CN103087054B - 4-pyridine phenyl ether compounds and preparation method thereof and application - Google Patents

4-pyridine phenyl ether compounds and preparation method thereof and application Download PDF

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CN103087054B
CN103087054B CN201310063090.4A CN201310063090A CN103087054B CN 103087054 B CN103087054 B CN 103087054B CN 201310063090 A CN201310063090 A CN 201310063090A CN 103087054 B CN103087054 B CN 103087054B
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methyl
pyridine
phenyl
oxadiazole
carboxamide
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CN103087054A (en
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赵桂森
王远游
谢红艳
刘建珍
刑华鲁
谢文成
张林娜
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Shandong University
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Abstract

The invention discloses 4-pyridine phenyl ether compounds, its structure is as shown in general formula (I): wherein, R 0for methyl or ethyl; R 1for substituted-phenyl or isobutyl-; X is 1,3,4-oxadiazole, 1,2,4-oxadiazole or bishydrazide base, and structural formula is as implied above.The invention also discloses the preparation method of 4-pyridine phenyl ether compounds, synthetic route is as follows:

Description

4-pyridine phenyl ether compounds and preparation method thereof and application
Technical field
The present invention relates to 4-pyridine phenyl ether compounds, and preparation method thereof with the application in pharmacy, belong to organic compound and medical applications field.
Background technology
Current, the health of the malignant tumour serious threat mankind and existence.Recent two decades comes, research about tumor development mechanism shows, specific effect in tumour high-expression signal transduction pathway can the propagation of selective exclusion tumour cell, transfer, thus make targeting therapy on tumor become possibility, tumour patient is avoided and by traditional dependence, there is the serious side effects that Cytotoxic chemotherapeutic drug therapy tumour brings.
Xarelto (sorafenib) is researched and developed by Bayer A.G, being used for the treatment of the novel signal transduction inhibitor of advanced renal cell carcinoma in 2005 by FDA (Food and Drug Adminstration) (FDA) approval listing, is the first antineoplastic target medicine acting on Mutiple Targets getting permission to go on the market.Xarelto action target spot comprises b-Raf kinases, vascular endothelial growth factor receptor-2(VEGFR-2), vascular endothelium growth factors (VEGFR-3), platelet derived growth factor receptor-β (PDGFR-β), c-Kit etc.It both can by the growing multiplication suppressing the target spot such as b-Raf to block the direct inhibition tumor cell of MAPK and Raf/MEK/ERK signal path, showed obviously in vitro and growth of tumour cell inhibit activities widely in activity experiment; The short tumor-blood-vessel growth effect of blocking VEGF signal path can be carried out again by suppression VEGFR-2 activity simultaneously, thus the growth of indirect inhibition tumor cell and transfer.Therefore, find the new Xarelto analogue containing 4-pyridine phenyl ether and possess good application prospect as antitumor drug.See: Siegel, A.B.; Olsen, S.K.; Magun, A.etal:Sorafenib:wheredowegofromhere Hepatology2010,52 (1), 360-9.
Summary of the invention
For above-mentioned prior art, the invention provides a kind of 4-pyridine phenyl ether compounds with anti-tumor activity based on marketed drug Xarelto design and synthesis, and disclose its preparation method and the purposes in pharmacy.
The present invention is achieved by the following technical solutions:
4-pyridine phenyl ether compounds, its structure is as shown in general formula (I):
Wherein, R 0for methyl or ethyl; R 1for substituted-phenyl or isobutyl-; X is 1,3,4-oxadiazole, 1,2,4-oxadiazole or bishydrazide base, and structural formula is as implied above.
Preferably, R 1for phenyl, to fluorophenyl, rubigan, to the chloro-3-trifluoromethyl of bromophenyl, p-nitrophenyl, p-trifluoromethyl phenyl, isobutyl-, 2-aminomethyl phenyl, p-methoxyphenyl or 4-.
Further preferably, described 4-pyridine phenyl ether compounds comprises the compound shown in table 1, and its title is as follows:
N-methyl-4-{4-[(5-phenyl-1,3,4-oxadiazole-2-base) methyl] phenoxy group } pyridine-2-carboxamide (vii-1);
N-methyl-4-{4-[[5-(4-chloro-phenyl-)-1,3,4-oxadiazole-2-base] methyl] phenoxy group } pyridine-2-carboxamide (vii-2);
N-methyl-4-{4-[[5-(2-aminomethyl phenyl)-1,3,4-oxadiazole-2-base] methyl] phenoxy group } pyridine-2-carboxamide (vii-3);
N-ethyl-4-{4-[(5-phenyl-1,3,4-oxadiazole-2-base) methyl] phenoxy group } pyridine-2-carboxamide (vii-4);
N-ethyl-4-{4-[[5-(4-p-methoxy-phenyl)-1,3,4-oxadiazole-2-base] methyl] phenoxy group } pyridine-2-carboxamide (vii-5);
N-methyl-4-{4-[2-(2-benzoyl diazanyl)-2-oxoethyl] phenoxy group } pyridine-2-carboxamide (viii-1);
N-methyl-4-{4-[2-[2-(4-chlorobenzene formacyl) diazanyl]-2-oxoethyl] phenoxy group } pyridine-2-carboxamide (viii-2);
N-ethyl-4-{4-[2-(2-benzoyl diazanyl)-2-oxoethyl] phenoxy group } pyridine-2-carboxamide (viii-3);
N-ethyl-4-{4-[2-(2-benzoyl diazanyl)-2-oxoethyl] phenoxy group } pyridine-2-carboxamide (viii-4);
N-methyl-4-{4-[[3-phenyl-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-1);
N-methyl-4-{4-[[3-(4-fluorophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-2);
N-methyl-4-{4-[[3-(4-chloro-phenyl-)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-3);
N-methyl-4-{4-[[3-(4-bromophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-4);
N-methyl-4-{4-[[3-(4-nitrophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-5);
N-methyl-4-{4-[[3-(4-trifluoromethyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-6);
N-methyl-4-{4-[(the 3-tertiary butyl-1,2,4-oxadiazole-5-base) methyl] phenoxy group } pyridine-2-carboxamide (ix-7);
N-methyl-4-{4-[[3-(2-aminomethyl phenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-8);
N-methyl-4-{4-[[3-(4-p-methoxy-phenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-9);
N-methyl-4-{4-[[3-(the chloro-3-trifluoromethyl of 4-)-1,2,4-oxadiazole-5-bases] methyl] phenoxy group } pyridine-2-carboxamide (ix-10);
N-ethyl-4-{4-[[3-(the chloro-3-trifluoromethyl of 4-)-1,2,4-oxadiazole-5-bases] methyl] phenoxy group } pyridine-2-carboxamide (ix-11).
Be the code name of its correspondence in bracket after above-mentioned preferred 20 compound titles, in order to describe convenient and be concise in expression, the code name in above-mentioned bracket will be used directly in the following content of this specification sheets.
The preparation method of described 4-pyridine phenyl ether compounds, synthetic route is as follows:
In above formula, reagent and reaction conditions as follows:
1. (a) thionyl chloride, DMF, 72 ° of C react 9h; (b) anhydrous methanol, room temperature;
2. the aqueous solution of amine, room temperature reaction 7h;
3. potassium tert.-butoxide, Anhydrous potassium carbonate, p-hydroxyphenylaceticacid, dimethyl sulfoxide (DMSO), 90 ° of C react 9h;
4.(a) thionyl chloride, methylene dichloride, 70 ° of C react 4h; (b) anhydrous methanol, 0 ° of C reacts 0.5h; (c) 80% hydrazine hydrate, 75 ° of C react 5h;
5.N, N-carbonyl dimidazoles, triphenylphosphine, carbon tetrabromide, 0 ° of C reacts 6h;
6.N, N-dicyclohexylcarbodiimide, tetrahydrofuran (THF), room temperature reaction 4h;
7. Anhydrous potassium carbonate, oxammonium hydrochloride, 80% ethanol, 78 ° of C react 4h;
8.N, N-carbonyl dimidazoles, DMF, 115 ° of C react 6h.
