255.6℃；1H NMR(400MHz,CDCl3), δ 8.68 (s, 1H), 7.66 (d, J=7.7Hz, 1H), 7.36-7.32 (m, 1H), 7.17-7.12 (m, 2H), 6.94-6.90 (m, 1H), 6.81-6.78 (m, 1H), 6.70-6.69 (m, 1H), 6.49 (d, J=7.5Hz, 1H), 6.43 (d, J=3.3Hz, 1H), 6.24 (s, 1H), 3.56 (d, J=15.6Hz, 1H), 3.13 (d, J=15.6Hz, 1H)；13C NMR(100MHz,CDCl3),δ (d, J=241.3Hz, 1C), 176.8,159.3 135.1,131.4 (d, J=7.9Hz, 1C), 130.2,129.0,128.7, (d, J=23.6Hz, 1C), 128.0,126.7,126.3,122.5,118.9,116.4 112.3 (d, J=24.9Hz, 1C), 111.6 (d, J=7.9Hz, 1C), 110.9,105.8,63.9,39.1.HRMS (ESI) calcd.for C19H14FN2O[M+H]+: 305.1085；found:305.1074.
3e:Light yellow solid；67.4mg, yield70%；mp290.6-291.2℃；1H NMR(400MHz, CDCl3), δ 8.66 (s, 1H), 7.67 (d, J=7.8Hz, 1H), 7.36-7.33 (m, 1H), 7.22-7.19 (m, 1H), 7.16- 7.15 (m, 2H), 6.79-6.77 (m, 2H), 6.70 (s, 1H), 6.41 (s, 1H), 6.25 (s, 1H), 3.51 (d, J=15.7Hz, 1H), 3.18 (d, J=15.6Hz, 1H)；13C NMR(100MHz,CDCl3),δ176.4,137.9,131.5,130.3,130.0, 128.9,128.8,128.6,128.0,126.7,126.3,124.8,122.5,118.9,111.9,110.9,105.8,63.6, 39.2.HRMS(ESI)calcd.for C19H14ClN2O[M+H]+:321.0789；found:321.0777.
3f:Yellow solid；48.4mg, yield53%；mp203.4-204.6℃；1H NMR(400MHz,CDCl3), δ 8.32 (s, 1H), 7.66 (d, J=7.8Hz, 1H), 7.36-7.32 (m, 1H), 7.17-7.13 (m, 2H), 7.05-7.00 (m, 1H), 6.86-6.81 (m, 1H), 6.71-6.70 (m, 1H), 6.55 (d, J=7.5Hz, 1H), 6.46-6.45 (m, 1H), 6.26- 6.24 (m, 1H), 3.60 (d, J=15.5Hz, 1H), 3.15 (d, J=15.5Hz, 1H)；13C NMR(100MHz,CDCl3),δ (d, J=243.9Hz, 1C), 175.6,147.2 132.5 (d, J=2.6Hz, 1C), 130.2,129.0,128.6,127.9, (d, J=12.6Hz, 1C), 126.8,126.5 126.1,124.2 (d, J=5.7Hz, 1C), 122.5,119.9 (d, J=3.6 Hz, 1C), 119.0,116.9 (d, J=16.9Hz, 1C), 110.8,105.7,63.7,39.2.HRMS (ESI) calcd.for C19H14FN2O[M+H]+:305.1085；found:305.1090.
3g:Yellow solid；69.3mg, yield72%；mp222.6-223.4℃；1H NMR(400MHz,CDCl3), δ 7.77 (s, 1H), 7.66 (d, J=7.7Hz, 1H), 7.35-7.32 (m, 1H), 7.23 (s, 1H), 7.17-7.13 (m, 2H), 6.86-6.82 (m, 1H), 6.70 (d, J=3.2Hz, 1H), 6.66 (d, J=7.5Hz, 1H), 6.44 (s, 1H), 6.26-6.24 (m, 1H), 3.59 (d, J=15.5Hz, 1H), 3.16 (d, J=15.5Hz, 1H)；13C NMR(100MHz,CDCl3),δ 175.1,136.8,131.3,130.2,129.7,129.0,128.6,128.0,126.8,126.2,124.4,122.6, 122.5,119.0,115.6,110.8,105.8,64.4,39.3.HRMS(ESI)calcd.for C19H13ClN2NaO[M+Na ]+:343.0609；found:343.0604.
