CN105418583A - 7-benz[c]acridine(4-p-methylphenyl)-1,2,3-triazole and preparation method thereof - Google Patents
7-benz[c]acridine(4-p-methylphenyl)-1,2,3-triazole and preparation method thereof Download PDFInfo
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- CN105418583A CN105418583A CN201510870219.1A CN201510870219A CN105418583A CN 105418583 A CN105418583 A CN 105418583A CN 201510870219 A CN201510870219 A CN 201510870219A CN 105418583 A CN105418583 A CN 105418583A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a benz[c]acridine-1,2,3-triazole compound as well as a preparation method and application thereof. The preparation method of the 7-benz[c]acridine-1,2,3-triazole compound comprises the following steps: 1) taking o-bromobenzoic acid and naphthylamine as raw materials, potassium carbonate and copper powder as catalysts and isoamyl alcohol or n-amyl alcohol as a solvent to undergo Ullmann reaction to obtain a compound 1; 2) carrying out ring closure on the compound 1 with phosphorus oxychloride to prepare a compound 2; 3) dissolving the compound 2 in dimethyl fumarate to undergo nucleophilic substitution reaction with sodium azide to prepare a compound 3; and 4) dissolving p-methylbenzene acetylene in a tert-butyl alcohol water solution, adding vitamin C sodium, anhydrous cupric sulfate and the compound 3 to react and carrying out suction filtration and recrystallization, thus obtaining the 7-benz[c]acridine-1,2,3-triazole compound.
Description
Technical field
The present invention relates to organic chemistry filed, be specifically related to a kind of fused heterocyclic compound 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles and its production and use.
Background technology
Benzo [c] acridine is the nitrogenous organic heterocyclic molecule that a class is subject to extensive concern, all shows very strong physiology and live in antitumor, biological fluorescent labeling etc.Benzo [c] acridine skeleton is studied less at home and abroad, and only 7-amino replacement benzo [c] acridine derivatives is studied at present, greatly limit it and further applies.1,2,3-triazoles ring is commonly used for the biological isostere of amino groups and shows multiple biological activity, and a lot of triazole type medicine can be used as cancer such as treatment mammary cancer, ovarian cancer etc. clinically.If introduce 1,2,3-triazoles structure at benzo [c] acridine 7-, replace amino, be expected to the antitumor drug obtaining new and effective low toxicity, have not yet to see relevant report.
Summary of the invention
The object of the invention is to overcome the problems referred to above, a kind of compound with anti-tumor activity is provided, 1 is being introduced at benzo [c] acridine 7-, 2,3-triazole structure, replaces amino, synthesizing new acridine derivatives, be expected to the antitumor drug obtaining new and effective low toxicity, can be applied in the preparation of antitumor drug.
Another object of the present invention is to provide 7-benzo [c] acridine (4-p-methylphenyl)-1,2, the preparation method of 3-triazole, synthesis condition is gentle, raw material is easy to get, purity and productive rate are all higher, may be used for benzo [c] acridine-1,2,3-triazoles compound synthesizing other types.
Technical scheme provided by the invention is:
7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles, its structural formula is:
The preparation method of 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles, is obtained by following synthetic route:
Preferably, the preparation method of described 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles, concrete steps are as follows:
Step one, with o-bromobenzoic acid or o-iodobenzoic acid and naphthylamines for raw material, salt of wormwood and copper powder are catalyzer, with primary isoamyl alcohol or Pentyl alcohol for solvent, obtain compound 1 at 100-140 DEG C through ullmann reaction; Wherein, o-bromobenzoic acid or o-iodobenzoic acid are 1: 1-2 with the ratio of the amount of substance of naphthylamines, and the consumption of salt of wormwood is 1-3 times of o-bromobenzoic acid or o-iodobenzoic acid, and copper powder consumption is 0.1-0.5 times of o-bromobenzoic acid or o-iodobenzoic acid;
Step 2, compound 1 closes ring with phosphorus oxychloride at 80-140 DEG C, obtained compound 2;
Step 3, gets compound 2 and is dissolved in dimethyl fumarate or acetonitrile solution, and react obtained compound 3 with aqueous sodium azide, temperature of reaction is 60-120 DEG C; Wherein, compound used therefor 2 is 1: 1-2 with the ratio of the amount of substance of sodiumazide;
Step 4, get and be dissolved in tertiary butanol aqueous solution to methylbenzene acetylene, then add sodium ascorbate, anhydrous cupric sulfate and compound 3 to react at 60-120 DEG C, gained reactant suction filtration, filter cake recrystallization, namely benzo [c] acridine-1,2,3-triazoles compounds 4 described in target product is obtained; Wherein, in tertiary butanol aqueous solution, the volume ratio of the trimethyl carbinol and water is 1-8: 9-2, and the consumption of sodium ascorbate is 0.1-0.5 times of compound 3 amount of substance, and the consumption of anhydrous cupric sulfate is 0.1-0.3 times of the amount of substance of compound 3.