Specifically, when X is 1,3,4-oxadiazole, step is as follows:
(1) thionyl chloride is warming up to 40 ~ 45 ° of C, the N of the drying treatment of slow dropping catalytic amount, dinethylformamide (DMF), insulated and stirred 0.5h, add 2-pyridine carboxylic acid (i), be warming up to 70 ~ 75 DEG C (preferably 72 ° of C), the preferred 9h of reaction 8 ~ 10h(), there is off-white color solid to separate out; After reaction, reaction solution is cooled to room temperature, adds toluene, removes solvent under reduced pressure, repeats this operation 2 ~ 3 times (referring to " add toluene, remove solvent under reduced pressure ") to excessive thionyl chloride and all steams, obtain pale yellow oil; Under condition of ice bath, in oily matter, slowly drip anhydrous methanol, no longer separate out to white solid, filter, use washed with diethylether filter cake, vacuum-drying, obtain intermediate 4-chloropyridine-2-methyl-formiate hydrochloride (ii);
(2) above-mentioned 4-chloropyridine-2-methyl-formiate hydrochloride is (ii) dissolved in the aqueous solution of excess amine, the preferred 7h of stirring at room temperature 5 ~ 10h(), dichloromethane extraction 2 ~ 4 times, merges organic phase, and saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, (elution system is petrol ether/ethyl acetate=6/1 to silica gel column chromatography separating purification, volume ratio), obtain N-alkyl-4-chloropyridine-2-methane amide (iii);
(3) potassium tert.-butoxide, p-hydroxyphenylaceticacid are fed intake and be dissolved in dry dimethyl sulfoxide (DMSO) (DMSO), 1h is stirred under 0 DEG C of condition, add N-alkyl-4-chloropyridine-2-methane amide (iii) and Anhydrous potassium carbonate again, be warming up to 85 ~ 95 DEG C (preferably 90 DEG C), the preferred 8h of reaction 6 ~ 9h(), wherein, the mol ratio of potassium tert.-butoxide, p-hydroxyphenylaceticacid, N-alkyl-4-chloropyridine-2-methane amide and Anhydrous potassium carbonate is 3:1:2:1; Be cooled to room temperature after completion of the reaction, slowly add distilled water, pH to 5 ~ 6 are regulated with the HCl solution of 2M, reaction solution is extracted with ethyl acetate 2 ~ 5 times, merge organic phase, wash with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, pressurization steaming desolventizes, silica gel column chromatography separating purification (elution system is sherwood oil: ethyl acetate: Glacial acetic acid=1:1:0.01, volume ratio), obtains intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid (iv);
(4) substituted benzoic acid and thionyl chloride (mol ratio 1:5) are dissolved in dry methylene dichloride, heating reflux reaction, TLC monitoring, to reacting completely, removes solvent and excessive thionyl chloride under reduced pressure; Under condition of ice bath, in residue, slowly drip anhydrous methanol, stirring at room temperature 0.5h, remove excessive methyl alcohol under reduced pressure, (substituted benzoic acid is 1:2 with the molecular volume ratio of hydrazine hydrate to add 80% hydrazine hydrate (80% refers to mass concentration), unit mmol:ml), be warming up to 75 DEG C, reaction 5h; After reaction, if 1. adularescent solid is separated out, then direct filtration, obtains white solid, column chromatography purification, obtains intermediate substituted benzoyl hydrazides (v); If 2. separate out without white solid, then use dichloromethane extraction 2 ~ 4 times, merge organic phase, anhydrous sodium sulfate drying, filters, removes solvent under reduced pressure, column chromatographic isolation and purification (moving phase is ethyl acetate: methyl alcohol=95:5, volume ratio), obtains intermediate substituted benzoyl hydrazides (v); Described substituted benzoic acid and substituted benzoyl hydrazides (v) in, R 1for phenyl, to fluorophenyl, rubigan, to the chloro-3-trifluoromethyl of bromophenyl, p-nitrophenyl, p-trifluoromethyl phenyl, isobutyl-, 2-aminomethyl phenyl, p-methoxyphenyl or 4-;
(5) under 0 DEG C of condition; by N; N-carbonyl dimidazoles (CDI) is added to containing 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl acetic acid (iv) dichloromethane solution in; stir 30 minutes; then substituted benzoyl hydrazides (v) is added; 0 DEG C of preferred 4h of reaction 3 ~ 5h(), then add CBr simultaneously 4and PPh 3, 0 DEG C of preferred 2h of reaction 1.5 ~ 2.5h(), complete cyclodehydration, purification by silica gel column chromatography, namely obtain target product (vii), wherein, R 0for methyl or ethyl, R 1for phenyl, to fluorophenyl, rubigan, to the chloro-3-trifluoromethyl of bromophenyl, p-nitrophenyl, p-trifluoromethyl phenyl, isobutyl-, 2-aminomethyl phenyl, p-methoxyphenyl or 4-; N, N-carbonyl dimidazoles, 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl acetic acid, substituted benzoyl hydrazides, CBr 4and PPh 3the mol ratio of five is 1.1:1:1:1.5:1.5.
When X is bishydrazide base, step is as follows:
(6) by intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid is (iv) and N, N-dicyclohexylcarbodiimide (DCC) is dissolved in anhydrous tetrahydro furan, stirring at room temperature 1h, add substituted benzoyl hydrazides (v), the preferred 4h of stirring at room temperature 3 ~ 5h(), filter, with tetrahydrofuran (THF) washing leaching cake several times, merging filtrate and washing lotion, remove solvent under reduced pressure, (eluent is sherwood oil to silica gel column chromatography separating purification: ethyl acetate=4:1 ~ 1:1 gradient elution, volume ratio), namely target product is obtained (viii), wherein, R 0for methyl or ethyl, R 1for phenyl, to fluorophenyl, rubigan, to the chloro-3-trifluoromethyl of bromophenyl, p-nitrophenyl, p-trifluoromethyl phenyl, isobutyl-, 2-aminomethyl phenyl, p-methoxyphenyl or 4-, 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl acetic acid, N, N-dicyclohexylcarbodiimide and substituted benzoyl hydrazides three mol ratio be 1:1.5:1.
When X is 1,2,4-oxadiazole, step is as follows:
(7) by oxammonium hydrochloride, Anhydrous potassium carbonate is in 1:1(mol ratio) ratio be dissolved in 80% ethanol (percent by volume), stirring at room temperature 0.5h, add and replace formonitrile HCN (mol ratio replacing formonitrile HCN and oxammonium hydrochloride is 1:1.2), the preferred 4h of back flow reaction 3 ~ 5h(), be cooled to room temperature, remove solvent under reduced pressure, add ethyl acetate to stir, cross and filter insolubles, collect filtrate, remove solvent under reduced pressure, obtain faint yellow solid, by ethyl acetate, sherwood oil mixed solvent ((volume ratio of ethyl acetate and sherwood oil is 2:1) recrystallization, obtain intermediate substituted formyl amidoxime (vi), wherein, described substituted benzene formonitrile HCN and substituted formyl amidoxime (vi) in, R 1for phenyl, to fluorophenyl, rubigan, to the chloro-3-trifluoromethyl of bromophenyl, p-nitrophenyl, p-trifluoromethyl phenyl, isobutyl-, 2-aminomethyl phenyl, p-methoxyphenyl or 4-,
(8) by intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid is (iv) dissolved in N, in dinethylformamide (DMF), add the N of 1mol/L, the DMF solution of N-carbonyl dimidazoles (CDI), stirring at room temperature 0.5h, adds substituted formyl amidoxime DMF solution (vi), the preferred 4h of stirring at room temperature 3 ~ 5h(), add the N of 1mol/L again, the DMF solution of N-carbonyl dimidazoles, be warming up to 115 DEG C of preferred 6h of reaction 5 ~ 7h(); React complete, be cooled to room temperature, add CH 2cl 2with distilled water (the two volume ratio is 1:1), stirring at room temperature 0.5h, aqueous phase dichloromethane extraction, merges mutually with original machine, and organic phase uses the hydrochloric acid of 1M, saturated NaHCO respectively 3solution and saturated NaCl solution respectively wash three times, then use anhydrous Na 2sO 4drying, filter, remove solvent under reduced pressure, silica gel column chromatography separating purification (eluent is sherwood oil: ethyl acetate=6:1, volume ratio), obtains end product ix, wherein, R 0for methyl or ethyl, R 1for phenyl, to fluorophenyl, rubigan, to the chloro-3-trifluoromethyl of bromophenyl, p-nitrophenyl, p-trifluoromethyl phenyl, isobutyl-, 2-aminomethyl phenyl, p-methoxyphenyl or 4-; 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl acetic acid (iv), the N that adds of first time; N-carbonyl dimidazoles, substituted formyl amidoxime (vi), the second N added, the mol ratio of N-carbonyl dimidazoles is 1:1.1:1:1.1.