3h:Grey solid；80.8mg, yield76%；mp232.6-233.7℃；1H NMR(400MHz,CDCl3),δ 8.41 (s, 1H), 7.68 (d, J=7.6Hz, 1H), 7.46 (d, J=7.8Hz, 1H), 7.37-7.34 (m, 1H), 7.18-7.15 (m, 2H), 6.99-6.95 (m, 1H), 6.91 (d, J=7.4Hz, 1H), 6.73-6.72 (m, 1H), 6.46 (s, 1H), 6.27 (s, 1H), 3.63 (d, J=15.5Hz, 1H), 3.15 (d, J=15.5Hz, 1H)；13C NMR(100MHz,CDCl3),δ175.8, 136.6,131.5,130.2,129.0,128.7,128.0,127.7,126.6,126.5,126.2,125.1,123.3, (q, J=33.1Hz, 1C), 122.5,119.0,112.9 110.9,105.9,62.6,39.2.HRMS (ESI) calcd.for C20H13F3N2NaO[M+Na]+:377.0872；found:377.0870.
3i:Yellow solid；82.2mg, yield74%；mp274.3-275.4℃；1H NMR(400MHz,CDCl3), δ8.12(s,1H),7.67-7.65(m,1H),7.36-7.32(m,1H),7.18-7.14(m,3H),6.92-6.88(m,1H), 6.71-6.69 (m, 2H), 6.44-6.43 (m, 1H), 6.26-6.24 (m, 1H), 3.60 (d, J=15.5Hz, 1H), 3.16 (d, J =15.5Hz, 1H)；13C NMR(100MHz,CDCl3),δ175.3,132.3,132.2,131.9,130.2,129.0,128.7, 128.0,126.7,126.2,124.1,122.9,122.6,122.5,119.0,110.9,105.9,63.7,39.2.HRMS (ESI)calcd.for C20H13F3N2NaO2[M+Na]+:393.0821；found:393.0804.
3j:Light yellowsolid；82.9mg, yield92%；mp155.3-157.1℃；1H NMR(400MHz, CDCl3), δ 7.67 (d, J=5.7Hz, 1H), 7.33-7.32 (m, 2H), 7.13 (s, 2H), 6.93-6.92 (m, 2H), 6.80 (d, J=5.0Hz, 1H), 6.69 (s, 1H), 6.36 (s, 1H), 6.22 (s, 1H), 3.55 (d, J=13.9Hz, 1H), 3.32 (s, 3H), 3.12 (d, J=13.6Hz, 1H)；13C NMR(100MHz,CDCl3),δ174.6,142.2,130.4,129.8,129.6, 129.3,128.6,127.7,127.4,126.0,124.0,123.4,122.4,118.9,110.4,108.8,105.5,63.2, 39.3,26.8.HRMS(ESI)calcd.for C20H16N2NaO[M+Na]+:323.1155；found:323.1165.
3k:Yellow solid；79.2mg, yield84%；mp156.8-158.2℃；1H NMR(400MHz,CDCl3), δ 7.65 (d, J=2.0Hz, 1H), 7.34-7.29 (m, 2H), 7.12 (s, 2H), 6.93 (d, J=7.7Hz, 1H), 6.90-6.86 (m, 1H), 6.77 (d, J=7.4Hz, 1H), 6.68 (s, 1H), 6.35 (s, 1H), 6.21 (s, 1H), 3.86 (q, J=6.7Hz, 2H), 3.57 (d, J=15.5Hz, 1H), 3.08 (d, J=15.4Hz, 1H), 1.35 (t, J=6.6Hz, 3H)；13C NMR (100MHz,CDCl3),δ174.3,141.2,130.3,129.9,129.7,129.3,128.6,127.7,127.4,126.0, 124.2,123.2,122.4,118.7,110.4,108.9,105.5,63.1,39.1,35.3,12.9.HRMS(ESI) calcd.for C21H19N2O[M+H]+:315.1492；found:315.1479.
