CN104327056B - The preparation method of 1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether and application thereof - Google Patents

The preparation method of 1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether and application thereof Download PDF

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CN104327056B
CN104327056B CN201410527364.5A CN201410527364A CN104327056B CN 104327056 B CN104327056 B CN 104327056B CN 201410527364 A CN201410527364 A CN 201410527364A CN 104327056 B CN104327056 B CN 104327056B
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triazol
base
dihydrobenzofuranes
ether
dimethyl
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CN104327056A (en
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胡艾希
李婉
丁娜
叶姣
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Hunan University
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Hunan University
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    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The present invention relates to 1-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether shown in chemical constitution formula I or II or its salt:Wherein, R1、R2It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R3Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C18Straight or branched alkyl；Pi-allyl, isobutenyl；X1、X2、X3、X4、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl.1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether or the application in preparing cancer therapy drug of its salt.

Description

The preparation method of 1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether and application thereof
Technical field
The present invention relates to new compound of a class and its preparation method and application, specifically 1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether and preparation method thereof and its as the application preparing cancer therapy drug.
Background technology
Chinese patent [CN102010405B, 2012.7.25 authorize] describe the preparation of 4-(benzofuran-5-base)-2-benzyl imino thiazole and as the application of antitumor drug, Chinese patent [CN102786515B, 2014.7.23 authorize] describe 2-(2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base) morpholine preparation method and as preparing antidepressants application.
Summary of the invention
It is an object of the invention to provide 1-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether shown in chemical constitution formula I or II or its salt:
Wherein, R1Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R2It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R3Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C18Straight or branched alkyl；Pi-allyl, isobutenyl；X1、X2、X3、X4、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；Its salt is selected from: hydrochlorate, hydrobromate, sulfate, nitrate, phosphate, mesylate, benzene sulfonate, tosilate, malate, lactate, succinate or butadiene hydrochlorate.
1-provided by the invention (benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether is selected from following compounds:
The preparation method that it is an object of the invention to provide 1-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether shown in chemical constitution formula I, it is characterised in that it to prepare reaction equation as follows:
Wherein, R1Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R2It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R3Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C18Straight or branched alkyl；Pi-allyl, isobutenyl；X is selected from: bromine or chlorine；R3X is selected from: sulfuric ester or phosphate ester.
The preparation method that it is an object of the invention to provide 1-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether shown in chemical constitution formula II, it is characterised in that it to prepare reaction equation as follows:
Wherein, R1Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R2It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；Pi-allyl, isobutenyl；X1、X2、X3、X4、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；X is selected from: bromine or chlorine.
1-provided by the invention (benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether application in preparing antitumor drug.
The present invention compared with prior art has the advantage that the present invention provides chemistry 1-(benzofuran-5-base)-2-(1 shown in formula I, 2,4-triazol-1-yls) ketoxime ether has the activity of anti-human cervical cancer cell (Hela), human breast cancer cell (MCF-7) and human lung carcinoma cell (A549).
Detailed description of the invention
Following example are intended to illustrate the present invention rather than limitation of the invention further.
Embodiment 1
(Z) preparation of-1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime
7.91g (26.5mmol) compound B-11,1.83g (26.5mmol) 1,2,4-triazole, 14.63g (106.0mmol) potassium carbonate, 50mL ethyl acetate, back flow reaction 3.0h.Reaction is finished, sucking filtration obtains brown liquid, under condition of ice bath, drip 27.0mmol concentrated nitric acid, precipitate out white solid, sucking filtration obtains crude product, adding appropriate acetic acid ethyl dissolution, dropping 30%NaOH is adjusted to pH7, stirs to solution clarification, separatory, aqueous phase is extracted with ethyl acetate 2 times, merges organic facies, and 6.10g1-(7-methoxyl group-2 is distilled to obtain in dry, decompression, 2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) ethyl ketone (C1), yield 80.1%, m.p.152～155 DEG C；1HNMR (400MHz, CDCl3) δ: 1.57 (s, 6H, 2 × CH3), 3.11 (s, 2H, CCH2), 3.93 (s, 3H, OCH3), 5.64 (s, 2H, CH2), 7.45 (s, 1H, C6H24-H), 7.47 (s, 1H, C6H26-H), 8.04 (s, 1H, triazole ring 3-H), 8.39 (s, 1H, triazole ring 5-H).