In described step (2), the aqueous solution of amine is aqueous methylamine solution or ethylamine solution, and the massfraction of aqueous methylamine solution is 40%, and the massfraction of ethylamine solution is 70%.
In described step (4), substituted benzoic acid is phenylformic acid, Chlorodracylic acid, o-toluic acid or anisic acid; Correspondingly, substituted benzoyl hydrazides is (v) benzoyl hydrazine, p-chloro benzoyl hydrazine, o-methyl-benzene formyl hydrazine or to methoxybenzoyl hydrazine.
In described step (7), substituted benzene formonitrile HCN is cyanobenzene, to fluorobenzonitrile, to 6-chlorophenyl nitrile, to bromoxynil, p-nitrophenyl nitrile, pchlorobenzotrifluoride, 2, 2,-dimethyl propionitrile, o-methyl-benzene nitrile, to methoxy cyanophenyl or the chloro-3-4-trifluoromethylbenzonitrile of 4-, correspondingly, substituted formyl amidoxime is (vi) benzoyl amidoxime, to fluorobenzoyl amidoxime, to chlorobenzoyl amidoxime, to Bromophenacyl amidoxime, p-nitrophenyl formyl amidoxime, to trifluoromethyl benzamide oxime, 2, 2-dimethylpropionamide oxime, o-methyl-benzene formyl amidoxime, to methoxy benzamide oxime or 4-chloro-3-trifluoromethyl benzamide oxime.
4-pyridine phenyl ether compounds of the present invention has growth of tumour cell inhibit activities, may be used for preparing antitumor drug, especially vii-1, vii-2, vii-4, vii-5, ix-6, ix-10, has good growth of tumour cell inhibit activities.
Compared with prior art, excellent results of the present invention is: the design and synthesis of the present invention Xarelto analogue of novel structure, innovative point is the structure division hydrazides of urea in Xarelto molecule, 1, 2, 4-oxadiazole and 1, 3, 4-oxadiazole replaces, obtain the compound that the structure with growth inhibitory activity to tumor cell is brand-new, wherein compound vii-1, vii-2, vii-4, vii-5, ix-6, ix-10 to the growth inhibiting IC50 value of human colon carcinoma tumour cell (HCT-116) all lower than 20 μMs, particularly the growth inhibitory activity of compound vii-1 to HCT-116 is better than lead compound Xarelto.Conventional Methyl thiazoly tetrazolium assay enzyme mark colorimetry (mtt assay) is adopted to the evaluation method that growth of tumour cell suppresses, as shown in table 1.
The numbering of table 1. compound, structural formula and determination of activity result
Experimental result shows, and most of 4-pyridine phenyl ether compounds of the present invention has obvious growth inhibitory activity to HCT-116 cell.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated, understands the present invention and advantage thereof and effect in order to more deep, but described embodiment is only for illustration of the present invention instead of restriction the present invention.
The preparation of embodiment 1 compound vii-1 ~ vii-5
(1) 4-chloropyridine-2-methyl-formiate hydrochloride preparation (ii)
Get thionyl chloride 40mL, be warming up to 42 DEG C, slowly drip the DMF(0.5mL of catalytic amount drying treatment), keep temperature to stir 0.5h, add 2-pyridine carboxylic acid (7.38g, 60mmol) at twice, be warming up to 72 DEG C, reaction 9h, has near-white solid to separate out; Stopped reaction, is cooled to room temperature, adds toluene 15mL in reaction solution, and outstanding steaming steaming desolventizes, and repeats this operation and all steams to excessive thionyl chloride for 2 ~ 3 times, obtain pale yellow oil; Under condition of ice bath, in oily matter, slowly drip anhydrous methanol, no longer separate out to white solid, filter, use washed with diethylether filter cake, vacuum-drying, obtain white solid (4-chloropyridine-2-methyl-formiate hydrochloride (ii)), yield 82.10%.
(2) N-alkyl-4-chloropyridine-2-methane amide preparation (iii)
Get the 4-chloropyridine-2-methyl-formiate hydrochloride (ii) (5.15g obtained by above-mentioned reaction, 25mmol), (aqueous methylamine solution massfraction is 40% to add the aqueous solution of amine, ethylamine solution massfraction is 70%) 50mL, stirring at room temperature 7h, dichloromethane extraction (30mL × 4), merge organic phase, saturated nacl aqueous solution washing (30mL × 4), anhydrous sodium sulfate drying, filters, filtrate is mixed sample, silica gel column chromatography separating purification, obtain white solid N-alkyl-4-chloropyridine-2-methane amide, elution system is sherwood oil: ethyl acetate=6:1.
The aqueous solution of above-mentioned amine is the aqueous solution (corresponding iii-1) of methylamine or the aqueous solution (corresponding iii-2) of ethamine.
Iii-1:N-methyl-4-Chloro-2-Pyridyle methane amide, white solid, yield 94.74%, mp:41 ~ 43 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.87(brd,1H),8.62(d,J=5.4Hz,1H),8.02(d,J=1.8Hz,1H),7.76(dd,J=5.4Hz,1.8Hz,1H),2.82(d,J=4.8Hz,3H)。MS(calcd/found)[M+H] +:171.02/171.3。
Iii-2:N-ethyl-4-Chloro-2-Pyridyle methane amide, white solid, yield 93.82%, mp:54 ~ 58 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.91(brt,1H),8.63(d,J=5.4Hz,1H),8.03(d,J=1.8Hz,1H),7.76(dd,J=4.8Hz,1.8Hz,1H),3.30-3.35(m,2H),1.22(t,J=7.2Hz,3H)。MS(calcd/found)[M+H] +:185.04/185.0。
(3) 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid preparation (iv)
By potassium tert.-butoxide (6.73g, 60mmol), p-hydroxyphenylaceticacid (3.04g, 20mmol) be dissolved in 35mLDMSO, 1h is stirred under 0 DEG C of condition, add N-alkyl-4-chloropyridine-2-methane amide (20mmol) of above-mentioned preparation, salt of wormwood (1.38g, 10mmol), be warming up to 90 DEG C, reaction 8h; React complete; be cooled to room temperature; slowly add distilled water 30mL; pH to 5 ~ 6 are regulated with the HCl solution of 2M; reaction solution is extracted with ethyl acetate (35mL × 5); merge organic phase; with saturated nacl aqueous solution washing (35mL × 2); anhydrous sodium sulfate drying; filter, mix sample, silica gel column chromatography separating purification; intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl acetic acid (iv), elution system is sherwood oil: ethyl acetate (a small amount of Glacial acetic acid)=1:1.