3l:Yellow solid；77.8mg, yield79%；mp157.4-158.6℃；1H NMR(400MHz,CDCl3), δ 7.66 (d, J=7.8Hz, 1H), 7.33-7.28 (m, 2H), 7.15-7.12 (m, 2H), 6.93-6.86 (m, 2H), 6.76 (d, J =7.2Hz, 1H), 6.68 (d, J=2.2Hz, 1H), 6.36 (s, 1H), 6.22-6.20 (m, 1H), 3.80-3.75 (m, 2H), 3.57 (d, J=15.5Hz, 1H), 3.08 (d, J=15.5Hz, 1H), 1.84-1.75 (m, 2H), 1.01 (t, J=7.4Hz, 3H)；13C NMR(100MHz,CDCl3),δ174.7,141.6,130.4,129.8,129.7,129.3,128.6,127.7, 127.5,126.0,124.1,123.2,122.4,118.8,110.4,109.1,105.5,63.2,42.0,39.3,20.9, 11.5.HRMS(ESI)calcd.for C22H20N2NaO[M+Na]+:351.1468；found:351.1473.
3m:Light yellow solid；61.7mg, yield63%；mp187.6-188.9℃；1H NMR(400MHz, CDCl3), δ 7.67 (d, J=7.4Hz, 1H), 7.33-7.28 (m, 2H), 7.13 (s, 2H), 6.92-6.90 (m, 2H), 6.84- 6.80 (m, 1H), 6.70 (s, 1H), 6.37 (s, 1H), 6.23 (s, 1H), 5.97-5.87 (m, 1H), 5.29 (d, J=13.5Hz, 2H), 4.43 (s, 2H), 3.58 (d, J=15.5Hz, 1H), 3.13 (d, J=15.4Hz, 1H)；13C NMR(100MHz, CDCl3),δ174.4,141.3,131.1,130.4,129.7,129.6,129.2,128.6,127.7,127.4,126.0, 124.1,123.4,122.4,118.8,118.1,110.5,109.7,105.6,63.1,42.7,39.3.HRMS(ESI) calcd.for C22H19N2O[M+H]+:327.1492；found:327.1478.
3n:Light yellow solid；84.7mg, yield75%；mp119.6-121.0℃；1H NMR(400MHz, CDCl3), δ 7.70 (d, J=7.8Hz, 1H), 7.41-7.32 (m, 6H), 7.23-7.19 (m, 1H), 7.18-7.16 (m, 2H), 6.90-6.87 (m, 1H), 6.83 (d, J=7.7Hz, 2H), 6.74-6.73 (m, 1H), 6.43-6.41 (m, 1H), 6.27-6.26 (m, 1H), 5.05 (d, J=15.6Hz, 1H), 4.98 (d, J=15.6Hz, 1H), 3.64 (d, J=15.5Hz, 1H), 3.19 (d, J=15.5Hz, 1H)；13C NMR(100MHz,CDCl3),δ174.8,141.2,135.5,130.4,129.7,129.5, 129.2,129.1,128.6,128.0,127.7,127.4,127.3,126.0,124.0,123.4,122.4,118.8, 110.6,109.8,105.6,63.2,44.2,39.3.HRMS(ESI)calcd.for C26H20N2NaO[M+Na]+: 399.1468；found:399.1483.
3o:Light yellow solid；69.6mg, yield64%；mp210.5-211.8℃；1H NMR(400MHz, CDCl3), δ 7.70 (d, J=7.9Hz, 1H), 7.59-7.55 (m, 2H), 7.52-7.49 (m, 2H), 7.47-7.43 (m, 1H), 7.37-7.33 (m, 1H), 7.26-7.23 (m, 1H), 7.18-7.16 (m, 2H), 6.97-6.93 (m, 2H), 6.89 (d, J= 7.4Hz, 1H), 6.75-6.73 (m, 1H), 6.53-6.52 (m, 1H), 6.29-6.27 (m, 1H), 3.70 (d, J=15.5Hz, 1H), 3.29 (d, J=15.5Hz, 1H)；13C NMR(100MHz,CDCl3),δ174.0,142.1,134.0,130.4,129.8, 129.7,129.4,129.2,128.6,128.5,127.8,127.2,126.5,126.0,124.3,123.9,122.4, 118.8,110.6,110.1,105.6,63.3,39.5.HRMS(ESI)calcd.for C25H18N2NaO[M+Na]+: 385.1311；found:385.1322.