3.5g (12.2mmol) compound C1,1.27g (18.2mmol) NH2OH.HCl, 1.50g (18.2mmol) anhydrous sodium acetate, dehydrated alcohol 50mL, it is back to and reacts completely.It is cooled to room temperature, sucking filtration obtains colourless liquid, white solid is distilled to obtain in decompression, second alcohol and water recrystallization obtains 3.50g white powder 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime (D1): yield 94.5%, m.p.203～206 DEG C；1HNMR (400MHz, CDCl3) δ: 1.52 (s, 6H, 2 × CH3), 3.04 (s, 2H, CCH2), 3.88 (s, 3H, OCH3), 5.44 (s, 2H, CH2), 7.20 (s, 1H, C6H24-H), 7.26 (s, 1H, C6H26-H), 7.96 (s, 1H, triazole ring 3-H), 8.35 (s, 1H, triazole ring 5-H).
Embodiment 2
The preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime
1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone (C2) is prepared: yield 81.3% by embodiment 1 method, m.p83～86 DEG C,1HNMR (400MHz, CDCl3) δ: 1.55 (s, 6H, 2 × CH3), 1.82 (d, J=7.4Hz, 3H, CHCH3), 3.09 (s, 2H, CH2), 3.91 (s, 3H, OCH3), 6.11 (q, J=7.4Hz, 1H, CHCH3), 7.45 (s, 1H, C6H24-H), 7.49 (s, 1H, C6H26-H), 7.94 (s, 1H, triazole ring 3-H), 8.33 (s, 1H, triazole ring 5-H).
1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime (D2) is prepared: yield 94.6% by embodiment 1 method, m.p.152～156 DEG C,1HNMR (400MHz, CDCl3) δ: 1.49 (s, 6H, 2 × CH3), 1.77 (d, J=7.2Hz, 3H, CHCH3), 2.99 (s, 2H, CCH2), 3.79 (s, 6H, 2 × OCH3), 5.50 (q, J=6.8Hz, 1H, CHCH3), 6.57～6.76 (m, 2H, C6H2), 8.00 (s, 1H, triazole ring 3-H), 8.25 (s, 1H, triazole ring 5-H).
Embodiment 3
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime methyl ether (A1)
By 0.14g (0.46mmol), tetrabutyl ammonium bromide (TBAB) 0.015g, KI0.001g, 25%NaOH aqueous solution 0.15g, toluene 10mL, stirring lower dropping 0.09g dimethyl sulfate, drip to finish and be warming up to 60 DEG C, TLC follows the tracks of reaction 1h.Reaction is finished, and adds appropriate ethyl acetate, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, sucking filtration, and crude product is distilled to obtain in decompression, and ethyl alcohol recrystallization obtains 0.13gA1, yield 92.8%, m.p.66～69 DEG C.1HNMR (400MHz, CDCl3) δ: 1.51 (s, 6H, 2 × CH3), 3.07 (s, 2H, CCH2), 3.71 (s, 3H, OCH3), 3.97 (s, 3H, NOCH3), 5.62 (s, 2H, NCH2), 7.15～7.19 (m, 2H, C6H2), 8.45 (s, 1H, triazole ring 3-H), 10.50 (s, 1H, triazole ring 5-H).
Embodiment 4
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime ethylether (A2)
By 0.10g (0.33mmol) compound D1,0.11g (1.0mmol) bromoethane, tetrabutyl ammonium bromide (TBAB) 0.015g, KI0.001g, 25%NaOH aqueous solution 0.12g, toluene 10mL, stirring is warming up to 60 DEG C, and TLC follows the tracks of reaction 1.5h.Reaction is finished, and adds appropriate ethyl acetate, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, and crystallize obtains 0.05gA2, yield 45.8%, m.p.95～98 DEG C.1HNMR (400MHz, CDCl3) δ: 1.34 (t, J=7.2Hz, 3H, CH2CH3), 1.51 (s, 6H, 2 × CH3), 3.04 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 4.30 (q, J=7.2Hz, 2H, CH2CH3), 7.18 (s, 1H, C6H24-H), 7.21 (s, 1H, C6H26-H), 7.96 (s, 1H, triazole ring 3-H), 8.27 (s, 1H, triazole ring 5-H).