Above-mentioned N-alkyl-4-chloropyridine-2-methane amide is respectively N-methyl-4-chloropyridine-2-methane amide and N-methyl-4-chloropyridine-2-methane amide.
Iv-1:2-{4-[[2-(methylcarbamoyl)-4-pyridyl] oxygen base] phenyl } acetic acid, white solid, yield 58.74%, mp:147 ~ 150 ° of C. 1HNMR(600MHz,DMSO-d 6)δ12.41(s,1H),8.78(d,J=4.5Hz,1H),8.52(d,J=6.0Hz,1H),7.40(d,J=9.0Hz,2H),7.38(d,J=3.0Hz,1H),7.15-7.18(m,3H),3.65(s,2H),2.78(d,J=4.5Hz,3H)。MS(calcd/found)[M+H] +:287.28/287.4。
Iv-2:2-{4-[[2-(ethyl carbamyl)-4-pyridyl] oxygen base] phenyl } acetic acid, white solid, yield 51.63%, mp:158 ~ 161 ° of C. 1HNMR(600MHz,DMSO-d 6)δ12.40(s,1H),8.82(t,J=6.0Hz,1H),8.52(d,J=6.0Hz,1H),7.40(d,J=8.4Hz,2H),7.38(d,J=2.4Hz,1H),7.16-7.19(m,3H),3.65(s,2H),3.25-3.30(m,2H),1.09(t,J=7.2Hz,3H)。MS(calcd/found)[M+H] +:301.31/301.3。
(4) substituted benzoyl hydrazides preparation (v)
By substituted benzoic acid (15mmol), thionyl chloride 9mL, is dissolved in dry 45mL methylene dichloride, heating reflux reaction 4h, to reacting completely, steaming and desolventizing and excessive thionyl chloride; Under condition of ice bath, in residue, slowly drip anhydrous methanol 25mL, stirring at room temperature 0.5h, steam except excessive methyl alcohol, add hydrazine hydrate (80% the refers to mass concentration) 30mL of 80%, be warming up to 75 DEG C, reaction 5h; If adularescent solid is separated out, then direct filtration, mixes sample by white solid, column chromatography; If separate out without white solid, then use methylene dichloride (20mL × 4) aqueous phase extracted, merge organic phase, anhydrous sodium sulfate drying, filter, mix sample column chromatography; Developping agent system ethyl acetate: methyl alcohol=95:5; After column chromatography, obtain intermediate substituted benzoyl hydrazides (v).
Above-mentioned substituted benzoic acid is phenylformic acid, Chlorodracylic acid, anisic acid, o-toluic acid, respectively corresponding v-1, v-2, v-3, v-4.
V-1: benzoyl hydrazine, white solid, yield 79.57%, mp:113 ~ 117 ° of C.MS(calcd/found)[M+H] +:137.06/137.3。
V-2:4-chlorobenzoyl hydrazine, white solid, yield 74.32%, mp:112 ~ 116 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.86(s,1H),7.83(d,J=8.4Hz,2H),7.53(d,J=8.4Hz,2H),4.51(s,2H)。MS(calcd/found)[M+H] +:171.02/171.2。
V-3:4-methoxybenzoyl hydrazine, white solid, yield 72.47%, mp:136 ~ 140 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.61(s,1H),7.79(d,J=8.7Hz,2H),6.97(d,J=8.7Hz,2H),4.41(brs,2H),3.80(s,3H)。MS(calcd/found)[M+H] +:167.07/167.4。
V-4:2-toluyl hydrazine, white solid, yield 72.47%, mp:122 ~ 124 ° of C.MS(calcd/found)[M+H] +:151.18/151.2。
(5) preparation of N-alkyl-4-[4-(5-substituted-phenyl-1,3,4-oxadiazole-2-methylene radical) phenoxy group]-2-pyridine carboxamide (vii)
By intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid iv(1mmol) be dissolved in methylene dichloride, add N ' N-carbonyl dimidazoles (0.18g, 1.1mmol), stirring at room temperature 0.5h, add substituted benzoyl hydrazides (v) (1mmol), stirring at room temperature reaction 4h, simultaneously disposablely under condition of ice bath add carbon tetrabromide (0.50g, 1.5mmol), triphenylphosphine (0.39g, 1.5mmol), stirring at room temperature 2.5h completes cyclization process, steaming desolventizes, mix sample, column chromatographic isolation and purification, namely target product N-alkyl-4-[4-(5-substituted-phenyl-1 is obtained, 3, 4-oxadiazole-2-methylene radical) phenoxy group]-2-pyridine carboxamide (vii), eluent system sherwood oil: ethyl acetate=8:1 ~ 4:1 gradient elution.
Above-mentioned 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid is 2-{4-[[2-(methylcarbamoyl)-4-pyridyl] oxygen base] phenyl acetic acid, 2-{4-[[2-(ethyl carbamyl)-4-pyridyl] oxygen base] phenyl acetic acid.
Above-mentioned substituted benzoyl hydrazides be benzoyl hydrazine, p-chloro benzoyl hydrazine, 2-toluyl hydrazine, to methoxybenzoyl hydrazine.
Target product is as follows:
Vii-1:N-methyl-4-[4-(5-phenyl-1,3,4 oxadiazole-2-methylene radical) phenoxy group]-2-pyridine carboxamide, white solid, yield 53.67%, mp:147 ~ 149 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.8Hz,1H),8.52(d,J=5.7Hz,1H),7.99(d,J=9.0Hz,2H),7.58-7.63(m,3H),7.54(d,J=8.4Hz,2H),7.39(d,J=3.0Hz,1H),7.25(d,J=8.4Hz,2H),7.17(dd,J=5.7Hz,3.0Hz,1H),4.45(s,2H),2.78(d,J=4.8Hz,3H)。HRMS(ESI)m/zforC 22H 19N 4O 3[M+H] +：calculated387.1452found387.1452。
Vii-2:N-methyl-4-{4-[5-(4-chloro-phenyl-)-1,3,4 oxadiazole-2-methylene radical] phenoxy group }-2-pyridine carboxamide, near-white solid, yield 42.63%, mp:235 ~ 237 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.8Hz,1H),8.52(d,J=5.7Hz,1H),7.99(d,J=9.0Hz,2H),7.67(d,J=9.0Hz,2H),7.54(d,J=9.0Hz,2H),7.39(d,J=3.0Hz,1H),7.25(d,J=9.0Hz,2H),7.18(dd,J=5.7Hz,3.0Hz,1H),4.45(s,2H),2.78(d,J=4.8Hz,3H)。HRMS(ESI)m/zforC 22H 18ClN 4O 3[M+H] +：calculated421.1062found421.1063。
Vii-3:N-methyl-4-{4-[5-(2-aminomethyl phenyl)-1,3,4 oxadiazole-2-methylene radical] phenoxy group }-2-pyridine carboxamide, yellow solid, yield 40.31%, mp:204 ~ 207 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.78(brd,J=4.8Hz,1H)，8.52(d,J=5.4Hz,1H),7.86(d,J=7.2Hz,1H),7.55(d,J=8.4Hz,2H),7.39-7.51(m,4H),7.25(d,J=8.4Hz,2H),7.17(dd,J=5.4Hz,2.4Hz,1H),4.45(s,2H),2.78(d,J=4.8Hz,3H),2.59(s,3H)。HRMS(ESI)m/zforC 23H 21N 4O 3[M+H] +：calculated401.1608found401.1611。
Vii-4:N-ethyl-4-[4-(5-phenyl-1,3,4 oxadiazole-2-methylene radical) phenoxy group]-2-pyridine carboxamide, white solid, yield 49.59%, mp:240 ~ 243 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.83(t,J=6.0Hz,1H),8.52(d,J=6.0Hz,1H),7.99(d,J=8.4Hz,2H),7.59-7.64(m,3H),7.54(d,J=8.4Hz,2H),7.39(d,J=2.4Hz,1H),7.24(d,J=8.4Hz,2H),7.18(dd,J=5.4Hz,2.4Hz,1H),4.45(s,2H),3.28(m,2H),1.09(t,J=7.2Hz,3H)。HRMS(ESI)m/zforC 23H 21N 4O 3[M+H] +：calculated401.1608found401.1610。
Vii-5:N-ethyl-4-{4-[5-(4-p-methoxy-phenyl)-1,3,4 oxadiazole-2-methylene radical] phenoxy group }-2-pyridine carboxamide, yield 50.55%, mp:211 ~ 214 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.83(t,J=6.0Hz,1H),8.52(d,J=6.0Hz,1H),7.92(d,J=9.0Hz,2H),7.53(d,J=8.4Hz,2H),7.39(d,J=2.4Hz,1H),7.24(d,J=8.4Hz,2H),7.18(dd,J=6.0Hz,2.4Hz,1H),4.42(s,2H),3.84(s,3H),3.28(m,2H),1.09(t,J=7.2Hz,3H)。HRMS(ESI)m/zforC 23H 21N 4O 3[M+H] +：calculated431.1714found431.1717。
The preparation of embodiment 2 compound viii-1 ~ viii-4
N-alkyl-4-{ [4-(2-substituted benzoyl hydrazide group)-2-oxoethyl] phenoxy group } preparation (viii) of-2-pyridine carboxamide
By intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid iv(0.75mmol), DCC (0.23g, 1.13mmol) join in 25mL eggplant-shape bottle, add anhydrous tetrahydro furan 8mL, stirring at room temperature 1h, add substituted benzoyl hydrazides (v) (0.75mmol), stirring at room temperature 4h, filter, with tetrahydrofuran (THF) washing leaching cake several times, merging filtrate, washing lotion, remove solvent under reduced pressure, silica gel column chromatography separating purification, namely target product N-alkyl-4-{ [4-(2-substituted benzoyl hydrazide group)-2-oxoethyl] phenoxy group is obtained }-2-pyridine carboxamide is (viii), eluent system sherwood oil: ethyl acetate=4:1 ~ 1:1 gradient elution.