3p:Yellow solid；58.5mg, yield59%；mp206.5-207.7℃；1H NMR(400MHz,CDCl3), δ 7.60-7.57 (m, 1H), 7.33-7.29 (m, 1H), 6.94-6.87 (m, 3H), 6.82 (d, J=7.9Hz, 1H), 6.67 (s, 1H), 6.57-6.55 (m, 1H), 6.31 (s, 1H), 6.20-6.17 (m, 1H), 3.80 (d, J=3.2Hz, 3H), 3.52 (d, J= 15.4Hz, 1H), 3.30 (d, J=3.2Hz, 3H), 3.08 (d, J=15.5Hz, 1H)；13C NMR(100MHz,CDCl3),δ 174.7,157.9,142.2,130.5,129.8,129.6,129.0,124.0,123.8,123.5,122.5,118.0, 113.9,113.4,110.2,108.7,104.0,63.1,55.4,39.4,26.8.HRMS(ESI)calcd.for C21H18N2NaO2[M+Na]+:353.1260；found:353.1276.
3q:Yellow solid；50.6mg, yield49%；mp206.5-207.7℃；1H NMR(400MHz,CDCl3), δ7.34-7.30(m,1H),7.13(s,1H),6.96-6.86(m,3H),6.59(s,1H),6.53(s,1H),6.30(s,1H), 6.18 (s, 1H), 5.98 (s, 1H), 5.94 (s, 1H), 3.44 (d, J=15.5Hz, 1H), 3.30 (s, 3H), 3.02 (d, J= 15.4Hz,1H)；13C NMR(100MHz,CDCl3),δ174.7,147.4,146.0,142.2,130.6,129.9,129.5, 124.1,123.5,121.0,118.4,110.2,109.0,108.8,104.6,103.3,101.1,63.2,39.4, 26.8.HRMS(ESI)calcd.for C21H17N2O3[M+H]+:345.1234；found:345.1216.
3r:Yellow solid；74.5mg, yield78%；mp198.5-199.5℃；1H NMR(400MHz,CDCl3), δ 7.45 (d, J=7.8Hz, 1H), 7.37-7.33 (m, 1H), 7.30-7.25 (m, 1H), 7.00-6.96 (m, 1H), 6.94- 6.91(m,2H),6.89-6.84(m,1H),6.72-6.71(m,1H),6.36(s,1H),6.23-6.21(m,1H),3.45(d, J=16.3Hz, 1H), 3.29 (s, 3H), 3.27 (d, J=16.3Hz, 1H)；1H NMR(400MHz,CDCl3),δ174.3, 160.7 (d, J=243.1Hz, 1C), 142.4,131.3,130.1,129.7,129.2,128.6 (d, J=8.7Hz, 1C), 123.8 (d, J=33.5Hz, 1C), 119.5,118.0,117.9,114.4 (d, J=17.8Hz, 1C), 112.4 (d, J= 21.8Hz,1C),110.6,108.9,106.7,62.4,31.6,26.8.HRMS(ESI)calcd.for C20H15FN2NaO[M+ Na]+:341.1061；found:341.1074.
3s:Light yellow solid；68.8mg, yield72%；mp266.5-267.2℃；1H NMR(400MHz, CDCl3), δ 7.36-7.32 (m, 1H), 7.15 (d, J=8.2Hz, 1H), 7.03-6.99 (m, 2H), 6.92 (d, J=7.4Hz, 1H), 6.83-6.78 (m, 2H), 6.66-6.62 (m, 1H), 6.22 (s, 2H), 3.87 (d, J=14.0Hz, 1H), 3.64 (d, J =14.0Hz, 1H), 3.17 (s, 3H)；13C NMR(100MHz,CDCl3), δ 174.4,162.6 (d, J=242.3Hz, 1C), 142.3,130.9,130.2,129.9,129.7,129.2,124.0,123.5,123.1,11 9.5,112.7 (d, J= 22.0Hz, 1C), 110.6,109.1 (d, J=23.4Hz, 1C), 108.9,106.5,63.1,38.7,26.8.HRMS (ESI) calcd.for C20H15FN2NaO[M+Na]+:341.1061；found:341.1068.
