CN105085495A - Preparation method of N-alkynyl benzimidazole derivatives - Google Patents

Preparation method of N-alkynyl benzimidazole derivatives Download PDF

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CN105085495A
CN105085495A CN201510590185.0A CN201510590185A CN105085495A CN 105085495 A CN105085495 A CN 105085495A CN 201510590185 A CN201510590185 A CN 201510590185A CN 105085495 A CN105085495 A CN 105085495A
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phenyl
lihmds
alkynyl
preparation
benzimidizole derivatives
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CN105085495B (en
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安德烈
张艳勤
董万荣
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Hunan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention discloses a preparation method of N-alkynyl benzimidazole derivatives, which comprises the following step: under the atmosphere of protective gas, sequentially adding LiHMDS, diethyl chlorophosphate and LiHMDS into an anhydrous solvent of 1-R1 formyl-methyl 2-R2 benzimidazole as shown in the general formula 2 so as to react to obtain an N-alkynyl benzimidazole derivative as shown in the general formula 1, wherein when LiHMDS is added for reacting, the temperature is controlled at -78-0 DEG C, and after ClP(O)(OEt)2 is added, the system temperature rises to 10-30 DEG C so as to react. The preparation method of the N-alkynyl benzimidazole derivatives has the advantages that (1) substrates can be conveniently prepared through cheap raw materials; (2) the universality is good, and preparation of benzimidazole alkyne amine derivatives containing different substituent combinations can be easily realized; (3) the operation is simple and convenient, and the separation of intermediates is not needed; and (4) target compounds are easy to separate and purify, and the yield is relatively high.

Description

The preparation method of N-alkynyl benzimidizole derivatives
Technical field
The present invention relates to benzoglyoxaline ynamine derivative, particularly relate to the preparation method of N-alkynyl benzimidizole derivatives.
Background technology
Benzoglyoxaline ynamine derivative compound contains the basic structure of alkynes and benzoglyoxaline, has the essential property of this two compounds concurrently, is the very important organic synthesis intermediate of a class.In organic synthesis, in biological chemistry, there is vital role, and this compounds have biological nature and photoconductive property.
About synthetic method bibliographical information mainly null method (J.Org.Chem.2002 such as Katritzky, A.R., 67 of benzoglyoxaline ynamine derivative, 7526 – 7529), the alkynyl isomerization (Org.Lett.2002 such as Huang, J., 4,2417.), the alkynyl salt compounded of iodine coupling (Heterocycles2000 such as Kitamura, T., 52,303), metal catalytic (Burley, G.A.; Deng J.Org.Chem.2010,75,980.).But the shortcoming of these methods is also apparent, is mainly reflected in: (1) raw material is difficult to obtain; (2) comparatively large (3) complex steps of metal-salt environmental pollution.Develop a kind of succinct, convenient, that there is widespread use value benzoglyoxaline ynamine derivative new synthesis method and have very important theoretical and practical significance.
Summary of the invention
Based on this, provide a kind of preparation method of N-alkynyl benzimidizole derivatives.
A preparation method for N-alkynyl benzimidizole derivatives, comprises the following steps:
Under the atmosphere of shielding gas, lithium hexamethyldisilazide, diethyl chloro-phosphate and lithium hexamethyldisilazide are joined the 1-R shown in general formula 2 successively 1formyl methyl 2-R 2react in the anhydrous solvent of base benzoglyoxaline, obtain the N-alkynyl benzimidizole derivatives shown in general formula 1;
Wherein, the temperature when adding LiHMDS reaction controls at-78 ~ 0 DEG C; Add ClP (O) (OEt) 2after, react at system is warming up to 10 ~ 30 DEG C, R 1for phenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 4-p-methoxy-phenyl, 2,5-Dimethoxyphenyl, 3, one in the fluorine-based phenyl of 4-methylenedioxybenzenes, 4-, 4-chloro-phenyl-, 4-bromophenyl, 4-iodophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, thienyl, the tertiary butyl, R 2for the one in furyl, H, propyl group, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3,4-methylenedioxybenzenes, 4-chloro-phenyl-, 4-nitrophenyl, 2-nitrophenyl.
Further, add LiHMDS reaction in first time to add ClP (O) (OEt) after 10 ~ 15 minutes 2; Adding ClP (O) (OEt) 2react second time after 1-2 hour and add LiHMDS, the reaction times that second time adds LiHMDS is 1 ~ 3 hour.
Further, 1-R 1formyl methyl 2-R 2base benzoglyoxaline is 1:1.5 ~ 2.0 with the mol ratio of the LiHMDS that first time adds.
Further, 1-R 1formyl methyl 2-R 2base benzoglyoxaline and ClP (O) (OEt) 2mol ratio be 1:1.8 ~ 2.0.
Further, 1-R 1formyl methyl 2-R 2base benzoglyoxaline is 1:2.0 ~ 2.5 with the mol ratio of the LiHMDS that second time adds.
Further, R 2during for furyl, R 1for phenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 4-p-methoxy-phenyl, 2, one in 5-Dimethoxyphenyl, 3,4-methylenedioxybenzenes, the fluorine-based phenyl of 4-, 4-chloro-phenyl-, 4-bromophenyl, 4-iodophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, thienyl, the tertiary butyl; R 1during for phenyl, R 2for the one in H, propyl group, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3,4-methylenedioxybenzenes, 4-chloro-phenyl-, 4-nitrophenyl, 2-nitrophenyl.
Further, anhydrous solvent is tetrahydrofuran (THF) or ether.
Further, add after LiHMDS react in second time, also comprise and add saturated ammonium chloride solution quencher reaction, extraction, washing, dry, separation obtains N-alkynyl benzimidizole derivatives.
Further, be separated into silica gel column chromatography and be separated, leacheate is sherwood oil.
Further, shielding gas is nitrogen.
The preparation method of above-mentioned N-alkynyl benzimidizole derivatives, provides a kind of 1-R 1formyl methyl 2-R 2the substrate 2, LiHMDS of base benzoglyoxaline and substrate 2 act on and form enol negative ion; Then ClP (O) (OEt) 2the intermediate 3 formed containing a good leaving group is reacted with enol negative ion; Finally under LiHMDS effect, eliminate a part diethyl phosphoric acid [HOP (O) (OEt) 2] form N-alkynyl benzimidizole derivatives.Substrate can obtain conveniently by cheap raw material, does not need to use expensive various aryne reagent; Preparation method (1) substrate of above-mentioned N-alkynyl benzimidizole derivatives can obtain conveniently by cheap raw material, does not need to use expensive various aryne reagent; (2) versatility is good, is easy to the preparation of the benzoglyoxaline ynamine derivative realized containing various different substituents combination; (3) easy and simple to handle, do not need to be separated intermediate; (4) target compound is easily separated and purify, and productive rate is higher.
Accompanying drawing explanation
Fig. 1 is compound 1a nucleus magnetic resonance 1h spectrogram;
Fig. 2 is the nucleus magnetic resonance of compound 1a 13c spectrogram;
Fig. 3 is the nucleus magnetic resonance of compound 1c 1h spectrogram;
Fig. 4 is the nucleus magnetic resonance of compound 1c 13c spectrogram.
Embodiment
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, are described in detail the specific embodiment of the present invention below in conjunction with accompanying drawing.Set forth a lot of detail in the following description so that fully understand the present invention.But the present invention can be much different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar improvement when intension of the present invention, therefore the present invention is by the restriction of following public concrete enforcement.
A preparation method for N-alkynyl benzimidizole derivatives, comprises the following steps:
Under the atmosphere of shielding gas, lithium hexamethyldisilazide, diethyl chloro-phosphate and lithium hexamethyldisilazide are joined the 1-R shown in general formula 2 successively 1formyl methyl 2-R 2react in the anhydrous solvent of base benzoglyoxaline, obtain the N-alkynyl benzimidizole derivatives shown in general formula 1;
Wherein, the temperature when adding LiHMDS reaction controls at-78 ~ 0 DEG C; Add ClP (O) (OEt) 2after, react at system is warming up to 10 ~ 30 DEG C, R 1for phenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 4-p-methoxy-phenyl, 2,5-Dimethoxyphenyl, 3, one in the fluorine-based phenyl of 4-methylenedioxybenzenes, 4-, 4-chloro-phenyl-, 4-bromophenyl, 4-iodophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, thienyl, the tertiary butyl, R 2for the one in furyl, H, propyl group, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3,4-methylenedioxybenzenes, 4-chloro-phenyl-, 4-nitrophenyl, 2-nitrophenyl.