Above-mentioned 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid is 2-{4-[[2-(methylcarbamoyl)-4-pyridyl] oxygen base] phenyl acetic acid, 2-{4-[[2-(ethyl carbamyl)-4-pyridyl] oxygen base] phenyl acetic acid.
Above-mentioned substituted benzoyl hydrazides is benzoyl hydrazine, p-chloro benzoyl hydrazine.
Target product is as follows:
Viii-1:N-methyl-4-{4-[2-(2-benzoyl diazanyl)-2-oxoethyl] phenoxy group }-2-pyridine carboxamide, white solid, yield 91.40%, mp:190 ~ 194 ° of C. 1HNMR(600MHz,DMSO-d 6)δ10.43(s,1H),10.26(s,1H),8.79(brd,J=4.8Hz,1H),8.52(d,J=6.0Hz,1H),7.88(d,J=8.4Hz,2H),7.48-7.59(m,5H),7.37(d,J=2.4Hz,1H),7.21(d,J=8.4Hz,2H),7.18(dd,J=5.4Hz,2.4Hz,1H),3.61(s,2H),2.78(d,J=5.4Hz,3H).HRMS(ESI)m/zforC 22H 21N 4O 4[M+H] +:calculated405.1557found405.1562。
Viii-2:N-methyl-4-{4-[2-[2-(4-chlorobenzene formacyl) diazanyl]-2-oxoethyl] phenoxy group }-2-pyridine carboxamide, white solid, yield 83.89%, mp:220 ~ 223 ° of C. 1HNMR(600MHz,DMSO-d 6)δ10.54(s,1H),10.29(s,1H),8.79(d,J=4.8Hz,1H),8.52(d,J=5.4Hz,1H),7.90(d,J=9.0Hz,2H),7.58(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),7.36(d,J=2.4Hz,1H),7.21(d,J=8.4Hz,2H),7.18(dd,J=5.4Hz,2.4Hz),3.61(s,2H),2.78(d,J=5.4Hz,3H)。HRMS(ESI)m/zforC 22H 20ClN 4O 4[M+H] +:calculated439.1168found436.1170。
Viii-3:N-ethyl-4-{4-[2-(2-benzoyl diazanyl)-2-oxoethyl] phenoxy group }-2-pyridine carboxamide, white solid, yield 84.76%, mp:187 ~ 191 ° of C. 1HNMR(600MHz,DMSO-d 6)δ10.43(s,1H),10.26(s,1H),8.83(t,J=6.0Hz,1H),8.52(d,J=5.4Hz,1H),7.89(d,J=6.6Hz,1H),7.48-7.79(m,5H),7.37(d,J=3Hz,1H),7.18-7.21(m,3H),3.61(s,2H),3.29(m,2H),1.10(t,J=6.6Hz,3H)。HRMS(ESI)m/zforC 23H 23N 4O 4[M+H] +:calculated419.1714found419.1717。
Viii-4:N-ethyl-4-{4-[2-[2-(4-chlorobenzene formacyl) diazanyl]-2-oxoethyl] phenoxy group }-2-pyridine carboxamide, white solid, yield 88.48%, mp:190 ~ 193 ° of C. 1HNMR(600MHz,DMSO-d 6)δ10.54(s,1H),10.29(s,1H),8.83(t,J=6.0Hz,1H),8.52(d,J=6.0Hz,1H),7.90(d,J=8.4Hz,2H),7.58(d,J=9.0Hz,2H),7.48(d,J=8.4Hz,2H),7.36(d,J=2.4Hz,1H),7.18-7.21(m,3H),3.61(s,2H),3.29(m,2H),1.09(t,J=6.6Hz,3H)。HRMS(ESI)m/zforC 23H 22ClN 4O 4[M+H] +:calculated453.1324found453.1325。
The preparation of embodiment 3 compound ix-1 ~ ix-11
(1) substituted formyl amidoxime synthesis (vi)
Oxammonium hydrochloride (12mmol), Anhydrous potassium carbonate (12mmol) are dissolved in stirring at room temperature 0.5h in the ethanol of volume fraction 80%, add and replace formonitrile HCN (10mmol), back flow reaction 4h, is cooled to room temperature, remove solvent under reduced pressure, add ethyl acetate to stir, cross and filter insolubles, collect filtrate, remove solvent under reduced pressure, obtain faint yellow solid, with ethyl acetate, sherwood oil mixed solvent (volume ratio of ethyl acetate and sherwood oil is 2:1) recrystallization, obtain intermediate substituted formyl amidoxime.
Above-mentioned replacement formonitrile HCN is cyanophenyl, to fluorobenzonitrile, to 6-chlorophenyl nitrile, to bromoxynil, pchlorobenzotrifluoride, p-nitrophenyl nitrile, trimethylacetonitrile, o-methyl-benzene nitrile, to methoxy cyanophenyl, the chloro-3-4-trifluoromethylbenzonitrile of 4-, distinguishes corresponding vi-1, vi-2, vi-3, vi-4, vi-5, vi-6, vi-7, vi-8, vi-9, vi-10.