Preferably, described 7-benzo [c] acridine (4-p-methylphenyl)-1, 2, the preparation method of 3-triazole, when carrying out ullmann reaction in step one, control temperature is at 100-140 DEG C of back flow reaction 1-3 hour, after reaction terminates, obtain the crude product of compound 1, then compound 1 crude product is purified, remove solvent under reduced pressure, and water is added in the thick product of compound 1, control temperature stirs 10-30min at 70-90 DEG C, filter, filtrate regulates pH to 2-4 by acid solution, precipitation purple precipitates, suction filtration, gained solid ethyl alcohol recrystallization, obtain compound 1 sterling.
Preferably, the preparation method of described 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles, described acid solution is the one in hydrochloric acid, sulfuric acid and phosphoric acid.
Preferably, described 7-benzo [c] acridine (4-p-methylphenyl)-1,2, the preparation method of 3-triazole, compound 1 described in step 2 mixes with phosphorus oxychloride, and oil bath is heated to 80-140 DEG C, reaction 1-3 hour, after reaction terminates, poured into by residuum in the mixture of strong aqua, trash ice and chloroform and dissolve residuum, isolate chloroform layer, water layer continues to use chloroform extraction 2-3 time, combining extraction liquid, and with the dry 10-24 hour of Calcium Chloride Powder Anhydrous, filter, steaming desolventizes, with acetone recrystallization, obtain compound 2.
Preferably, described 7-benzo [c] acridine (4-p-methylphenyl)-1,2, the preparation method of 3-triazole, in the mixture of strong aqua, trash ice and chloroform, the consumption of strong aqua is 10 ~ 20 times of the volume of phosphorus oxychloride, and the consumption of chloroform is 20-40 times of volume of the thick product weight of compound 1.
The invention has the beneficial effects as follows, the present invention is by active superposition and the biological principle waiting row, ullmann reaction, nucleophilic substitution reaction, click chemistry reaction etc. are used to introduce 1 at benzo [c] acridine 7-, 2,3-triazole structure, synthesis 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazole, has good potential pharmaceutical use, is expected to the discovery for various antitumor drug lead compound.Synthesis condition provided by the invention is gentle, raw material is easy to get, and purity and productive rate are all higher, may be used for benzo [c] acridine-1,2,3-triazoles compound synthesizing other types.
Accompanying drawing explanation
Fig. 1 is the collection of illustrative plates faint yellow crystalline thing being carried out to the detection of hydrogen spectrum.
Fig. 2 is the collection of illustrative plates faint yellow crystalline thing being carried out to the detection of carbon spectrum
Embodiment
With specific embodiment, invention is elaborated below.
Embodiment 1
The preparation of 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles, concrete steps are as follows:
Step one, in 250mL three-necked bottle, add 5.20g (26mmol) o-bromobenzoic acid, 4.86g (34mmol) naphthylamines, 7.5g (36.2mmol) salt of wormwood and 0.3g (4.7mmol) copper powder, add 30mL primary isoamyl alcohol again as solvent, 140 DEG C of return stirring reaction 2h, after reaction terminates, obtain the thick product of compound 1, remove solvent under reduced pressure, obtain the thick product of compound 1 at gained and add 600mL water, 20min is stirred at 80 DEG C, filtered while hot, wash filter cake with water, combining water layer, water layer concentrated hydrochloric acid is acidified to pH=2, separate out a large amount of atropurpureus precipitation, suction filtration, gained solid ethyl alcohol recrystallization, obtain compound 1 sterling, productive rate 58%,
Step 2, in 100mL round-bottomed flask, add 1.14g (4.3mmol) compound 1 and 4.5mL phosphorus oxychloride, reactant is heated to by oil bath 140 DEG C of reaction 2h, after reaction terminates, obtain the thick product of compound 2, by the slow well-beaten strong aqua of impouring after thick for compound 2 product cooling, in the mixture of chloroform and rubble ice, the cumulative volume of the mixture of wherein said strong aqua and chloroform is 72mL, the volume of strong aqua is 21mL, the volume of chloroform is 51mL, with chloroform and ammonia water mixture washing flask, chloroform and ammonia water mixture mix containing the thick strong aqua of product of compound 2 and the mixture of chloroform with aforementioned, treat after 30min that the thick product of compound 2 all dissolves, isolate chloroform layer, water layer continues to use chloroform extraction 3 times, be separated chloroform layer, combined chloroform layer, dry 20 hours of Calcium Chloride Powder Anhydrous, filter, steaming desolventizes, obtain purple-brown powder, acetone recrystallization is compound 2 sterling, productive rate 52%,
3) 0.49g (2mmoL) compound 2 is dissolved in 20mL fumaric acid diformazan, then adds 0.13g (2mmoL) sodiumazide and 10mL water, under 60 DEG C of conditions, react 2h, leave standstill, have crystal to separate out, be separated, obtain obtaining pale yellow powder and compound 3, productive rate 66%;
4) 0.07g (0.5mmoL) is added in 5mL tertiary butanol aqueous solution to methylbenzene acetylene, in described tertiary butanol aqueous solution, the volume ratio of the trimethyl carbinol and water is 1: 1, add 0.02g (0.2mmoL) sodium ascorbate, 0.01g (0.125mmoL) anhydrous cupric sulfate and 0.14g (1mmoL) compound 3 again, 2h is reacted, suction filtration, water washing under 60 DEG C of conditions, with recrystallized from acetonitrile, obtain faint yellow needle-like crystal, productive rate 45%, m.p.168-173 DEG C.