Embodiment 5
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime propyl ether (A3)
Preparing compound A-13 by embodiment 4 method, react 5h, column chromatography obtains 0.09g1-[1-(7-methoxyl group 2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime propyl ether, yield 38.6%, m.p.63～65 DEG C.1HNMR (400MHz, CDCl3) δ: 0.96 (t, J=7.2Hz, 3H, CH3), 1.51 (s, 6H, 2 × CH3), 1.74～1.76 (m, 2H, CH2), 3.04 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 4.21 (t, J=7.2Hz, 2H, CH2), 5.38 (s, 2H, CH2), 7.18 (s, 1H, C6H24-H), 7.21 (s, 1H, C6H26-H), 7.94 (s, 1H, triazole ring, 3-H), 8.23 (s, 1H, triazole ring, 5-H).
Embodiment 6
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime butyl ether (A4)
Prepare compound A4 by embodiment 4 method, react 1.5h, prepare 0.14g1-[1-(7-methoxyl group 2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime butyl ether, yield 93.3%, m.p.77～79 DEG C.1HNMR (400MHz, CDCl3) δ: 0.96 (t, J=7.6Hz, 3H, CH2CH3), 1.40 (q, J=7.2Hz, 2H, CH2CH3), 1.51 (s, 6H, 2 × CH3), 1.71 (t, J=7.6Hz, 2H, CH2CH2CH3), 3.04 (s, 2H, CH2), 3.90 (s, 3H, OCH3), 4.25 (t, J=7.2Hz, 2H, OCH2CH2), 5.36 (s, 2H, NCH2), 7.18～7.27 (m, 2H, C6H2), 7.92 (s, 1H, triazole ring 3-H), 8.17 (s, 1H, triazole ring 5-H).
Embodiment 7
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime isobutenyl ether (A5)
Preparing compound A-45 by embodiment 4 method, react 2h, column chromatography prepares 0.10g1-[1-(7-methoxyl group 2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime isobutenyl ether, yield 63.6%, m.p.75～78 DEG C.1HNMR (400MHz, CDCl3) δ: 1.52 (s, 6H, 2 × CH3), 1.77 (s, 3H, CH3), 3.05 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 4.67 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.42 (s, 2H, CCH2), 7.18～1.72 (m, 2H, C6H2), 8.02 (s, 1H, triazole ring 3-H), 8.37 (s, 1H, triazole ring 5-H).
Embodiment 8
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime benzylic ether (A6)
By 0.10g (0.33mmol) compound D1,0.13g (1.0mmol) benzyl chloride, tetrabutyl ammonium bromide (TBAB) 0.015g, KI0.001g, 25%NaOH aqueous solution 0.12g, toluene 10mL, stirring is warming up to 60 DEG C, and TLC follows the tracks of reaction 1h.Reaction is finished, and adds appropriate ethyl acetate, washing, and saturated common salt is washed, and anhydrous sodium sulfate dries, and column chromatography obtains 0.08gA6, yield 61.5%, m.p.94～96 DEG C.1HNMR (400MHz, CDCl3) δ: 1.51 (s, 6H, 2 × CH3), 3.04 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 5.26 (s, 2H, CH2), 5.37 (s, 2H, CH2), 7.20～7.23 (m, 2H, C6H2), 7.38 (s, 5H, C6H5), 7.90 (s, 1H, triazole ring 3-H), 8.06 (s, 1H, triazole ring 5-H).