The preparation method of a kind of N-alkynyl benzimidizole derivatives of the present invention, adopts 1-R 1formyl methyl 2-R 2base benzoglyoxaline is as substrate 2, and the α-hydrogen of its carbonyl is very active, and easily lose under alkali effect, form carbanion, structure tautomeric with enol negative ion formation, for follow-up building-up reactions provides favourable reactive group plinth.
The preparation method of N-alkynyl benzimidizole derivatives of the present invention is one pot reaction, and a point three phases carries out, and the reaction mechanism related to is: i) first LiHMDS and substrate 2 act on and form enol negative ion; Ii) then ClP (O) (OEt) 2the intermediate 3 formed containing a good leaving group is reacted with enol negative ion; Iii) finally under LiHMDS effect, a part diethyl phosphoric acid [HOP (O) (OEt) is eliminated 2] form benzoglyoxaline ynamine derivative 1.In order to make reaction carry out completely, ClP (O) (OEt) 2generally excessive.
The substrate 2 used in the present invention can obtain by the following method: be first obtained by reacting alpha-brominated aryl or fatty group ethyl ketone by aryl or fatty group ethyl ketone and cupric bromide, then alpha-brominated aryl or fatty group ethyl ketone and benzimidizole derivatives is carried out nucleophilic substitution reaction and obtains substrate 2.
Aryl in alpha-brominated aryl methyl ketone is aryl or the fatty group of different replacement, and the carbon atom number of aryl or fatty group is 4 ~ 15.
Further, add LiHMDS reaction in first time to add ClP (O) (OEt) after 10 ~ 15 minutes 2; Adding ClP (O) (OEt) 2react second time after 1-2 hour and add LiHMDS, the reaction times that second time adds LiHMDS is 1 ~ 3 hour.Time is too short, reacts insufficient; Overlong time, side reaction increases.
Further, 1-R 1formyl methyl 2-R 2base benzoglyoxaline is 1:1.5 ~ 2.0 with the mol ratio of the LiHMDS that first time adds.Equivalent is too low, reacts insufficient, causes starting material left; Equivalent is excessive, and the decomposition of substrate or side reaction can be caused to increase.
Further, 1-R 1formyl methyl 2-R 2base benzoglyoxaline and ClP (O) (OEt) 2mol ratio be 1:1.8 ~ 2.0.Equivalent is too low, reacts insufficient, causes starting material left; Equivalent is excessive, and the decomposition of substrate or side reaction can be caused to increase.
Further, 1-R 1formyl methyl 2-R 2base benzoglyoxaline is 1:2.0 ~ 2.5 with the mol ratio of the LiHMDS that second time adds.Equivalent is too low, reacts insufficient, causes starting material left; Equivalent is excessive, and the decomposition of substrate or side reaction can be caused to increase.
Further, R 2during for furyl, R 1for phenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 4-p-methoxy-phenyl, 2, one in 5-Dimethoxyphenyl, 3,4-methylenedioxybenzenes, the fluorine-based phenyl of 4-, 4-chloro-phenyl-, 4-bromophenyl, 4-iodophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, thienyl, the tertiary butyl; R 1during for phenyl, R 2for the one in H, propyl group, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3,4-methylenedioxybenzenes, 4-chloro-phenyl-, 4-nitrophenyl, 2-nitrophenyl.
Further, anhydrous solvent is tetrahydrofuran (THF) or ether.
Further, add after LiHMDS react in second time, also comprise and add saturated ammonium chloride solution quencher reaction, extraction, washing, dry, separation obtains N-alkynyl benzimidizole derivatives.Add after LiHMDS has reacted in second time and aftertreatment is carried out to reaction, be specifically as follows: with saturated ammonium chloride solution quencher reaction, mixed solution is injected water, be extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, removes solvent under reduced pressure after filtration; Resistates is by silica gel (300 ~ 400 order) column chromatography for separation, and leacheate is sherwood oil, obtains benzoglyoxaline ynamine derivative.
Further, be separated into silica gel column chromatography and be separated, leacheate is sherwood oil.
Further, shielding gas is nitrogen.
It is below specific embodiment.
Embodiment 1
R 1=Ph, R 2=2-furyl
First by 2-fuberidazole (184.06mg, 1.0mmol), alpha-brominated methyl phenyl ketone (237.6mg, 1.2mmol) be dissolved in anhydrous propanone (20mL), add Anhydrous potassium carbonate (165.6mg, 1.2mmol), backflow, TLC follows the tracks of reaction (about 12h), after treating raw material total overall reaction, mixture is poured in large water gaging and washs, with dichloromethane extraction (30mL × 3), organic phase saturated common salt water washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent after filtering, resistates is separated [V (sherwood oil): V (ethyl acetate)=5:1] by silica gel column chromatography and obtains substrate 2a265.9mg, productive rate 88.2%.
2a white solid, 150 ~ 151 DEG C
1HNMR(400MHz,DMSO)δ8.17(d,J＝7.4Hz,2H),7.81–7.74(m,2H),7.67(dt,J＝14.6,7.2Hz,4H),7.27(d,J＝3.7Hz,2H),7.18(d,1H),6.67(m,1H),6.27(s,2H).
MS(EI)m/z(％):302(M +,100).
Embodiment 2
Preparation 1a
The chemical structural formula of 1a is as follows
Under 0 DEG C of nitrogen protection, LiHMDS (concentration is the tetrahydrofuran solution 0.75mL of 1.0mol/L) is added drop-wise in tetrahydrofuran (THF) (10mL) solution of substrate 2a (151.5mg, 0.5mmol), stirs 15 minutes.By ClP (O) (OEt) 2(0.13mL, 1.0mmol) is added dropwise in above-mentioned reaction system.After dropwising, remove refrigerating unit, rise to 10 DEG C and continue stirring 2 hours.Again reaction is cooled to 0 DEG C, then in above-mentioned reaction system, drips LiHMDS (concentration is the tetrahydrofuran solution 1.0mL of 1.0mol/L), and continue stirring 2 hours at this temperature.React with saturated ammonium chloride solution quencher, reaction mixture is injected water, be extracted with ethyl acetate (30mL × 3), organic phase saturated common salt water washing, anhydrous sodium sulfate drying, remove solvent under reduced pressure after filtration, resistates is separated (sherwood oil) by silica gel column chromatography and obtains 1a116.5mg, productive rate 82.8%.
1a white solid, fusing point: 100 ~ 101 DEG C, gets and carries out magnetic resonance detection and mass spectrometric detection in right amount.
Nucleus magnetic resonance H composes as shown in Figure 1: 1hNMR (400MHz, DMSO) δ 8.08 (s, 1H), 7.80 – 7.66 (m, 4H), 7.55 (s, 1H), 7.47 (s, 3H), 7.45 – 7.34 (m, 2H), 6.80 (m, 1H).
Nucleus magnetic resonance 13c composes as shown in Figure 2: 13cNMR (101MHz, DMSO) δ 146.41,144.07,143.12,141.84,135.44,131.72,129.54,129.17,125.07,125.00,120.99,120.26,114.11,112.77,111.21,77.12 (C ≡), 75.73 (C ≡).
MS(EI)m/z(％):284(M +,100).
Embodiment 3
Step is with embodiment 1.With 2-fuberidazole and α-bromo-2 dimethyl acetophenones for substrate 2c [R prepared by raw material 1=2-CH 3c 6h 4, R 2=2-furyl], productive rate 86%.
2c faint yellow solid thing, fusing point: 129 ~ 130 DEG C
1HNMR(400MHz,CDCl 3)δ7.78–7.71(m,2H),7.40(t,J＝7.5Hz,1H),7.36–7.33(m,1H),7.31–7.11(m,6H),6.46(dd,J＝3.2,1.7Hz,1H),5.68(s,2H),2.38(s,3H).