Vi-1: benzoyl amidoxime, white solid, yield 74.32%, mp:72 ~ 73 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.62(s,1H),7.67(m,2H),7.36(m,3H),5.80(s,2H)。MS(calcd/found)[M+H]+:137.06/137.2。
Vi-2:4-fluorobenzoyl amidoxime, white crystal, yield 77.63%, mp:92 ~ 95 ° of C.MS(calcd/found)[M+H] +:155.05/155.2。
Vi-3:4-chlorobenzoyl amidoxime, white solid, yield 89.28%, mp:124 ~ 127 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.73(s,1H),7.69(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,2H),5.87(brs,2H)。MS(calcd/found)[M+H] +:171.02/171.3。
Vi-4:4-Bromophenacyl amidoxime, white solid, yield 80.41%, mp:128 ~ 131 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.74(s,1H),7.62(d,J=8.7Hz,2H),7.57(d,J=8.7Hz,2H),5.87(brs,2H)。MS(calcd/found)[M+H] +:214.97/215.1。
Vi-5:4-trifluoromethyl benzamide oxime, white solid, yield 85.79%, mp:95 ~ 97 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.92(s,1H),7.89(d,J=7.8Hz,2H),7.74(d,2H),5.98(s,2H)。MS(calcd/found)[M+H] +:205.05/204.9。
Vi-6:4-nitrobenzamide oxime, yellow solid, yield 54.32%, mp:116 ~ 118 ° of C. 1HNMR(600MHz,DMSO-d 6)δ10.13(s,1H),8.23(d,J=9.0Hz,2H),7.94(d,J=9.0Hz,2H),6.07(s,2H)。MS(calcd/found)[M+H] +:182.05/182.3。
Vi-7:2,2-dimethylpropionamide oxime, white solid, yield 84.33%, mp:117 ~ 120 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.85(s,1H),5.21(s,2H),1.08(s,9H)。MS(calcd/found)[M+H] +:117.09/117.2。
Vi-8:2-toluyl amidoxime, white solid, yield 71.47%, mp:127 ~ 130 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.30(s,1H),7.27(m,2H),7.19(m,2H),5.71(s,2H),2.35(s,3H)。MS(calcd/found)[M+H] +:151.08/151.2。
Vi-9:4-methoxy benzamide oxime, white solid, yield 69.59%, mp:97 ~ 100 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.45(s,1H),7.60(d,J=9.0Hz,2H),6.92(d,J=9.0Hz,2H),5.72(brs,2H),3.77(s,3H).MS(calcd/found)[M+H] +:167.07/167.4。
Vi-10:4-chloro-3-trifluoromethyl benzamide oxime, white solid, yield 92.23%, mp:94 ~ 97 ° of C. 1HNMR(600MHz,DMSO-d 6)δ9.96(s,1H),8.11(s,1H),7.97(d,J=8.4Hz,1H),7.76(d,J=8.4Hz,1H),6.08(brs,2H).MS(calcd/found)[M+H] +:239.01/239.2。
(2) N-alkyl-4-{4-[(3-substituted-phenyl-1,2,4-oxadiazole-5-base) methyl] phenoxy group } pyridine-2-carboxamide preparation (ix)
By intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid iv(0.75mmol) be dissolved in DMF(8mL) in, add the N of 1mol/L, the DMF solution 0.8mL of N-carbonyl dimidazoles, stirring at room temperature 0.5h, add the DMF solution (0.75mmol) of 1mol/L substituted formyl amidoxime, stirring at room temperature 4h, then the DMF solution 0.8mL of N ' N-carbonyl dimidazoles adding 1mol/L, be warming up to 115 DEG C of reaction 6h; React complete, be cooled to room temperature, add CH 2cl 210mL each with distilled water, stirring at room temperature 0.5h, aqueous phase methylene dichloride (10mL × 3) extraction, merge mutually with original machine, organic phase uses the HCl of 1M (10mL × 3), saturated NaHCO respectively 3solution (10mL × 3) and saturated NaCl solution (10mL × 3) washing; Mix sample, silica gel column chromatography separating purification, namely obtain target product.Development system sherwood oil: ethyl acetate=6:1.
Above-mentioned 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid is 2-{4-[[2-(methylcarbamoyl)-4-pyridyl] oxygen base] phenyl acetic acid, 2-{4-[[2-(ethyl carbamyl)-4-pyridyl] oxygen base] phenyl acetic acid.
Above-mentioned substituted formyl amidoxime be benzoyl amidoxime, to fluorobenzoyl amidoxime, to chlorobenzoyl oxime, to Bromophenacyl amidoxime, p-nitrophenyl formyl amidoxime, to trifluoromethyl benzamide oxime, tert-butylformamide oxime, o-methyl-benzene formyl amidoxime, to methoxy benzamide oxime, 4-chloro-3-trifluoromethyl benzamide oxime.
Target product is as follows:
Ix-1:N-methyl-4-{4-[[3-phenyl-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, white solid, yield 67.80%, mp:115 ~ 119 DEG C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.5Hz,1H),8.52(d,J=5.4Hz,1H),8.01(d,J=9.0Hz,2H),7.59-7.60(m,3H),7.56(d,J=8.4Hz,2H),7.40(d,J=2.7Hz,1H),7.26(d,J=8.4Hz,2H),7.18（dd,J=5.4Hz,2.7Hz,1H),4.53(s,2H),2.81(d,J=4.5Hz,3H)。HRMS(ESI)m/zforC 22H 19N 4O 3[M+H] +：calculated387.1452found387.1452。
Ix-2:N-methyl-4-{4-[[3-(4-fluorophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, white solid, yield 56.11%, mp:107 ~ 110 DEG C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.8Hz,1H),8.52(d,J=5.4Hz,1H),8.06(m,2H),7.56(d,J=8.4Hz,2H),7.39-7.43(m,3H),7.25(d,J=8.4Hz,2H),7.18(dd,J=6.6Hz,3.0Hz,1H),4.52(s,2H),2.78(d,J=4.8Hz,3H)。HRMS(ESI)m/zforC 22H 18FN 4O 3[M+H] +：calculated405.1357found405.1359。
Ix-3:N-methyl-4-{4-[[3-(4-chloro-phenyl-)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, faint yellow solid, yield 53.27%, mp:109 ~ 113 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.5Hz,1H),8.52(d,J=5.4Hz,1H),8.02(d,J=8.4Hz,2H),7.64(d,J=8.4Hz,2H),7.55(d,J=8.7Hz,2H),7.39(d,J=2.7Hz,1H),7.18(dd,J=5.4Hz,2.7Hz,1H),4.53(s,2H),2.79(d,J=4.5Hz,3H)。HRMS(ESI)m/zforC 22H 18ClN 4O 3[M+H] +:calculated421.1062found421.1063。
Ix-4:N-methyl-4-{4-[[3-(4-bromophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, faint yellow solid, yield 43.84%, mp:142 ~ 144 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.8Hz,1H),8.52(d,J=5.4Hz,1H),7.95(d,J=9.0Hz,2H),7.78(d,J=9.0Hz,2H),7.56(d,J=8.4Hz,2H),7.39(d,J=2.7Hz,1H),7.25(d,J=8.4Hz,2H),7.18(dd,J=5.4Hz,2.7Hz,1H),4.53(s,2H),2.78(d,J=5.4Hz,3H)。HRMS(ESI)m/zforC 22H 18BrN 4O 3[M+H] +:calculated465.0557found465.0557。