Embodiment 9
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime methyl ether (A7)
Preparing A7 by embodiment 3, react 3.5h, column chromatography obtains 0.20g1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime methyl ether, yield 92.2%, m.p.66～69 DEG C.1HNMR (400MHz, CDCl3) δ: 1.49 (s, 6H, 2 × CH3), 1.77 (d, J=6.8Hz, 3H, CHCH3), 2.99 (s, 2H, CH2), 3.77 (s, 3H, OCH3), 3.94 (s, 3H, NOCH3), 5.62 (s, 2H, NCH2), 6.08 (q, J=6.8Hz, 1H, CHCH3), 6.61～6.78 (m, 2H, C6H2), 7.95 (s, 1H, triazole ring 3-H), 8.12 (s, 1H, triazole ring 5-H).
Embodiment 10
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime ethylether (A8)
0.20g (0.63mmol) compound D2,0.07g (0.63mmol) bromoethane, 0.18g potassium carbonate, DMF10mL, 80 DEG C of reaction 5h, add 20mL water, 10mL extraction into ethyl acetate three times, dry organic layer, column chromatography obtains 0.18g1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime ethylether, yield 81.2%, m.p.86～91 DEG C.1HNMR (400MHz, CDCl3) δ: 1.29 (t, J=6.8Hz, 3H, CH3), 1.49 (s, 6H, 2 × CH3), 1.85 (d, J=7.2Hz, 3H, CHCH3), 2.99 (s, 2H, CCH2), 3.79 (s, 3H, OCH3), 4.16 (q, J=7.2Hz, 1H, CHCH3), 4.22 (q, J=6.8Hz, 2H, CH2CH3), 6.60 (s, 1H, C6H2), 6.78 (s, 1H, C6H2), 7.95 (s, 1H, triazole ring 3-H), 8.16 (s, 1H, triazole ring 5-H).
Embodiment 11
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime propyl ether (A9)
Prepare compound A9 by embodiment 4 method, react 4.5h, obtain 0.20g1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime propyl ether, yield 85.6%, m.p.61～64 DEG C.1HNMR (400MHz, CDCl3) δ: 0.95 (t, J=8.0Hz, 3H, CH3), 1.50 (s, 6H, 2 × CH3), 1.65～1.70 (m, 2H, CH2), 1.87 (d, J=4.0Hz, 3H, CH), 2.99 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 4.06 (t, J=8.0Hz, 2H, CH2), 6.05 (q, J=4.0Hz, 3H, CCH3), 6.66 (s, 1H, C6H24-H), 6.78 (s, 1H, C6H26-H), 7.99 (s, 1H, triazole 3-H), 8.26 (s, 1H, triazole 5-H).
Embodiment 12
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime butyl ether (A10)
Preparing reaction 1h in A10, DMF by embodiment 4, column chromatography obtains 0.006g1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime butyl ether.Yield 50.8%, m.p.78～81 DEG C.1HNMR (400MHz, CDCl3) δ: 0.95 (t, J=7.6Hz, 3H, CH2CH3), 1.39 (q, J=7.6Hz, 2H, CH2CH3), 1.49 (s, 6H, 2 × CH3), 1.68 (t, J=7.6Hz, 2H, CH2CH2CH3), 1.85 (d, J=7.6Hz, 3H, CHCH3), 2.99 (s, 2H, CH2), 3.79 (s, 3H, OCH3), 4.18 (t, J=7.6Hz, 2H, OCH2CH2), 6.05 (q, J=7.6Hz, 1H, CHCH3), 6.65 (s, 1H, C6H2), 6.77 (s, 1H, C6H2), 7.95 (s, 1H, triazole 3-H), 8.15 (s, 1H, triazole 5-H).