Carry out hydrogen spectrum, carbon spectrum analysis to the faint yellow needle-like crystal of gained, its spectral characteristic is as follows:
1HNMR(400MHz，CDCl3)δ9.65(d，J＝8.5Hz，1H，ArH)，8.56(d，J＝8.8Hz，1H，ArH)，8.27(s，1H，ArH)，7.96(d，J＝8.7Hz，2H，ArH)，7.77～7.88(m，6H，ArH)，7.66(d，J＝6.4Hz，1H，ArH)，7.61(d，J＝8.4Hz，1H，ArH)，7.37(d，J＝8.0Hz，2H，ArH)，7.32(d，J＝9.2Hz，1H，ArH)，2.48(s，3H，-CH3)；
13CNMR(CDCl3，100MHz)，δ131.35，130.24，130.21，129.96，128.43，128.27，127.43，125.68，122.47，119.46，114.64，33.78；
Therefore, can determine that the faint yellow needle-like crystal of gained is 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles, its chemical structural formula is as follows:
molecular formula is: C
26h
18n
4, relative molecular weight is: 386.15.
Embodiment 2
Repeat embodiment 1, unlike:
In step one, the consumption of salt of wormwood is 5.39g (26mmol), copper powder 0.17g (2.6mmol), is Pentyl alcohol with solvent, and temperature during backflow is 100 DEG C, and the water layer concentrated hydrochloric acid of merging is acidified to pH=4;
In step 2, temperature during reaction is 100 DEG C;
In step 3, compound 2 is dissolved in acetonitrile solution, and the consumption of sodiumazide is 0.26g (4mmoL), and temperature during reaction is 80 DEG C;
In step 4, be 4: 6 by the trimethyl carbinol in tertiary butanol aqueous solution and water volume ratio.
Carrying out hydrogen spectrum, carbon spectrum analysis to being separated the faint yellow needle-like crystal obtained, being defined as 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles.
Embodiment 3
Repeat embodiment 1, unlike:
In step one, temperature during backflow is 160 DEG C, and the water layer concentrated hydrochloric acid of merging is acidified to pH=2;
In step 3, the consumption of sodiumazide is 0.26g (4mmoL), and temperature during reaction is 100 DEG C;
In step 4, in tertiary butanol aqueous solution, the trimethyl carbinol and water volume ratio are 6: 4, and temperature of reaction is 100 DEG C, are ethanol or chloroform by the solvent of recrystallization.
Carrying out hydrogen spectrum, carbon spectrum analysis to being separated the faint yellow needle-like crystal obtained, being defined as 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles.
Embodiment 4
Repeat embodiment 1, unlike:
In step one, o-bromobenzoic acid is changed into o-iodobenzoic acid, consumption is 6.45g (26mmol).
Although embodiment of the present invention are open as above, but it is not restricted to listed in specification sheets and embodiment utilization, it can be applied to various applicable the field of the invention completely, for those skilled in the art, can easily realize other amendment, therefore do not deviating under the universal that claim and equivalency range limit, the present invention is not limited to specific details.