Ix-5:N-methyl-4-{4-[[3-(4-nitrophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, yellow solid, yield, mp:159 ~ 163 ° C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.2Hz,1H),8.52(d,J=5.4Hz,1H),8.41(d,J=9.0Hz,2H),8.27(d,J=9.0Hz,2H),7.57(d,J=8.4Hz,2H),7.39(d,J=2.7Hz,1H),7.26(d,J=8.4Hz,2H),7.19(dd,J=5.4Hz,2.7Hz,1H),4.57(s,2H),2.78(d,J=4.2Hz,3H)。HRMS(ESI)m/zforC 22H 18N 5O 5[M+H] +:calculated432.1302found432.1304。
Ix-6:N-methyl-4-{4-[[3-(4-trifluoromethyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, white solid, yield 54.72%, mp:90 ~ 93 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.5Hz,1H),8.52(d,J=5.4Hz,1H),8.23(d,J=8.1Hz,2H),7.95(d,J=8.1Hz,2H),7.57(d,J=8.7Hz,2H),7.39(d,J=2.7Hz,1H),7.26(d,J=8.7Hz,2H),7.19(dd,J=5.4Hz,2.7Hz,1H),4.56(s,2H),2.78(d,J=4.5Hz,3H)。HRMS(ESI)m/zforC 23H 18F 3N 4O 3[M+H] +:calculated455.1326found455.1327。
Ix-7:N-methyl-4-{4-[(the 3-tertiary butyl-1,2,4-oxadiazole-5-base) methyl] phenoxy group } pyridine-2-carboxamide, white solid, yield 45.49%, mp:69 ~ 72 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.8Hz,1H),8.52(d,J=5.4Hz,1H),7.48(d,J=8.7Hz,2H),7.38(d,J=2.4Hz,1H),7.24(d,J=8.7Hz,2H),7.17(dd,J=5.4Hz,2.4Hz,1H),4.41(s,2H),2.78(d,J=4.8Hz,3H),1.31(s,9H)。HRMS(ESI)m/zforC 20H 23N 4O 3[M+H] +:calculated367.1765found367.1768。
Ix-8:N-methyl-4-{4-[[3-(2-aminomethyl phenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, pale yellow oil, yield 47.52%. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=4.8Hz,1H),8.52(d,J=5.4Hz,1H),7.92(d,J=7.8Hz,1H),7.57(d,J=8.7Hz,2H),7.36-7.48(m,3H),7.26(d,J=8.7Hz,2H),7.18(dd,J=5.4Hz,3.2Hz,1H),4.53(s,2H),2.78(d,J=4.8Hz,3H),2.55(s,3H)。HRMS(ESI)m/zforC 23H 21N 4O 3[M+H] +:calculated401.1608found401.1610。
Ix-9:N-methyl-4-{4-[[3-(4-p-methoxy-phenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide, white solid, yield 43.54%, mp:122 ~ 125 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=5.1Hz,1H)，8.52(d,J=5.4Hz,1H),7.95(dd,J=7.2Hz,2.4Hz,2H),7.55(d,J=8.7Hz,2H),7.39(d,J=2.4Hz,1H),7.25(d,J=8.7Hz,2H),7.18(dd,J=5.4Hz,2.4Hz,1H),7.11(dd,J=7.2Hz,2.4Hz,2H),4.50(s,2H),3.83(s,3H),2.78(d,J=5.1Hz,3H)。HRMS(ESI)m/zforC 23H 21N 4O 4[M+H] +:calculated417.1557found417.1560。
Ix-10:N-methyl-4-{4-[[3-(the chloro-3-trifluoromethyl of 4-)-1,2,4-oxadiazole-5-bases] methyl] phenoxy group } pyridine-2-carboxamide, white solid, yield 44.53%, mp:122 ~ 125 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.79(brd,J=5.4Hz,1H),8.52(d,J=5.7Hz,1H),8.30(d,J=1.8Hz,1H),8.30(dd,J=8.4Hz,1.8Hz,1H),7.96(d,J=8.4Hz,1H),7.57(d,J=8.4Hz,2H),7.38(d,J=2.7Hz,1H),7.26(d,J=8.4Hz,2H),7.18(dd,J=5.7Hz,2.7Hz,1H),4.56(s,2H),2.78(d,J=5.4Hz,3H)。HRMS(ESI)m/zforC 23H 17ClF 3N 4O 3[M+H] +:calculated489.0936found489.0937。
Ix-11:N-ethyl-4-{4-[[3-(the chloro-3-trifluoromethyl of 4-)-1,2,4-oxadiazole-5-bases] methyl] phenoxy group } pyridine-2-carboxamide, white solid, yield 47.69%, mp:122 ~ 125 ° of C. 1HNMR(600MHz,DMSO-d 6)δ8.83(t,J=6.0Hz,1H),8.52(d.J=5.7Hz,1H),8.32(d,J=2.1Hz,1H),8.29(dd,J=8.4Hz,2.1Hz,1H),7.96(d,J=8.4Hz,1H),7.57(d,J=8.4Hz,2H),7.39(d,J=2.7Hz,1H),7.26(d,J=8.4Hz,2H),7.19(dd,J=5.7Hz,2.7Hz,1H),4.56(s,2H),3.25-3.30(m,2H),1.09(t,J=7.2Hz,3H)。HRMS(ESI)m/zforC 24H 19ClF 3N 4O 3[M+H] +:calculated503.1092found503.1095。

Claims (4)

1.4-pyridine phenyl ether compounds, its structure is as shown in general formula (I):
Wherein, R 0represent methyl and ethyl; R 1represent phenyl, to fluorophenyl, rubigan, to the chloro-3-trifluoromethyl of bromophenyl, p-nitrophenyl, p-trifluoromethyl phenyl, 2-aminomethyl phenyl, p-methoxyphenyl or 4-; X represents 1,3,4-oxadiazole, and 1,2,4-oxadiazole, structural formula is as implied above.
2. 4-pyridine phenyl ether compounds according to claim 1, is characterized in that: be following compound:
N-methyl-4-{4-[(5-phenyl-1,3,4-oxadiazole-2-base) methyl] phenoxy group } pyridine-2-carboxamide (vii-1);
N-methyl-4-{4-[[5-(4-chloro-phenyl-)-1,3,4-oxadiazole-2-base] methyl] phenoxy group } pyridine-2-carboxamide (vii-2);
N-methyl-4-{4-[[5-(2-aminomethyl phenyl)-1,3,4-oxadiazole-2-base] methyl] phenoxy group } pyridine-2-carboxamide (vii-3);
N-ethyl-4-{4-[(5-phenyl-1,3,4-oxadiazole-2-base) methyl] phenoxy group } pyridine-2-carboxamide (vii-4);
N-ethyl-4-{4-[[5-(4-p-methoxy-phenyl)-1,3,4-oxadiazole-2-base] methyl] phenoxy group } pyridine-2-carboxamide (vii-5);
N-methyl-4-{4-[[3-phenyl-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-1);
N-methyl-4-{4-[[3-(4-fluorophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-2);
N-methyl-4-{4-[[3-(4-chloro-phenyl-)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-3);
N-methyl-4-{4-[[3-(4-bromophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-4);
N-methyl-4-{4-[[3-(4-nitrophenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-5);
N-methyl-4-{4-[[3-(4-trifluoromethyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-6);
N-methyl-4-{4-[[3-(2-aminomethyl phenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-8);
N-methyl-4-{4-[[3-(4-p-methoxy-phenyl)-1,2,4-oxadiazole-5-base] methyl] phenoxy group } pyridine-2-carboxamide (ix-9);
N-methyl-4-{4-[[3-(the chloro-3-trifluoromethyl of 4-)-1,2,4-oxadiazole-5-bases] methyl] phenoxy group } pyridine-2-carboxamide (ix-10);
N-ethyl-4-{4-[[3-(the chloro-3-trifluoromethyl of 4-)-1,2,4-oxadiazole-5-bases] methyl] phenoxy group } pyridine-2-carboxamide (ix-11).