Embodiment 13
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime allyl ether (A11)
Compound A11 is prepared by embodiment 4 method, reaction 5h, column chromatography obtains 0.10g (E)-1-[1-(7-methoxyl group-2 respectively, 2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime allyl ether and 0.09g (Z)-1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime allyl ether, yield 80.9%, (E)-A11:m.p.78～81 DEG C；1HNMR (400MHz, CDCl3) δ: 1.49 (s, 6H, 2 × CH3), 1.86 (d, J=7.2Hz, 3H, CHCH3), 2.99 (s, 2H, CCH2), 3.79 (s, 3H, OCH3), 4.67～4.69 (m, 2H, OCH2CH), 5.24～5.33 (m, 2H, CHCH2), 5.95～6.05 (m, 1H, CHCH2), 6.09 (q, J=7.2Hz, 1H, CHCH3), 6.34 (s, 1H, C6H24-H), 6.76 (s, 1H, C6H26-H), 7.95 (s, 1H, triazole ring 3-H), 8.14 (s, 1H, triazole ring 5-H)；(Z)-A11: yellow liquid；1HNMR (400MHz, CDCl3) δ: 1.50 (s, 6H, 2 × CH3), 1.77 (d, J=7.2Hz, 3H, CHCH3), 3.00 (s, 2H, CCH2), 3.77 (s, 3H, OCH3), 4.60～4.62 (m, 2H, OCH2CH), 5.20～5.28 (m, 2H, CHCH2), 5.48 (q, J=7.2Hz, 1H, CHCH3), 5.94～6.01 (m, 1H, CHCH2), 6.57 (s, 1H, C6H24-H), 6.66 (s, 1H, C6H26-H), 7.96 (s, 1H, triazole ring 3-H), 8.16 (s, 1H, triazole ring 5-H).
Embodiment 14
1-[the preparation of 1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime benzylic ether (A12)
Preparing compound A12 by embodiment 8 method, react 1h, column chromatography obtains 0.16g1-[1-(7-methoxyl group-2 respectively, 2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetone oxime benzylic ether, yield 61.4%, m.p.152～156 DEG C；1HNMR (400MHz, CDCl3) δ: 1.49 (s, 6H, 2 × CH3), 1.83 (d, J=7.2Hz, 3H, CHCH3), 2.99 (s, 2H, CH2), 3.79 (s, 3H, OCH3), 5.20 (s, 2H, CH2C6H5), 6.08 (q, J=7.2Hz, 1H, CHCH3), 6.70 (s, 1H, C6H24-H), 6.78 (s, 1H, C6H26-H), 7.32～7.37 (m, 5H, C6H5), 7.93 (s, 1H, triazole ring 3-H), 8.06 (s, 1H, triazole ring 5-H).
Embodiment 15
1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether active anticancer measures
1. anti-tumor activity principle
Mtt assay biological activity test, also known as MTT colorimetry, is a kind of method detecting cell survival and growth.MTT analytic process is with living cells metabolite reducing agent tetrazolium bromide [3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl bromination tetrazoles；3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, MTT] based on.MTT is a kind of dyestuff that can accept hydrogen atom.The MTT of yellow can be changed into insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon) by dehydrogenase relevant to NADP in living cells mitochondrion in cell, and dead cell is then without this function.After dissolving formazon with DMSO, under certain wavelength, measure optical density value by microplate reader, both can quantitatively measure the survival rate of cell.The sample inhibitory action to tumor cell is observed in change according to optical density value.
2. anti-tumor activity experiment
Sample: 1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether (I, II) or its salt:
Wherein, R1Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R2It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R3Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C18Straight or branched alkyl；Pi-allyl, isobutenyl；X1、X2、X3、X4、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；
Cell line: cervical cancer tumer line Hela, human breast cancer cell (MCF-7) and hepatoma cell line A-549 (offer of Xiangya Medical College, Zhongnan Univ cell bank).
Reagent: tetrazolium bromide (MTT), RPMI1640 culture fluid, new-born calf serum, antibiotic (hero Life Technologies, Inc. of the U.S.)；Pancreatin (AMRESCO company of the U.S.)；96 well culture plates (hero Life Technologies, Inc. of the U.S.)；Dimethyl sulfoxide (Sigma Co., USA).
Instrument: HFsafe-1500 type superclean bench, HF151UV type CO2Incubator (Shanghai Lishen Scientific Equipment Co., Ltd.)；XSP-15C type inverted microscope (the rectangular optical instrument company limited in Shanghai)；MultiskanMK3 type microplate reader (Thermo company of the U.S.)；Ultra-pure water preparing instrument (Milli-Q company of the U.S.).