MS(EI)m/z(％):316(M +,100).
Prepare product 1c
Compare difference with embodiment 2 to be, substrate 2c is dissolved in ether, and the stirring reaction time that first time adds LiHMDS is 12 minutes, ClP (O) (OEt) 2the stirring reaction time be 1.5 hours, temperature of reaction is 15 DEG C, and all the other are with embodiment 2.Substrate is 2c [R 1=2-CH 3c 6h 4, R 2=2-furyl], product is 1c, productive rate 65%.
1c white solid, fusing point: 116 ~ 117 DEG C
Nucleus magnetic resonance 1h composes as shown in Figure 3: 1hNMR (400MHz, CDCl 3) δ 7.82 – 7.68 (m, 1H), 7.61 (d, J=1.2Hz, 1H), 7.57 – 7.54 (m, 1H), 7.52 (d, J=7.7Hz, 1H), 7.49 (d, J=3.5Hz, 1H), 7.36 – 7.28 (m, 2H), 7.28 – 7.22 (m, 2H), 7.21 – 7.14 (m, 1H), 6.54 (dd, J=3.5,1.7Hz, 1H), 2.52 (s, 3H).
Nucleus magnetic resonance 13c composes as shown in Figure 4: 13cNMR (101MHz, CDCl 3) δ 150.19 (CH), 144.94 (C), 144.50 (C), 143.76 (C), 142.09 (C), 140.23 (C), 135.87 (CH), 132.17 (CH), 129.83 (CH), 129.10 (CH), 125.93 (CH), 124.61 (CH), 124.58 (CH), 121.33 (C), 120.47 (CH), 113.25 (CH), 111.96 (CH), 110.78 (CH), 80.75 (C ≡), 74.70 (C ≡), 21.01 (CH 3).
MS(EI)m/z(％):298(M +,100).
Embodiment 4
Step is with embodiment 1.With 2-fuberidazole and α-bromo-4-methyl acetophenone for substrate 2b (R prepared by raw material 1=4-CH 3c 6h 4, R 2=2-furyl), productive rate 87.6%.
2b faint yellow solid, 164 ~ 165 DEG C
1HNMR(400MHz,CDCl 3)δ7.87(d,J＝8.2Hz,2H),7.74(d,J＝7.8Hz,1H),7.30(d,J＝1.0Hz,1H),7.28(d,1H),7.26(d,1H),7.24–7.19(m,1H),7.19–7.14(m,1H),7.13(d,J＝3.4Hz,1H),7.10(d,J＝7.7Hz,1H),6.43(dd,J＝3.5,1.8Hz,1H),5.77(s,2H),2.39(s,3H).
MS(EI)m/z(％):316(M +,100).
Prepare product 1b
The chemical structural formula of 1b is as follows
Compare difference with embodiment 2 to be: substrate 2b is dissolved in ether, at-78 DEG C, first time adds LiHMDS, and the stirring reaction time is 10 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 10 DEG C and stirs 1 hour.Be cooled to-60 DEG C, second time adds LiHMDS and stirs 1 hour.The mol ratio of wherein 2b: LiHMDS:ClP (O) (OEt) 2 that first time adds: the LiHMDS that second time adds is=1:1.5:1.8:2.0.All the other are with embodiment 2.Substrate is 2b (R 1=4-CH 3c 6h 4, R 2=2-furyl), product is 1b, productive rate 67%.
1b clear crystal, fusing point: 125 ~ 127 DEG C
1HNMR(400MHz,CDCl 3)δ7.78–7.73(m,1H),7.62(d,J＝1.1Hz,1H),7.59–7.53(m,1H),7.50–7.46(m,2H),7.44(d,1H),7.34–7.29(m,2H),7.17(d,J＝7.9Hz,2H),6.54(dd,J＝3.5,1.7Hz,1H),2.35(s,3H).
13CNMR(100MHz,CDCl 3)δ144.92(CH),144.63(C),143.73(C),142.05(C),139.49(C),135.81(C),131.83(C),129.44(CH),124.53(CH),124.48(CH),120.44(CH),118.31(C),113.16(CH),111.91(CH),110.86(CH),77.21(C≡),75.93(C≡),21.57(CH 3).
MS(EI)m/z(％):298(M +,100).
Embodiment 5
Step is with embodiment 1.With 2-fuberidazole and α-bromo-4-methoxyacetophenone for substrate 2d (R prepared by raw material 1=4-OCH 3c 6h 4, R 2=2-furyl), productive rate 90%.
2d yellow solid, fusing point: 163 ~ 164 DEG C
1HNMR(400MHz,CDCl 3)δ7.98–7.93(m,2H),7.74(d,J＝7.6Hz,1H),7.32(d,J＝1.5Hz,1H),7.25–7.19(m,1H),7.16(dd,J＝7.0,0.9Hz,1H),7.14–7.10(m,2H),6.98–6.91(m,2H),6.44(dd,J＝3.5,1.8Hz,1H),5.77(s,2H),3.84(s,3H).
MS(EI)m/z(％):332(M +,100).
Prepare product 1d
The chemical structural formula of 1d is as follows
Compare difference with embodiment 2 to be: substrate 2d is dissolved in ether, at-60 DEG C, first time adds LiHMDS, and the stirring reaction time is 12 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 16 DEG C and stirs 2 hours.Be cooled to-60 DEG C, second time adds LiHMDS and stirs 2 hours, and leacheate is [V (sherwood oil): V (ethyl acetate)=5:1].Wherein, the mol ratio of 2d: LiHMDS:ClP (O) (OEt) 2 that first time adds: the LiHMDS that second time adds is=1:1.5:1.9:2.All the other are with embodiment 2.Substrate is 2d (R 1=4-OCH 3c 6h 4, R 2=2-furyl), product is 1d, productive rate 58%.
1d clear crystal, fusing point: 156 ~ 158 DEG C
1HNMR(400MHz,CDCl 3)δ7.77–7.72(m,1H),7.61(d,J＝1.1Hz,1H),7.57–7.52(m,1H),7.52–7.48(m,2H),7.46(d,J＝3.5Hz,1H),7.34–7.27(m,2H),6.91–6.86(m,2H),6.53(dd,J＝3.5,1.7Hz,1H),3.79(s,3H).
13CNMR(101MHz,CDCl 3)δ160.41(CH),144.91(C),144.66(C),143.72(C),142.01(C),135.86(CH),133.68(CH),124.49(CH),124.44(CH),120.41(CH),114.34(CH),113.27(C),113.15(CH),111.92(CH),110.88(CH),75.93(C≡),75.76(C≡),55.43(CH 3).
MS(EI)m/z(％):314(M +,100).
Embodiment 6
Step is with embodiment 1.Be that substrate 2e (R prepared by raw material with 2-(2-furyl) benzoglyoxaline and α-bromo-3,4-methylene-dioxy methyl phenyl ketones 1=3,4-(OCH 2o) C 6h 3, R 2=2-furyl), productive rate 81%.
2e white solid, fusing point: 183 ~ 184 DEG C
1HNMR(400MHz,CDCl 3)δ7.71(d,J＝7.7Hz,1H),7.55(dd,J＝8.2,1.7Hz,1H),7.37(d,J＝1.6Hz,1H),7.21–7.18(m,1H),7.16(dt,J＝4.1,2.4Hz,1H),7.14–7.10(m,1H),7.10–7.08(m,1H),7.06(d,J＝7.8Hz,1H),6.82(d,J＝8.1Hz,1H),6.41(dd,J＝3.5,1.8Hz,1H),5.98(s,2H),5.66(s,3H).
MS(EI)m/z(％):358(M +,100).
Prepare product 1e
The chemical structural formula of 1e is as follows
Compare difference with embodiment 2 to be: substrate 2e is dissolved in ether, at-50 DEG C, first time adds LiHMDS, and the stirring reaction time is 13 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 18 DEG C and stirs 1.5 hours.Be cooled to-60 DEG C, second time adds LiHMDS and stirs 2.5 hours.Wherein, 2e: LiHMDS:ClP (O) (OEt) that first time adds 2: the mol ratio of the LiHMDS that second time adds is=1:1.6:2.0:2.1.All the other are with embodiment 2.Substrate is 2e (R 1=3,4-(OCH 2o) C 6h 3, R 2=2-furyl), product is 1e, productive rate 57%.