3. the preparation method of the 4-pyridine phenyl ether compounds according to any one of claim 1 ~ 2, is characterized in that:
When X is 1,3,4-oxadiazole, step is as follows:
(1) thionyl chloride is warming up to 40 ~ 45 DEG C, slowly drips the DMF of the drying treatment of catalytic amount, insulated and stirred 0.5h, adds 2-pyridine carboxylic acid (i), is warming up to 70 ~ 75 DEG C, reaction 8 ~ 10h, has off-white color solid to separate out; After reaction, reaction solution is cooled to room temperature, adds toluene, removes solvent under reduced pressure, repeats this operation and all steams to excessive thionyl chloride for 2 ~ 3 times, obtain pale yellow oil; Under condition of ice bath, in oily matter, slowly drip anhydrous methanol, no longer separate out to white solid, filter, use washed with diethylether filter cake, vacuum-drying, obtain intermediate 4-chloropyridine-2-methyl-formiate hydrochloride (ii);
(2) above-mentioned 4-chloropyridine-2-methyl-formiate hydrochloride (ii) is dissolved in the aqueous solution of excess amine, stirring at room temperature 5 ~ 10h, dichloromethane extraction 2 ~ 4 times, merge organic phase, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, silica gel column chromatography separating purification, obtain N-alkyl-4-chloropyridine-2-methane amide (iii); (3) potassium tert.-butoxide, p-hydroxyphenylaceticacid are fed intake and be dissolved in dry dimethyl sulfoxide (DMSO), 1h is stirred under 0 DEG C of condition, add N-alkyl-4-chloropyridine-2-methane amide (iii) and Anhydrous potassium carbonate again, be warming up to 85 ~ 95 DEG C, reaction 6 ~ 9h, wherein, the mol ratio of potassium tert.-butoxide, p-hydroxyphenylaceticacid, N-alkyl-4-chloropyridine-2-methane amide and Anhydrous potassium carbonate is 3: 1: 2: 1; Be cooled to room temperature after completion of the reaction, slowly add distilled water, regulate pH to 5 ~ 6 with the HCl solution of 2M, reaction solution is extracted with ethyl acetate 2 ~ 5 times, merge organic phase, wash with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filters, and pressurization steaming desolventizes, silica gel column chromatography separating purification, obtains intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid (iv);
(4) substituted benzoic acid of mol ratio 1: 5 and thionyl chloride are dissolved in dry methylene dichloride, heating reflux reaction, TLC monitoring, to reacting completely, removes solvent and excessive thionyl chloride under reduced pressure; Under condition of ice bath, in residue, slowly drip anhydrous methanol, stirring at room temperature 0.5h, remove excessive methyl alcohol under reduced pressure, add 80% hydrazine hydrate, be warming up to 75 DEG C, reaction 5h; After reaction,
If 1. adularescent solid is separated out, then direct filtration, obtains white solid, and column chromatography purification obtains intermediate substituted benzoyl hydrazides (v);
If 2. separate out without white solid, then use dichloromethane extraction 2 ~ 4 times, merge organic phase, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, column chromatographic isolation and purification, obtain intermediate substituted benzoyl hydrazides (v); (5) under 0 DEG C of condition; by N; N-carbonyl dimidazoles is added to containing 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } in the dichloromethane solution of acetic acid (iv); stir 30 minutes; then step (4) gained substituted benzoyl hydrazides is added; 0 DEG C of reaction 3 ~ 5h, then adds CBr simultaneously 4and PPh 3, 0 DEG C of reaction 1.5 ~ 2.5h, completes cyclodehydration, purification by silica gel column chromatography, namely obtains target product; N, N-carbonyl dimidazoles, 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid, substituted benzoyl hydrazides, CBr 4and PPh 3the mol ratio of five is 1.1: 1: 1: 1.5: 1.5;
When X is 1,2,4-oxadiazole, step is as follows:
(7) by oxammonium hydrochloride, Anhydrous potassium carbonate in molar ratio 1: 1 ratio be dissolved in 80% ethanol, stirring at room temperature 0.5h, adds replacement formonitrile HCN, the mol ratio replacing formonitrile HCN and oxammonium hydrochloride is 1: 1.2, and back flow reaction 3 ~ 5h, is cooled to room temperature, remove solvent under reduced pressure, add ethyl acetate to stir, cross and filter insolubles, collect filtrate, remove solvent under reduced pressure, obtain faint yellow solid, with ethyl acetate, sherwood oil mixed solvent recrystallization, obtain intermediate substituted formyl amidoxime (vi);
(8) by intermediate 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid (iv) is dissolved in N, in dinethylformamide, add the N of 1mol/L, the DMF solution of N-carbonyl dimidazoles, stirring at room temperature 0.5h, adds the DMF solution of step (7) gained benzoyl amidoxime, stirring at room temperature 3 ~ 5h, add the N of 1mol/L again, the DMF solution of N-carbonyl dimidazoles, be warming up to 115 DEG C of reaction 5 ~ 7h; React complete, be cooled to room temperature, add CH 2cl 2and distilled water, stirring at room temperature 0.5h, aqueous phase dichloromethane extraction, merges mutually with original machine, and organic phase uses the hydrochloric acid of 1M, saturated NaHCO respectively 3solution and saturated NaCl solution respectively wash three times, then use anhydrous Na 2sO 4drying, filters, removes solvent under reduced pressure, silica gel column chromatography separating purification, obtain end product; 2-{4-[[2-(alkylcarbamoyl group)-4-pyridyl] oxygen base] phenyl } acetic acid (iv), the N that adds of first time, N-carbonyl dimidazoles, substituted formyl amidoxime (vi), the second N added, the mol ratio of N-carbonyl dimidazoles is 1: 1.1: 1: 1.1;
In described step (2), the aqueous solution of amine is aqueous methylamine solution or ethylamine solution, and the massfraction of aqueous methylamine solution is 40%, and the massfraction of ethylamine solution is 70%;
In described step (4), substituted benzoic acid is phenylformic acid, Chlorodracylic acid, 2-tolyl acid, anisic acid; Described substituted benzoyl hydrazides be benzoyl hydrazine, p-chloro benzoyl hydrazine, 2-toluyl hydrazine, to methoxybenzoyl hydrazine;
In described step (7), replacement formonitrile HCN be cyanobenzene, p-Fluorophenyl cyanide, p-Cyanochlorobenzene, to bromobenzylcyanide, p-nitrobenzonitfile, to trifluoromethylbenzonitrile, 2-methyl benzonitrile, to methoxy benzonitrile or the chloro-3-trifluoromethylbenzonitrile of 4-; Described substituted benzene formyl amidoxime be benzoyl amidoxime, to fluorobenzoyl amidoxime, to chlorobenzoyl amidoxime, to Bromophenacyl amidoxime, p-nitrophenyl formyl amidoxime, to trifluoromethyl benzamide oxime, 2-toluyl amidoxime, to methoxy benzamide oxime or 4-chloro-3-trifluoromethyl benzamide oxime.
4. the 4-pyridine phenyl ether compounds according to any one of claim 1 ~ 2 is preparing the application in antitumor drug.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058832A1 (en) * 2003-12-10 2005-06-30 Merck Patent Gmbh Diacylhydrazine derivatives
CN102653522A (en) * 2012-04-13 2012-09-05 烟台大学 Omega-carboxy-substituted diphenylthiourea compounds, and preparation method and application thereof
CN102898363A (en) * 2011-10-13 2013-01-30 南京圣和药业有限公司 Carbamate compound and application thereof in antitumor drug

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058832A1 (en) * 2003-12-10 2005-06-30 Merck Patent Gmbh Diacylhydrazine derivatives
CN102898363A (en) * 2011-10-13 2013-01-30 南京圣和药业有限公司 Carbamate compound and application thereof in antitumor drug
CN102653522A (en) * 2012-04-13 2012-09-05 烟台大学 Omega-carboxy-substituted diphenylthiourea compounds, and preparation method and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Design, Synthesis and Evaluation of Novel Rhodanine-containing Sorafenib Analogs as Potential Antitumor Agents;Wei Li等;《Arch.Pharm.Chem.Life Sci.》;20110324;第344卷(第6期);图1，方案1 *
Oxadiazoles in Medicinal Chemistry;Jonas Boström等;《J. Med. Chem.》;20111219;第55卷(第5期);第1817页左栏第2段第17-20行 *
多靶点抗肿瘤药物索拉非尼结构改造的研究进展;姚建文，等;《药学学报》;20120930;第47卷(第9期);第1111-1119页 *

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