3t:Light yellow solid；72.6mg, yield76%；mp198.5-199.6℃；1H NMR(400MHz, CDCl3), δ 7.63-7.60 (m, 1H), 7.36-7.32 (m, 1H), 7.05-7.00 (m, 1H), 6.97 (d, J=7.5Hz, 1H), 6.92 (d, J=8.0Hz, 1H), 6.87-6.84 (m, 2H), 6.62 (d, J=3.1Hz, 1H), 6.32 (s, 1H), 6.20-6.19 (m, 1H), 3.48 (d, J=15.7Hz, 1H), 3.29 (s, 3H), 3.14 (d, J=15.7Hz, 1H)；13C NMR(100MHz, CDCl3), δ 174.4,161.1 (d, J=244.0Hz, 1C), 142.3,130.1,129.8,129.5 (d, J=7.6Hz, 1C), 129.2,125.7,124.0,123.9,123.6,118.7,115.4 (d, J=22.1Hz, 1C), 114.8 (d, J=21.8Hz, 1C),110.4,108.9,105.2,62.9,39.2,26.8.HRMS(ESI)calcd.for C20H16FN2O[M+H]+: 319.1241；found:319.1248.
3u:Yellow solid；75.3mg, yield75%；mp206.5-207.7℃；1H NMR(400MHz,CDCl3), δ 7.58 (d, J=8.3Hz, 1H), 7.37-7.33 (m, 1H), 7.30-7.27 (m, 1H), 7.11 (s, 1H), 6.99-6.95 (m, 1H), 6.93 (d, J=7.8Hz, 1H), 6.88-6.86 (m, 1H), 6.68-6.66 (m, 1H), 6.35-6.34 (m, 1H), 6.22- 6.20 (m, 1H), 3.46 (d, J=15.7Hz, 1H), 3.29 (s, 3H), 3.13 (d, J=15.7Hz, 1H)；13C NMR (100MHz,CDCl3),δ174.3,142.3,131.1,130.1,129.6,129.1,129.0,128.4,127.9,127.8, 124.0,123.6,123.5,119.2,110.6,108.9,106.0,62.9,38.9,26.8.HRMS(ESI)calcd.for C20H16ClN2O[M+H]+:335.0946；found:335.0931.
3v:Light yellow solid；91.7mg, yield 83%；mp 142.5-143.6℃；1H NMR (400MHz,CDCl3), δ 7.73 (d, J=8.1Hz, 1H), 7.55 (d, J=8.2Hz, 1H), 7.38-7.35 (m, 2H), 7.01- 6.97 (m, 1H), 6.94 (d, J=7.8Hz, 1H), 6.88 (d, J=7.5Hz, 1H), 6.79-6.78 (m, 1H), 6.39 (d, J= 1.4Hz, 1H), 6.25-6.24 (m, 1H), 3.49 (d, J=15.8Hz, 1H), 3.30-3.29 (m, 3H), 3.24 (d, J= 15.9Hz,1H)；13C NMR(100MHz,CDCl3),δ174.1,142.5,132.4,130.3,129.3,128.9,127.7, (q, J=3.8Hz, 1C), 127.6,127.3,125.4 124.8 (q, J=3.8Hz, 1C), 124.0,123.7,122.4, 120.1,111.0,109.0,107.6,62.9,39.0,26.8.HRMS(ESI)calcd.for C21H16F3N2O[M+H]+: 369.1209；found:369.1222.
3w:Orange solid；91.5mg, yield 87%；mp 298.3-299.7℃；1H NMR(400MHz, CDCl3), δ 8.81 (d, J=8.6Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.67 (d, J=8.2Hz, 1H), 7.63-7.59 (m, 1H), 7.55-7.51 (m, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.05 (d, J=3.7Hz, 1H), 6.92 (d, J= 7.8Hz, 1H), 6.79-6.75 (m, 1H), 6.63 (d, J=7.5Hz, 1H), 6.55-6.54 (m, 1H), 6.36-6.34 (m, 1H), 3.78 (d, J=15.5Hz, 1H), 3.36 (s, 3H), 3.14 (d, J=15.6Hz, 1H)；13C NMR(100MHz, CDCl3),δ174.7,142.1,134.0,129.7,129.3,128.9,128.8,128.3,127.0,126.9,126.8, 126.6,126.1,125.7,125.5,124.3,123.4,119.0,110.9,109.5,108.8,62.3,41.0, 27.0.HRMS(ESI)calcd.for C24H18N2NaO[M+Na]+:373.1311；found:373.1318.