The white yellow solid of 1e, fusing point: 146 ~ 148 DEG C
. 1HNMR(400MHz,CDCl 3)δ7.77–7.71(m,1H),7.61(d,J＝1.2Hz,1H),7.56–7.50(m,1H),7.44(d,J＝3.5Hz,1H),7.35–7.25(m,2H),7.09(dd,J＝8.0,1.6Hz,1H),6.99(d,J＝1.5Hz,1H),6.79(d,J＝8.0Hz,1H),6.54(dd,J＝3.5,1.8Hz,1H),5.97(s,2H).
13CNMR(101MHz,CDCl 3)δ148.74(C),147.77(C),144.95(CH),144.64(C),143.68(C),142.00(C),135.79(C),126.93(CH),124.55(CH),124.49(CH),120.44(C),114.43(CH),113.15(CH),111.94(CH),111.89(CH),110.84(CH),108.79(CH),101.61(CH 2),75.74(C≡),75.62(C≡).
MS(EI)m/z(％):340(M +,100).
Embodiment 7
Step is with embodiment 1.Be that substrate 2f (R prepared by raw material with 2-fuberidazole and 2,5-dimethoxy-acetophenone 1=2,5-(OCH 3) 2c 6h 3, R 2=2-furyl)), productive rate 82%.
2f brown solid, fusing point: 190 ~ 191 DEG C
1HNMR(400MHz,CDCl 3)δ7.76–7.70(m,1H),7.35(d,J＝1.0Hz,1H),7.33(d,J＝3.2Hz,1H),7.23–7.19(m,1H),7.18–7.15(m,2H),7.10(d,J＝2.9Hz,1H),7.09–7.05(m,1H),6.97–6.93(m,1H),6.45(dd,J＝3.5,1.8Hz,1H),5.77(s,2H),3.92(s,3H),3.69(s,3H).
MS(EI)m/z(％):362(M +,100).
Prepare product 1f
The chemical structural formula of 1f is as follows
Compare difference with embodiment 2 to be: substrate 2f is dissolved in ether, at-40 DEG C, first time adds LiHMDS, and the stirring reaction time is 14 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 20 DEG C and stirs 2 hours.Be cooled to-30 DEG C, second time adds LiHMDS and stirs 3 hours.Wherein, 2f: LiHMDS:ClP (O) (OEt) that first time adds 2: the mol ratio of the LiHMDS that second time adds is=1:1.8:1.8:2.2.All the other are with embodiment 2.Substrate is 2f (R 1=2,5-(OCH 3) 2c 6h 3, R 2=2-furyl), product is 1f, productive rate 54%.
1f clear crystal, fusing point: 135 ~ 136 DEG C
1HNMR(400MHz,CDCl 3)δ7.80(d,J＝3.6Hz,1H),7.77–7.73(m,1H),7.63–7.61(m,1H),7.61–7.57(m,1H),7.35–7.27(m,2H),7.02(d,J＝2.8Hz,1H),6.89–6.79(m,2H),6.54(dd,J＝3.6,1.7Hz,1H),3.85(s,3H),3.75(s,3H).
13CNMR(101MHz,CDCl 3)δ153.54(C),152.40(C),143.93(CH),143.53(C),142.59(C),141.06(C),134.72(C),123.52(CH),123.42(CH),119.39(CH),116.94(CH),114.82(CH),112.44(CH),110.99(CH),110.85(CH),110.40(C),109.90(CH),79.76(C≡),71.85(C≡),55.26(OCH 3),54.91(OCH 3).
MS(EI)m/z(％):344(M +,100).
Embodiment 8
Step is with embodiment 1.With 2-fuberidazole and 4-fluoro acetophenone for substrate 2g (R prepared by raw material 1=4-FC 6h 4, R 2=2-furyl), productive rate 86%.
2g faint yellow solid, fusing point: 204 ~ 206 DEG C
1HNMR(400MHz,CDCl 3)δ8.01(dd,J＝5.0,1.8Hz,1H),8.00–7.97(m,1H),7.74(d,J＝7.9Hz,1H),7.32–7.28(m,1H),7.25–7.20(m,1H),7.17(d,J＝3.8Hz,1H),7.15(s,2H),7.14(d,J＝3.8Hz,1H),7.10(d,J＝7.6Hz,1H),6.45(dd,J＝3.5,1.8Hz,1H),5.77(s,2H).
MS(EI)m/z(％):320(M +,100).
Prepare product 1g
The chemical structural formula of 1g is as follows
Compare difference with embodiment 2 to be: substrate 2g is dissolved in ether, at-30 DEG C, first time adds LiHMDS, and the stirring reaction time is 14 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 22 DEG C and stirs 1.2 hours.Be cooled to-40 DEG C, second time adds LiHMDS and stirs 3 hours.Wherein, 2g: LiHMDS:ClP (O) (OEt) that first time adds 2: the mol ratio of the LiHMDS that second time adds is=1:2.0:1.9:2.2.All the other are with embodiment 2.Substrate is 2g (R 1=4-FC 6h 4, R 2=2-furyl), product is 1g, productive rate 69%.
1g faint yellow solid, fusing point: 97 ~ 98 DEG C
1HNMR(400MHz,CDCl 3)δ7.78–7.72(m,1H),7.61(d,J＝1.2Hz,1H),7.56–7.51(m,3H),7.43(d,J＝3.4Hz,1H),7.34–7.27(m,2H),7.10–7.01(m,2H),6.54(dd,J＝3.5,1.8Hz,1H).
13CNMR(101MHz,CDCl 3)δ164.31(CH),161.81(CH),145.01(CH),144.56(C),143.64(C),142.02(C),135.71(C),133.98(CH),133.90(CH),124.66(CH),124.59(CH),120.50(CH),117.50(CH),117.46(C),116.20(CH),115.98(CH),113.18(CH),111.97(CH),110.80(CH),76.83(C≡),74.73(C≡).
MS(EI)m/z(％):302(M +,100).
Embodiment 9
Step is with embodiment 1.With 2-fuberidazole and α-bromo-4-chloro-acetophenone for substrate 2h (R prepared by raw material 1=4-ClC 6h 4, R 2=2-furyl), productive rate 90%.
2h white solid, fusing point: 186 ~ 187 DEG C
1HNMR(400MHz,CDCl 3)δ7.90(d,J＝8.5Hz,2H),7.74(d,J＝7.7Hz,1H),7.45(d,J＝8.5Hz,2H),7.29(d,J＝1.1Hz,1H),7.22(dd,J＝11.1,4.1Hz,1H),7.20–7.17(m,1H),7.15(d,J＝3.5Hz,1H),7.10(d,J＝7.7Hz,1H),6.45(dd,J＝3.5,1.8Hz,1H),5.76(s,2H).
MS(EI)m/z(％):336[M +( 35Cl),100]
Prepare product 1h
The chemical structural formula of 1h is as follows
Compare difference with embodiment 2 to be: substrate 2h is dissolved in ether, at-20 DEG C, first time adds LiHMDS, and the stirring reaction time is 15 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 23 DEG C and stirs 1.6 hours.Be cooled to-20 DEG C, second time adds LiHMDS and stirs 2 hours.Wherein, 2h: LiHMDS:ClP (O) (OEt) that first time adds 2: the mol ratio of the LiHMDS that second time adds is=1:2.0:1.2:2.5.All the other are with embodiment 2.Substrate is 2h (R 1=4-ClC 6h 4, R 2=2-furyl), product is 1h, productive rate 63%.
1h white solid, fusing point: 98 ~ 100 DEG C
1HNMR(400MHz,CDCl 3)δ7.78–7.72(m,1H),7.61(d,J＝1.1Hz,1H),7.55–7.50(m,1H),7.49–7.44(m,2H),7.41(d,J＝3.5Hz,1H),7.36–7.28(m,4H),6.54(dd,J＝3.5,1.8Hz,1H).