Claims (7)
1. 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles, it is characterized in that, its structural formula is:
2. a preparation method for 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles as claimed in claim 1, is characterized in that, obtained by following synthetic route:
3. the preparation method of 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles as claimed in claim 2, it is characterized in that, concrete steps are as follows:
Step one, with o-bromobenzoic acid or o-iodobenzoic acid and naphthylamines for raw material, salt of wormwood and copper powder are catalyzer, with primary isoamyl alcohol or Pentyl alcohol for solvent, obtain compound 1 at 100-140 DEG C through ullmann reaction; Wherein, o-bromobenzoic acid or o-iodobenzoic acid are 1 with the ratio of the amount of substance of naphthylamines
:1-2, the consumption of salt of wormwood is 1-3 times of o-bromobenzoic acid or o-iodobenzoic acid, and copper powder consumption is 0.1-0.5 times of o-bromobenzoic acid or o-iodobenzoic acid;
Step 2, compound 1 closes ring with phosphorus oxychloride at 80-140 DEG C, obtained compound 2;
Step 3, gets compound 2 and is dissolved in dimethyl fumarate or acetonitrile solution, and react obtained compound 3 with aqueous sodium azide, temperature of reaction is 60-120 DEG C; Wherein, compound used therefor 2 is 1: 1-2 with the ratio of the amount of substance of sodiumazide;
Step 4, get and be dissolved in tertiary butanol aqueous solution to methylbenzene acetylene, then add sodium ascorbate, anhydrous cupric sulfate and compound 3 to react at 60-120 DEG C, gained reactant suction filtration, filter cake recrystallization, namely benzo [c] acridine-1,2,3-triazoles compounds 4 described in target product is obtained; Wherein, in tertiary butanol aqueous solution, the volume ratio of the trimethyl carbinol and water is 1-8: 9-2, and the consumption of sodium ascorbate is 0.1-0.5 times of compound 3 amount of substance, and the consumption of anhydrous cupric sulfate is 0.1-0.3 times of the amount of substance of compound 3.
4. 7-benzo [c] acridine (4-p-methylphenyl)-1 as claimed in claim 3, 2, the preparation method of 3-triazole, it is characterized in that, when carrying out ullmann reaction in step one, control temperature is at 100-140 DEG C of back flow reaction 1-3 hour, after reaction terminates, obtain the crude product of compound 1, then compound 1 crude product is purified, remove solvent under reduced pressure, and water is added in the thick product of compound 1, control temperature stirs 10-30min at 70-90 DEG C, filter, filtrate regulates pH to 2-4 by acid solution, precipitation purple precipitates, suction filtration, gained solid ethyl alcohol recrystallization, obtain compound 1 sterling.
5. the preparation method of 7-benzo [c] acridine (4-p-methylphenyl)-1,2,3-triazoles as claimed in claim 4, is characterized in that, described acid solution is in hydrochloric acid, sulfuric acid and phosphoric acid-kind.
6. 7-benzo [c] acridine (4-p-methylphenyl)-1 as claimed in claim 3,2, the preparation method of 3-triazole, it is characterized in that, compound 1 described in step 2 mixes with phosphorus oxychloride, and oil bath is heated to 80-140 DEG C, reaction 1-3 hour, after reaction terminates, poured into by residuum in the mixture of strong aqua, trash ice and chloroform and dissolve residuum, isolate chloroform layer, water layer continues to use chloroform extraction 2-3 time, combining extraction liquid, and with the dry 10-24 hour of Calcium Chloride Powder Anhydrous, filter, steaming desolventizes, with acetone recrystallization, obtain compound 2.
7. 7-benzo [c] acridine (4-p-methylphenyl)-1 as claimed in claim 6,2, the preparation method of 3-triazole, it is characterized in that, in the mixture of strong aqua, trash ice and chloroform, the consumption of strong aqua is 10 ~ 20 times of the volume of phosphorus oxychloride, and the consumption of chloroform is 20-40 times of volume of the thick product weight of compound 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113683552A (en) * | 2020-10-13 | 2021-11-23 | 兰州大学 | Tryptamine salicylic acid compound and preparation and application thereof |
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| CN104277029A (en) * | 2014-09-30 | 2015-01-14 | 刘华钢 | Acridine-1, 2, 3-triazole type compound and preparation method and application thereof |
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Patent Citations (2)
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| CN104277035A (en) * | 2014-09-30 | 2015-01-14 | 刘华钢 | Acridine-1, 3, 4-thiadiazole type compound and preparation method and application thereof |
| CN104277029A (en) * | 2014-09-30 | 2015-01-14 | 刘华钢 | Acridine-1, 2, 3-triazole type compound and preparation method and application thereof |
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| Title |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113683552A (en) * | 2020-10-13 | 2021-11-23 | 兰州大学 | Tryptamine salicylic acid compound and preparation and application thereof |
| CN113683552B (en) * | 2020-10-13 | 2024-03-19 | 兰州大学 | Tryptamine salicylic acid compound and preparation and application thereof |
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