3x:Light yellow solid；75.4mg, yield 82%；mp 157.7-158.5℃；1H NMR (400MHz,CDCl3),δ7.34-7.29(m,1H),7.11-7.09(m,1H),6.96-6.90(m,2H),6.86-6.84(m, 2H), 6.41-6.40 (m, 1H), 6.32-6.31 (m, 1H), 6.16-6.14 (m, 1H), 3.48 (d, J=13.9Hz, 1H), 3.32-3.31(m,3H),3.12-3.07(m,1H)；13C NMR(100MHz,CDCl3),δ174.8,141.8,129.9, 129.8,127.4,127.3,127.2,123.7,123.5,121.7,118.6,110.2,110.1,108.8,105.2,64.0, 35.5,26.8.HRMS(ESI)calcd.for C18H15N2OS[M+H]+:307.0900；found:307.0905.
Above-described is only embodiments of the invention, and the general knowledge such as known concrete structure and characteristic is not made herein in scheme Excessive description.It should be pointed out that for a person skilled in the art, on the premise of structure of the present invention is not departed from, can be with Some deformations and improvement are made, these should also be considered as protection scope of the present invention, these are implemented all without the influence present invention Effect and practical applicability.This application claims protection domain should be defined by the content of its claim, in specification Specific embodiment etc. records the content that can be used for explaining claim.

Claims (8)

1. a kind of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound, it is characterised in that general structure is,
In formula：R1It is each independently selected from 5-Me, 5-OMe, 5-F, 5-OCF3、5-Cl、5-Br、7-F、7-Cl、7-CF3Or 7- OCF3；
R2Be each independently selected from H, Me, Et,nPr、nBu、iPr, allyl, Ph or Bn；
Ar is each independently selected from phenyl, methoxy substitution phenyl, [1,3] dioxolane and phenyl, fluorine substituted-phenyl, fluoroform Base substituted-phenyl, chlorine substituted-phenyl, naphthyl or thienyl.
2. the preparation side of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound according to claim 1 Method, it is characterised in that comprise the following steps to prepare：Using 3- oxidizable pyrroles indoles, 2- bromomethyls aromatic bromide as substrate, will Metal palladium catalyst, Phosphine ligands and inorganic base are added sequentially in organic solvent, after completion of the reaction through extraction, dry, column chromatography Or spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound is obtained after recrystallization treatment, synthetic route is as follows It is shown：
3. the preparation side of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound according to claim 2 Method, it is characterised in that described metal palladium catalyst is zero valent palladium catalyst or divalence palladium catalyst, the zero valent palladium catalyst It is tetrakis triphenylphosphine palladium or three (dibenzalacetone) two palladium, the divalence palladium catalyst is palladium, palladium trifluoroacetate, spy Valeric acid palladium or palladium bichloride.
4. the preparation side of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound according to claim 1 Method, it is characterised in that the organic solvent is toluene, chlorobenzene, fluorobenzene, benzotrifluoride, mesitylene, dimethyl sulfoxide (DMSO), special penta Alcohol, N,N-dimethylformamide, 1,4- dioxane or acetonitrile.
5. the preparation side of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound according to claim 1 Method, it is characterised in that the inorganic base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, pivalic acid sodium, potassium phosphate, the tert-butyl alcohol Sodium or potassium tert-butoxide.
6. the preparation side of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound according to claim 1 Method, it is characterised in that the reaction temperature is 120~160 DEG C, the reaction time is 24~48h.
7. the preparation side of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound according to claim 1 Method, it is characterised in that the Phosphine ligands be triphenylphosphine, Isosorbide-5-Nitrae-bis- diphenylphosphine butane, 2,2'- it is double-(diphenyl phosphine) -1, 1'- dinaphthalenes or the double diphenylphosphine -9,9- dimethyl xanthenes of 4,5-.
8. the preparation side of spiral shell [3,5'- pyrroles [2,1-a] isoquinolin-Oxoindole] class compound according to claim 1 Method, it is characterised in that the processing method is column chromatography separation method.
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CN114790212A (en) * 2021-01-24 2022-07-26 复旦大学 Oxazinoindole and oxazinoisoquinoline compounds and process for preparing same
CN114790212B (en) * 2021-01-24 2024-04-30 复旦大学 Oxazinoisoindole and oxazinoisoquinoline compounds and preparation method thereof
CN114213431A (en) * 2022-01-19 2022-03-22 河南师范大学 Spiro [ benzo [ d ] [1,3] oxazine-isoquinoline dione ] compound and synthetic method thereof

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Application publication date: 20170620