13CNMR(101MHz,CDCl 3)δ145.04(CH),144.50(C),143.62(C),142.04(C),135.62(C),135.26(C),132.98(CH),129.08(CH),124.72(CH),124.64(CH),120.53(CH),119.94(C),113.21(CH),111.99(CH),110.79(CH),77.99(C≡),74.73(C≡).
MS(EI)m/z(％):318[M +( 35Cl),100]
Embodiment 10
Step is with embodiment 1.With 2-fuberidazole and α-bromo-4-bromoacetophenone for substrate 2i (R prepared by raw material 1=4-ClC 6h 4, R 2=2-furyl), productive rate 89%.
2i faint yellow solid, fusing point: 190 ~ 191 DEG C
1HNMR(400MHz,CDCl 3)δ7.94–7.88(m,2H),7.83(d,J＝7.8Hz,1H),7.74–7.68(m,2H),7.38(d,J＝1.1Hz,1H),7.34–7.29(m,1H),7.29–7.26(m,1H),7.24(d,J＝3.6Hz,1H),7.19(d,J＝7.7Hz,1H),6.59–6.49(m,1H),5.83(s,2H).
MS(EI)m/z(％):380(M +,100).
Prepare product 1i
The chemical structural formula of 1i is as follows
Compare difference with embodiment 2 to be: at-10 DEG C, first time adds LiHMDS, and the stirring reaction time is 15 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 25 DEG C and stirs 2 hours.Be cooled to-10 DEG C, second time adds LiHMDS and stirs 2.5 hours.Wherein, 2i: LiHMDS:ClP (O) (OEt) that first time adds 2: the mol ratio of the LiHMDS that second time adds is=1:2.0:1.8:2.4.All the other are with embodiment 2.Substrate is 2i (R 1=4-BrC 6h 4, R 2=2-furyl), product is 1i, productive rate 69%.
1i faint yellow solid, fusing point: 111 ~ 112 DEG C
1HNMR(400MHz,CDCl 3)δ7.77–7.71(m,1H),7.64–7.59(m,1H),7.53(dd,J＝5.2,4.0Hz,1H),7.49(d,J＝8.3Hz,2H),7.40(t,J＝5.7Hz,3H),7.34–7.27(m,2H),6.54(dd,J＝3.3,1.5Hz,1H).
13CNMR(101MHz,CDCl 3)δ145.05(CH),144.49(C),143.61(C),142.03(C),135.60(C),133.13(CH),132.00(CH),124.74(CH),124.65(CH),123.46(C),120.52(CH),120.43(C),113.23(CH),111.99(CH),110.78(CH),78.15(C≡),74.82(C≡).
MS(EI)m/z(％):362(M +,100).
Embodiment 11
Step is with embodiment 1.With 2-fuberidazole and α-bromo-4-Iodoacetophenone for substrate 2j (R prepared by raw material 1=4-IC 6h 4, R 2=2-furyl), productive rate 90%.
2j yellow solid, fusing point: 188 ~ 189 DEG C
1HNMR(400MHz,CDCl 3)δ7.84(d,J＝8.2Hz,2H),7.74(d,J＝7.8Hz,1H),7.66(d,J＝8.2Hz,2H),7.29(d,1H),7.22(t,J＝7.5Hz,1H),7.18(d,J＝6.2Hz,1H),7.14(d,J＝3.5Hz,1H),7.09(d,J＝7.9Hz,1H),6.47–6.42(m,1H),5.74(s,2H).
MS(EI)m/z(％):428(M +,100).
Prepare product 1j
The chemical structural formula of 1j is as follows
Compare difference with embodiment 2 to be: at-5 DEG C, first time adds LiHMDS, and the stirring reaction time is 10 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 28 DEG C and stirs 2 hours.Be cooled to-10 DEG C, second time adds LiHMDS and stirs 2 hours.Wherein, the mol ratio of 2j: LiHMDS:ClP (O) (OEt) 2 that first time adds: the LiHMDS that second time adds is=1:2.0:1.8:2.0.All the other are with embodiment 2.Substrate is 2j (R 1=4-IC 6h 4, R 2=2-furyl), product is 1j, productive rate 57%.
1j white solid, fusing point: 121 ~ 122 DEG C
1HNMR(400MHz,CDCl 3)δ7.77–7.73(m,1H),7.73–7.68(m,2H),7.62(d,J＝1.2Hz,1H),7.56–7.51(m,1H),7.42(d,J＝3.3Hz,1H),7.32(dq,J＝5.3,1.9Hz,2H),7.29–7.24(m,2H),6.55(dd,J＝3.5,1.8Hz,1H).
13CNMR(101MHz,CDCl 3)δ145.06(CH),144.49(C),143.60(C),142.03(C),137.90(CH),135.58(CH),133.14(CH),124.75(CH),124.66(CH),120.98(CH),120.53(CH),113.24(C),112.00(CH),110.80(CH),105.26(CH),95.11(C),78.40(C≡),74.98(C≡).
MS(EI)m/z(％):410(M +,100).
Embodiment 12
Step is with embodiment 1.With 2-fuberidazole and alpha-brominated 2-naphthyl methyl phenyl ketone for substrate 2k (R prepared by raw material 1=2-C 10h 6, R 2=2-furyl), productive rate 85%.
2k yellow solid, fusing point: 172 ~ 173 DEG C
1HNMR(400MHz,CDCl 3)δ8.54(s,1H),8.00(dd,J＝8.6,1.7Hz,1H),7.95(d,J＝8.1Hz,1H),7.91(d,J＝8.6Hz,1H),7.86(d,J＝8.0Hz,1H),7.79–7.75(m,1H),7.63–7.58(m,1H),7.58–7.52(m,1H),7.29(dd,J＝1.7,0.7Hz,1H),7.26–7.18(m,2H),7.16(dd,J＝3.9,1.1Hz,1H),6.92(t,J＝4.9Hz,1H),6.45(dd,J＝3.5,1.8Hz,1H),5.96(s,2H).
MS(EI)m/z(％):352(M +,100).
Prepare product 1k
Compare difference with embodiment 2 to be: substrate 2k is dissolved in ether, at 0 DEG C, first time adds LiHMDS, and the stirring reaction time is 12 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 30 DEG C and stirs 2 hours.Be cooled to-40 DEG C, second time adds LiHMDS and stirs 1 hour.Wherein, 2k: LiHMDS:ClP (O) (OEt) that first time adds 2: the mol ratio of the LiHMDS that second time adds is=1:1.5:2.0:2.5.All the other are with embodiment 2.Substrate is 2k (R 1=C 10h 7, R 2=2-furyl), product is 1k, productive rate 60%.
1k faint yellow solid, fusing point: 118 ~ 120 DEG C
118～120℃ 1HNMR(400MHz,CDCl 3)δ8.05(s,1H),7.77(tt,J＝6.9,5.2Hz,4H),7.65–7.54(m,3H),7.51(d,J＝3.5Hz,1H),7.46(dd,J＝6.2,3.2Hz,2H),7.36–7.27(m,2H),6.54(dd,J＝3.5,1.7Hz,1H).
13CNMR(101MHz,CDCl 3)δ145.02(CH),144.61(C),143.70(C),142.06(C),135.77(C),133.14(C),133.00(C),131.88(CH),128.46(CH),128.15(CH),127.90(CH),127.84(CH),127.19(CH),126.94(CH),124.66(CH),124.59(CH),120.50(CH),118.67(CH),113.28(CH),112.01(CH),110.90(CH),77.27(C≡),76.27(C≡).
MS(EI)m/z(％):334(M +,100).
Embodiment 13
Step is with embodiment 1.With 2-fuberidazole and alpha-brominated 6-methoxyl group-2-naphthyl methyl phenyl ketone for substrate 2l (R prepared by raw material 1=5-(OCH 3) C 10h 6, R 2=2-furyl)), productive rate 90%.
2l yellow solid, fusing point: 192 ~ 193 DEG C
1HNMR(400MHz,CDCl 3)δ8.45(s,1H),7.96(dd,J＝8.6,1.5Hz,1H),7.82(d,J＝9.0Hz,1H),7.76(d,J＝8.8Hz,2H),7.31–7.28(m,1H),7.25–7.11(m,7H),6.43(dd,J＝3.3,1.7Hz,1H),5.91(s,2H),3.89(s,3H).