Experimental implementation: sample is for the test of cancerous cell.In experimentation, per sample (p.s.) arranges 5 Concentraton gradient (1.000 μm of ol/mL, 0.300 μm of ol/mL, 0.100 μm of ol/mL, 0.030 μm of ol/mL and 0.010 μm of ol/mL), four parallel samples of each concentration, often parallel 3 times of group experiment, and reached a conclusion by the comparison of blank group.Microplate reader detects each hole OD value, detects wavelength 570nm.
3. antitumor activity evaluation
1) cell inhibitory rate calculates:
2)IC50Value calculates
Sample solution concentration logarithm value and cell inhibitory rate linear regression, utilize software SPSS to calculate the sample half-inhibition concentration IC to cell50Value.1-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether IC to cancerous cell50In Table 1～3.
Table 11-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether IC to Hela cancerous cell50
Table 21-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether IC to MCF-7 cancerous cell50
Table 31-(benzofuran-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether IC to A549 cancerous cell50
Test result display 1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether is to human cervical carcinoma cell (Hela), human lung carcinoma cell (A549) or human breast cancer cell (MCF-7) have good inhibitory activity, can as the application preparing anticarcinogen.

Claims (8)

1. 1-(Dihydrobenzofuranes-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether shown in chemical constitution formula I or II or its salt:
Wherein, R1Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R2It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl；R3Selected from hydrogen, deuterium, C1～C2Alkyl, C3～C18Straight or branched alkyl；Pi-allyl, isobutenyl；X1、X2、X3、X4、X5It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；Its salt is selected from: hydrochlorate, hydrobromate, sulfate, nitrate, phosphate, mesylate, benzene sulfonate, tosilate, malate, lactate, succinate or butadiene hydrochlorate.
2. 1-(Dihydrobenzofuranes-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether described in claim 1 is selected from following compounds:
3. the preparation method of 1-(Dihydrobenzofuranes-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether shown in chemical constitution formula I described in claim 1, it is characterised in that its preparation reaction is as follows:
R in formula1～R3Definition as claimed in claim 1；X is selected from: bromine or chlorine.
4. the preparation method of 1-(Dihydrobenzofuranes-5-base)-2-(1,2, the 4-triazol-1-yl) ketoxime ether shown in chemical constitution formula II described in claim 1, it is characterised in that its preparation reaction is as follows:
R in formula1、R2, X1～X5Definition as claimed in claim 1；X is selected from: bromine or chlorine.
5. 1-(Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether according to any one of claim 1～2 or the application in preparing cancer therapy drug of its salt.
6.1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime isobutenyl ether or 1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yls) application in preparing anti-human cervical cancer cell medicine of the acetone oxime benzylic ether.
7.1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime propyl ether, 1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yl) acetophenone oxime isobutenyl ether or 1-[1-(7-methoxyl group-2,2-dimethyl-2,3-Dihydrobenzofuranes-5-base)-2-(1,2,4-triazol-1-yls) application in preparing anti-human breast cancer cell medicine of the acetone oxime benzylic ether.
8.1-[1-(7-methoxyl group-2, 2-dimethyl-2, 3-Dihydrobenzofuranes-5-base)-2-(1, 2, 4-triazol-1-yl) acetophenone oxime butyl ether, 1-[1-(7-methoxyl group-2, 2-dimethyl-2, 3-Dihydrobenzofuranes-5-base)-2-(1, 2, 4-triazol-1-yl) acetophenone oxime isobutenyl ether, 1-[1-(7-methoxyl group-2, 2-dimethyl-2, 3-Dihydrobenzofuranes-5-base)-2-(1, 2, 4-triazol-1-yl) acetophenone oxime benzylic ether or 1-[1-(7-methoxyl group-2, 2-dimethyl-2, 3-Dihydrobenzofuranes-5-base)-2-(1, 2, 4-triazol-1-yl) application in preparing anti-human lung carcinoma cell medicine of the acetone oxime benzylic ether.
CN201410527364.5A 2014-10-09 2014-10-09 The preparation method of 1-(benzofuran-5-base)-2-(1,2,4-triazol-1-yl) ketoxime ether and application thereof Expired - Fee Related CN104327056B (en)

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