MS(EI)m/z(％):382(M +,100).
Prepare product 1l
The chemical structural formula of 1l is as follows
Compare difference with embodiment 2 to be: substrate 2l is dissolved in ether, at 0 DEG C, first time adds LiHMDS, and the stirring reaction time is 10 minutes.Dropwise ClP (O) (OEt) 2system temperature rises to 10 DEG C and stirs 2 hours.Be cooled to-10 DEG C, second time adds LiHMDS and stirs 1 hour.Wherein, 2l: LiHMDS:ClP (O) (OEt) that first time adds 2: the mol ratio of the LiHMDS that second time adds is=1:1.5:2.1:2.4.All the other are with embodiment 2.Substrate is 2l (R 1=6-(OCH 3) 2-C 10h 6, R 2=2-furyl)), product is 1l, productive rate 64%.
1l faint yellow solid, fusing point: 140 ~ 141 DEG C
1HNMR(400MHz,CDCl 3)δ7.98(s,1H),7.78–7.73(m,1H),7.69(d,J＝2.8Hz,1H),7.67(d,J＝3.3Hz,1H),7.61(d,J＝1.1Hz,1H),7.60–7.56(m,1H),7.55–7.50(m,2H),7.34–7.27(m,2H),7.13(dd,J＝8.9,2.5Hz,1H),7.07(d,J＝2.3Hz,1H),6.54(dd,J＝3.5,1.7Hz,1H),3.86(s,3H).
13CNMR(101MHz,CDCl 3)δ158.71(C),144.97(CH),144.64(C),143.72(C),142.06(C),135.83(C),134.60(C),131.87(CH),129.42(CH),128.89(CH),128.47(C),127.23(CH),124.58(CH),124.52(CH),120.47(CH),119.84(CH),116.12(C),113.23(CH),111.98(CH),110.91(CH),105.88(CH),77.26(C≡),76.42(C≡),55.42(CH 3).
MS(EI)m/z(％):364(M +,100).
Embodiment 14
Step is with embodiment 1.With 2-fuberidazole and alpha-brominated 2-thienyl ethyl ketone for substrate 2m (R prepared by raw material 1=2-C 4h 3s,R 2=2-furyl)), productive rate 85%.
2m dark brown solid, fusing point: 170 ~ 171 DEG C
1HNMR(400MHz,CDCl 3)δ7.76(d,J＝3.8Hz,1H),7.73(d,J＝7.8Hz,1H),7.67(d,J＝4.9Hz,1H),7.35(d,1H),7.25–7.12(m,5H),6.46(dd,J＝3.3,1.7Hz,1H),5.69(s,2H).
MS(EI)m/z(％):308(M +,100).
Prepare product 1m
The chemical structural formula of 1m is as follows
Step is with embodiment 2.Substrate is 2m (R 1=2-C 4h 3s,R 2=2-furyl)), product is 1m, productive rate 51%.
1m faint yellow solid, fusing point: 123 ~ 124 DEG C
1HNMR(400MHz,CDCl 3)δ7.91–7.85(m,1H),7.74(d,J＝1.5Hz,1H),7.69–7.63(m,1H),7.55(d,J＝3.5Hz,1H),7.52–7.47(m,2H),7.47–7.41(m,2H),7.19–7.13(m,1H),6.66(dd,J＝3.4,1.6Hz,1H).
13CNMR(101MHz,CDCl 3)δ145.06(CH),144.69(C),143.51(C),142.04(C),135.74(C),133.79(CH),128.96(CH),127.43(CH),124.73(CH),124.65(C),121.15(CH),120.49(CH),113.35(CH),112.00(CH),110.90(CH),80.39(C≡),69.46(C≡).
MS(EI)m/z(％):290(M +,100).
Embodiment 15
Step is with embodiment 1.With 2-fuberidazole and alpha-brominated tertiary butyl ethyl ketone for substrate 2n (R prepared by raw material 1=C 4h 9, R 2=2-furyl)), productive rate 80%.
2n yellow solid, fusing point: 111 ~ 112 DEG C
1HNMR(400MHz,CDCl 3)δ7.71(d,J＝7.8Hz,1H),7.39(s,1H),7.23–7.15(m,2H),7.14(d,J＝3.5Hz,1H),7.00(t,J＝7.9Hz,1H),6.51–6.46(m,1H),5.35(s,2H),1.26(s,9H).
MS(EI)m/z(％):282(M +,100).
Prepare product 1n
The chemical structural formula of 1n is as follows
Step is with embodiment 2.Substrate is 2n (R 1=C 4h 9, R 2=2-furyl)), product is 1n, productive rate 52%.
1n white solid, fusing point: 92 ~ 94 DEG C
1HNMR(400MHz,CDCl 3)δ7.74–7.68(m,1H),7.58(d,J＝1.6Hz,1H),7.45–7.38(m,2H),7.31–7.23(m,2H),6.53(dd,J＝3.5,1.7Hz,1H),1.37(s,9H).
13CNMR(101MHz,CDCl 3)δ144.69(CH),144.55(C),143.87(C),141.88(C),135.97(C),124.22(CH),124.20(CH),120.27(CH),112.67(CH),111.73(CH),110.61(CH),84.01(C≡),68.01(C≡),30.99(CH 3),27.91(C).
MS(EI)m/z(％):264(M +,100).
Embodiment 16
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, benzoglyoxaline is that substrate 2o (R prepared by raw material 1=C 6h 5, R 2=H), productive rate 80%.
2o white solid, fusing point: 154 ~ 156 DEG C
1HNMR(400MHz,CDCl 3)δ7.98(t,J＝13.2Hz,2H),7.89(s,1H),7.86–7.81(m,1H),7.67(t,J＝7.4Hz,1H),7.54(t,J＝7.7Hz,2H),7.32–7.26(m,1H),7.21(dd,J＝13.3,6.8Hz,1H),5.52(s,2H).
MS(EI)m/z(％):236(M +,100).
Prepare product 1o
The chemical structural formula of 1o is as follows
Step is with embodiment 2.Substrate is 2o (R 1=C 6h 5, R 2=H), product is 1o, productive rate 19%.
1o colourless liquid,
1HNMR(400MHz,CDCl 3)δ8.08(s,1H),7.77(d,J＝7.7Hz,1H),7.63–7.57(m,1H),7.51(dd,J＝7.3,4.9,3.4Hz,2H),7.42–7.26(m,5H).
13CNMR(101MHz,CDCl 3)δ143.57(CH),141.96(C),134.49(C),131.76(CH),128.96(CH),128.57(CH),124.77(CH),124.01(CH),121.30(C),120.80(CH),110.96(CH),76.41(C≡),73.49(C≡).
MS(EI)m/z(％):236(M +,100).
Embodiment 17
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-propylbenzimidazole is that substrate 2p (R prepared by raw material 1=C 6h 5, R 2=C 3h 7), productive rate 85%.
2p faint yellow solid, fusing point: 155 ~ 157 DEG C
1HNMR(400MHz,CDCl 3)δ8.00–7.92(m,2H),7.68(d,J＝7.7Hz,1H),7.61(t,J＝7.5Hz,1H),7.48(t,J＝7.8Hz,2H),7.18–7.07(m,2H),7.00(d,J＝8.0Hz,1H),5.40(s,2H),2.68–2.59(t,2H),1.87–1.76(m,2H),0.94(t,J＝7.4Hz,3H).
MS(EI)m/z(％):278(M +,100).
Prepare product 1p
The chemical structural formula of 1p is as follows
Step is with embodiment 2.Substrate is 2p (R 1=C 6h 5, R 2=C 3h 7), product is 1p, productive rate 55%.
1p colourless liquid,
1HNMR(400MHz,CDCl 3)δ7.65(dd,J＝6.4,2.4Hz,1H),7.52–7.46(m,3H),7.36–7.30(m,3H),7.27–7.22(m,2H),2.98(t,J＝7.5Hz,2H),1.97–1.87(m,2H),1.01(t,J＝7.4Hz,3H).
13CNMR(101MHz,CDCl 3)δ156.83(CH),141.62(CH),135.36(C),131.62(CH),129.49(C),128.79(CH),128.55(CH),123.76(CH),123.68(CH),121.63(C),119.64(CH),115.53(C),110.59(CH),76.29(C≡),75.81(C≡),29.82(CH 2),20.77(CH 2),13.86(CH 3).
MS(EI)m/z(％):260(M +,100).
Embodiment 18
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-Phenylbenzimidazole is that substrate 2q (R prepared by raw material 1=C 6h 5, R 2=C 6h 5), productive rate 84%.
2q faint yellow solid, fusing point: 201 ~ 202 DEG C
1HNMR(400MHz,DMSO)δ8.07(d,J＝7.6Hz,2H),7.77–7.70(m,2H),7.66(dd,J＝6.5,2.9Hz,2H),7.62–7.54(m,3H),7.51–7.45(m,3H),7.29–7.22(m,2H),6.06(s,2H).
MS(EI)m/z(％):312(M +,100).
Prepare product 1q
The chemical structural formula of 1q is as follows
Step is with embodiment 2.Substrate is 2q (R 1=C 6h 5, R 2=C 6h 4), product is 1q, productive rate 61%.
1q white solid, fusing point, 79 ~ 80 DEG C 1hNMR (400MHz, DMSO) δ 8.23 (dd, J=5.8,2.2Hz, 2H), 7.81 (d, J=7.6Hz, 1H), 7.75 (d, J=7.8Hz, 1H), 7.65 – 7.57 (m, 5H), 7.48 – 7.37 (m, 5H). 13cNMR (101MHz, DMSO) δ 157.19 (C), 146.69 (C), 141.10 (C), 136.33 (CH), 136.08 (CH), 134.24 (CH), 133.97 (CH), 133.93 (CH), 133.59 (CH), 133.39 (C), 129.81 (CH), 129.65 (CH), 125.86 (C), 125.13 (CH), 116.25 (CH), 82.55 (C ≡), 80.38 (C ≡).
MS(EI)m/z(％):294(M +,100).
Embodiment 19
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-(4-aminomethyl phenyl) benzoglyoxaline is that substrate 2r (R prepared by raw material 1=C 6h 5, R 2=(4-CH 3) C 6h 5), productive rate 85%.
2r white solid, fusing point: 274 ~ 275 DEG C
1HNMR(400MHz,DMSO)δ8.90–8.83(d,2H),8.55–8.47(m,2H),8.38(t,J＝7.7Hz,2H),8.32(dd,J＝7.4,5.0Hz,3H),8.11–7.98(m,4H),6.81(s,2H),3.11(s,3H).
MS(EI)m/z(％):326(M +,100).
Prepare product 1r
The chemical structural formula of 1r is as follows
Step is with embodiment 2.Substrate is 2r (R 1=C 6h 5, R 2=(4-CH 3) C 6h 4), product is 1r, productive rate 67%, fusing point, 80 ~ 81 DEG C
1r white solid, fusing point, 80 ~ 81 DEG C
1HNMR(400MHz,DMSO)δ8.24(d,J＝7.8Hz,2H),7.78(d,J＝7.3Hz,1H),7.74(d,J＝7.8Hz,1H),7.68–7.62(m,2H),7.47(s,3H),7.40(dd,J＝15.4,7.8Hz,2H),7.18(d,J＝7.8Hz,2H),3.86(s,3H).
13CNMR(101MHz,DMSO)δ157.26(C),146.71(C),146.07(C),141.07(C),136.33(CH),134.46(CH),134.21(CH),133.96(CH),133.44(CH),130.60(CH),129.61(C),129.58(CH),125.90(C),124.97(CH),116.15(CH),82.65(C≡),80.29(C≡),26.15(CH 3).
MS(EI)m/z(％):308(M +,100).
Embodiment 20
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-(4-p-methoxy-phenyl) benzoglyoxaline is that substrate 2s (R prepared by raw material 1=C 6h 5, R 2=(4-OCH 3) C 6h 4), productive rate 86%.
2s white solid, fusing point: 224 ~ 226 DEG C
1HNMR(400MHz,DMSO)δ7.76(d,J＝6.3Hz,2H),7.39(t,2H),7.28(dd,4H),7.17(d,1H),6.92(d,2H),6.72(d,J＝7.2Hz,2H),5.69(s,2H),3.45(s,3H).
MS(EI)m/z(％):342(M +,100).
Prepare product 1s
The chemical structural formula of 1s is as follows
Step is with embodiment 2.Substrate is 2s (R 1=C 6h 5, R 2=(4-OCH 3) C 6h 4), product is 1s, productive rate 67%.
1s white solid, fusing point, 100 ~ 102 DEG C
1HNMR(400MHz,DMSO)δ8.24(d,J＝7.8Hz,2H),7.78(d,J＝7.3Hz,1H),7.74(d,J＝7.8Hz,1H),7.68–7.63(m,2H),7.47(s,3H),7.40(dd,J＝15.4,7.8Hz,2H),7.18(d,J＝7.8Hz,2H),3.86(s,3H).
13CNMR(101MHz,DMSO)δ161.81(C),152.49(C),142.15(C),136.46(C),131.76(CH),130.55(CH),129.58(CH),129.34(CH),124.90(CH),124.75(CH),121.31(C),121.08(C),120.17(CH),114.77(CH),111.45(CH),78.18(C≡),75.61(C≡),55.91(OCH 3).
MS(EI)m/z(％):324(M +,100).
Embodiment 22
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-(3,4-methylenedioxyphenyl) benzoglyoxaline is that substrate 2t (R prepared by raw material 1=C 6h 5, R 2=(3,4-OCH 2cH 2o) C 6h 3), productive rate 88%.
2t white solid, fusing point: 208 ~ 206 DEG C
1HNMR(400MHz,DMSO)δ8.09(d,J＝7.6Hz,2H),7.73(dd,J＝16.6,7.7Hz,2H),7.60(t,J＝7.3Hz,2H),7.53(d,J＝7.1Hz,1H),7.29–7.17(m,3H),7.13(d,J＝8.0Hz,1H),7.01(d,J＝7.9Hz,1H),6.08(s,2H),6.04(s,2H).
MS(EI)m/z(％):356(M +,100).
Prepare product 1t
The chemical structural formula of 1t is as follows
Step is with embodiment 2.Substrate is 2t (R 1=C 6h 5, R 2=(3,4-OCH 2o) C 6h 3), product is 1t, productive rate 67%.
1t white solid, fusing point, 80 ~ 81 DEG C
1HNMR(400MHz,DMSO)δ7.65(d,J＝7.6Hz,1H),7.58(d,J＝7.5Hz,1H),7.53(d,J＝7.3Hz,2H),7.43(d,2H),7.27(d,J＝2.0Hz,3H),7.21(dd,J＝15.6,7.3Hz,2H),6.97(d,J＝8.1Hz,1H),5.96(s,2H).
13CNMR(101MHz,DMSO)δ152.21(C),150.08(C),148.15(C),141.98(C),136.44(C),131.72(CH),129.62(C),129.36(CH),124.96(CH),124.91(CH),123.74(CH),122.45(C),121.26(C),120.24(CH),111.48(CH),109.06(CH),108.78(CH),102.36(CH 2),78.05(C≡),75.80(C≡)
MS(EI)m/z(％):338(M +,100).
Embodiment 22
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-(4-chloro-phenyl-) benzoglyoxaline is that substrate 2u (R prepared by raw material 1=C 6h 5, R 2=4-ClC 6h 4), productive rate 85%.
2u faint yellow solid, fusing point: 206 ~ 208 DEG C
1HNMR(400MHz,DMSO)δ8.09(d,J＝7.4Hz,2H),7.77–7.69(m,4H),7.59(dd,J＝17.4,7.8Hz,5H),7.30–7.25(m,2H),6.10(s,2H).
MS(EI)m/z(％):346(M +,100).
Prepare product 1u
The chemical structural formula of 1u is as follows
Step is with embodiment 2.Substrate is 2u (R 1=C 6h 5, R 2=4-ClC 6h 4), product is 1u, productive rate 62%.
1u white solid, fusing point, 106 ~ 107 DEG C
1HNMR(400MHz,DMSO)δ8.27(d,J＝7.4Hz,2H),7.83(d,J＝7.7Hz,1H),7.79(d,J＝7.9Hz,1H),7.72(d,J＝7.5Hz,2H),7.65(d,J＝2.2Hz,2H),7.51–7.41(m,5H).
13CNMR(101MHz,DMSO)δ151.45(C),141.97(C),136.50(C),136.32(C),131.77(CH),130.69(CH),129.69(CH),129.49(CH),129.36(CH),127.60(C),125.40(CH),125.16(CH),121.11(C),120.58(CH),111.71(CH),77.68(C≡),76.02(C≡).
MS(EI)m/z(％):328(M +,100).
Embodiment 23
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-(4-nitrophenyl) benzoglyoxaline is that substrate 2v (R prepared by raw material 1=C 6h 5, R 2=4-NO 2c 6h 4), productive rate 75%.
2v faint yellow solid, fusing point: 215 ~ 216 DEG C
1HNMR(400MHz,DMSO)δ8.33(d,J＝8.3Hz,2H),8.09(d,J＝7.2Hz,2H),8.00(d,J＝8.2Hz,2H),7.81–7.72(m,2H),7.62(d,J＝7.3Hz,3H),7.32(d,2H),6.19(s,2H).
MS(EI)m/z(％):357(M +,100).
Prepare product 1v
The chemical structural formula of 1v is as follows
Step is with embodiment 2.Substrate is 2v (R 1=C 6h 5, R 2=4-NO 2c 6h 4), product is 1, productive rate 48.34%.
1v faint yellow solid, fusing point, 178 ~ 179 DEG C
1HNMR(400MHz,CDCl 3)δ8.54(d,J＝8.9Hz,2H),8.40(d,J＝8.8Hz,2H),7.88(d,J＝7.4Hz,1H),7.71(d,J＝7.9Hz,1H),7.57(dd,J＝6.6,3.0Hz,2H),7.49–7.41(m,5H).
13CNMR(101MHz,CDCl 3)δ150.07(C),148.77(C),142.00(C),136.78(C),134.84(C),131.62(CH),129.47(CH),129.29(CH),128.73(CH),125.43(CH),124.98(CH),123.81(CH),120.97(C),120.79(CH),111.36(CH).77.20(C≡),76.41(C≡).
MS(EI)m/z(％):339(M +,100).
Embodiment 24
Step is with embodiment 1.With alpha-brominated methyl phenyl ketone, 2-(2-nitrophenyl) benzoglyoxaline is that substrate 2w (R prepared by raw material 1=C 6h 5, R 2=2-NO 2c 6h 4), productive rate 85%.
2w white solid, fusing point: 190 ~ 192 DEG C
1HNMR(400MHz,DMSO)δ8.46(d,1H),8.33(d,J＝7.9Hz,1H),8.16(d,J＝7.3Hz,1H),8.10(d,J＝7.1Hz,2H),7.85–7.70(m,3H),7.62(d,J＝6.5Hz,3H),7.32(d,2H),6.19(s,2H).
MS(EI)m/z(％):357(M +,100).
Prepare product 1w
The chemical structural formula of 1w is as follows
Step is with embodiment 2.Substrate is 2w (R 1=C 6h 5, R 2=2-(2-NO 2c 6h 4), product is 1w, productive rate 52%.
1w white solid, fusing point, 152 ~ 153 DEG C
1HNMR(400MHz,CDCl 3)δ9.38(d,J＝1.7Hz,1H),8.66(dd,J＝7.8,1.0Hz,1H),8.38(dd,J＝8.2,0.9Hz,1H),7.86(d,J＝7.5Hz,1H),7.76–7.69(m,2H),7.64–7.60(m,2H),7.49–7.40(m,6H).
13CNMR(101MHz,CDCl 3)δ150.07(C),148.56(C),142.15(C),136.96(C),134.84(CH),131.84(CH),130.92(C),130.13(CH),129.44(CH),128.99(CH),125.53(CH),125.35(CH),125.18(CH),123.44(CH),121.30(CH),120.96(CH),111.60(CH),77.23(C≡),77.07(C≡).
MS(EI)m/z(％):339(M +,100).
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (10)

1. a preparation method for N-alkynyl benzimidizole derivatives, is characterized in that, comprises the following steps:
Under the atmosphere of shielding gas, by lithium hexamethyldisilazide LiHMDS, diethyl chloro-phosphate ClP (O) (OEt) 2the 1-R shown in general formula 2 is joined successively with lithium hexamethyldisilazide 1formyl methyl 2-R 2react in the anhydrous solvent of base benzoglyoxaline, obtain the N-alkynyl benzimidizole derivatives shown in general formula 1;
Wherein, the temperature when adding LiHMDS reaction controls at-78 ~ 0 DEG C; Add ClP (O) (OEt) 2after, react at system is warming up to 10 ~ 30 DEG C, R 1for phenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 4-p-methoxy-phenyl, 2,5-Dimethoxyphenyl, 3, one in the fluorine-based phenyl of 4-methylenedioxybenzenes, 4-, 4-chloro-phenyl-, 4-bromophenyl, 4-iodophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, thienyl, the tertiary butyl, R 2for the one in furyl, H, propyl group, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3,4-methylenedioxybenzenes, 4-chloro-phenyl-, 4-nitrophenyl, 2-nitrophenyl.
2. the preparation method of N-alkynyl benzimidizole derivatives according to claim 1, is characterized in that, adds LiHMDS reaction add ClP (O) (OEt) after 10 ~ 15 minutes in first time 2; Adding ClP (O) (OEt) 2react second time after 1-2 hour and add LiHMDS, the reaction times that second time adds LiHMDS is 1 ~ 3 hour.
3. the preparation method of N-alkynyl benzimidizole derivatives according to claim 1, is characterized in that, described 1-R 1formyl methyl 2-R 2base benzoglyoxaline is 1:1.5 ~ 2.0 with the mol ratio of the LiHMDS that first time adds.
4. the preparation method of N-alkynyl benzimidizole derivatives according to claim 1, is characterized in that, described 1-R 1formyl methyl 2-R 2base benzoglyoxaline and described ClP (O) (OEt) 2mol ratio be 1:1.8 ~ 2.0.
5. the preparation method of N-alkynyl benzimidizole derivatives according to claim 1, is characterized in that, described 1-R 1formyl methyl 2-R 2base benzoglyoxaline is 1:2.0 ~ 2.5 with the mol ratio of the LiHMDS that second time adds.
6. the preparation method of N-alkynyl benzimidizole derivatives according to claim 1, is characterized in that, R 2during for furyl, R 1for phenyl, 4-aminomethyl phenyl, 2-aminomethyl phenyl, 4-p-methoxy-phenyl, 2, one in 5-Dimethoxyphenyl, 3,4-methylenedioxybenzenes, the fluorine-based phenyl of 4-, 4-chloro-phenyl-, 4-bromophenyl, 4-iodophenyl, 2-naphthyl, 6-methoxyl group-2-naphthyl, thienyl, the tertiary butyl; R 1during for phenyl, R 2for the one in H, propyl group, phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 3,4-methylenedioxybenzenes, 4-chloro-phenyl-, 4-nitrophenyl, 2-nitrophenyl.
7. the preparation method of N-alkynyl benzimidizole derivatives according to claim 1, is characterized in that, described anhydrous solvent is tetrahydrofuran (THF) or ether.
8. the preparation method of N-alkynyl benzimidizole derivatives according to claim 1, is characterized in that, adds after LiHMDS reacted in second time, also comprise and add saturated ammonium chloride solution quencher reaction, extraction, washing, drying, is separated and obtains N-alkynyl benzimidizole derivatives.
9. the preparation method of N-alkynyl benzimidizole derivatives according to claim 8, is characterized in that, described in be separated into silica gel column chromatography be separated, leacheate is sherwood oil.
10. the preparation method of the N-alkynyl benzimidizole derivatives according to any one of claim 1 ~ 9, described shielding gas is nitrogen.
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