CN105418585A - 7-benz[c]acridine(4-p-fluorophenyl)-1,2,3-triazole as well as preparation method and application thereof - Google Patents
7-benz[c]acridine(4-p-fluorophenyl)-1,2,3-triazole as well as preparation method and application thereof Download PDFInfo
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- 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
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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-fluorophenyl 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-is to fluorophenyl)-1,2,3-triazoles and its production and use.
Background technology
Acridine is the nitrogenous organic heterocyclic molecule that a class is subject to extensive concern, all shows very strong physiology and live in antitumor, antiviral, anti-malarial, antibacterial, biological fluorescent labeling and treatment acquired immune deficiency syndrome (AIDS) etc.Benzo [c] acridine skeleton is studied less at present at home and abroad, there are some researches show, this compounds has stronger Developing restraint effect to L1210 cell, and individual derivatives suppresses IC
50reach nmol rank, and be only limitted to, at the amino substitutive derivative of 7-, greatly limit it and further apply to the research of this compounds.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.In addition, Drugs Containing Fluorine has that biological activity is higher, stability produces the advantages such as resistance more by force and not easily, if introduce 1 at benzo [c] acridine 7-, 2,3-triazole structure and fluoro-containing group, 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 and fluoro-containing group, synthesizing new acridine derivatives, has extremely strong anti-tumor activity, can be applied in the preparation of antitumor drug.
Another object of the present invention is to provide 7-benzo [c] acridine (4-is to fluorophenyl)-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-is to fluorophenyl)-1,2,3-triazoles, its structural formula is:
The preparation method of 7-benzo [c] acridine (4-is to fluorophenyl)-1,2,3-triazoles, is obtained by following synthetic route:
Preferably, the preparation method of described 7-benzo [c] acridine (4-is to fluorophenyl)-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 fluorobenzene 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-is to fluorophenyl)-1,2, the preparation method of 3-triazole, when carrying out ullmann reaction in step one, control temperature, at 100-140 DEG C of back flow reaction 1-3 hour, reacts after terminating, obtain the thick product of compound 1, remove thick for compound 1 product under reduced pressure solvent, and add water in gained residue, control temperature stirs 20min at 70-90 DEG C, filter, filtrate regulates pH to 2-4 by acid solution, separates out purple precipitation, suction filtration, gained solid ethyl alcohol recrystallization, obtains compound 1 sterling.
Preferably, the preparation method of described 7-benzo [c] acridine (4-is to fluorophenyl)-1,2,3-triazoles, described acid solution is the middle one in hydrochloric acid, sulfuric acid and phosphoric acid
Preferably, described 7-benzo [c] acridine (4-is to fluorophenyl)-1, 2, the preparation method of 3-triazole, compound 1 described in step 2 mixes with phosphorus oxychloride, oil bath is heated to 80-140 DEG C, reaction 1-3 hour, after reaction terminates, obtain the thick product of compound 2, compound is poured into strong aqua without 2 thick products, in the mixture of trash ice and chloroform, 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 sterling.
Preferably, the preparation method of described 7-benzo [c] acridine (4-is to fluorophenyl)-1,2,3-triazoles, in the mixture of described strong aqua, trash ice and chloroform, the consumption of strong aqua is 10 ~ 20 times of the volume of phosphorus oxychloride; The consumption of chloroform is 20-40 times of volume of the thick product weight of compound 2.
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-is to fluorophenyl)-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-is to fluorophenyl)-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, remove solvent under reduced pressure, gained residue adds 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, productive rate 58%,
Step 2, in 100mL round-bottomed flask, adds 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, by the residuum slow well-beaten strong aqua of impouring after the cooling period, 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, washings mixes containing the strong aqua of residuum and the mixture of chloroform with aforementioned, treat after 30min that residuum all dissolves, isolate chloroform layer, water layer continuation chloroform extraction, 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, 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 asphyxia powder and compound 3, productive rate 66%;
4) 0.07g (0.5mmoL) is added in 5mL tertiary butanol aqueous solution to fluorobenzene 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 41%, 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，CDCl
3)δ9.63(d，J＝7.60Hz，1H，ArH)，8.57(d，J＝7.6Hz，1H，ArH)，8.27(s，1H，ArH)，8.05(s，2H，ArH)，7.78～7.94(m，5H，ArH)，7.67(d，J＝7.2Hz，1H，ArH)，7.60(d，J＝8.4Hz，1H，ArH)，7.23～7.32(m，2H，ArH)；
13CNMR(DMSO-d
6，100MHz)，δ130.58，130.40，130.11，129.85，128.20，128.11，127.37，125.55，122.31，119.34，114.53，55.42；
Therefore, can determine that the faint yellow needle-like crystal of gained is 7-benzo [c] acridine (4-is to fluorophenyl)-1,2,3-triazoles, its chemical structural formula is as follows:
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-is to fluorophenyl)-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, be 6: 4 by the trimethyl carbinol in tertiary butanol aqueous solution and water volume ratio, temperature of reaction changes 100 DEG C into, is 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-is to fluorophenyl)-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-is to fluorophenyl)-1,2,3-triazoles, is characterized in that, its structural formula is:
2. a preparation method for 7-benzo [c] acridine (4-is to fluorophenyl)-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-is to fluorophenyl)-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: 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 fluorobenzene 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-is to fluorophenyl)-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 thick product of compound 1, remove thick for compound 1 product under reduced pressure solvent, and water is added in gained residue, 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-is to fluorophenyl)-1,2,3-triazoles as claimed in claim 4, it is characterized in that, described acid solution is the middle one in hydrochloric acid, sulfuric acid and phosphoric acid.
6. 7-benzo [c] acridine (4-is to fluorophenyl)-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, oil bath is heated to 80-140 DEG C, reaction 1-3 hour, after reaction terminates, obtain the thick product of compound 2, pour thick for compound 2 product into strong aqua, in the mixture of trash ice and chloroform, 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-is to fluorophenyl)-1 as claimed in claim 6,2, the preparation method of 3-triazole, is characterized in that, in the mixture of described strong aqua, trash ice and chloroform, the consumption of strong aqua is 10 ~ 20 times of the volume of phosphorus oxychloride; The consumption of chloroform is 20-40 times of volume of the thick product weight of compound 2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108250135A (en) * | 2018-01-19 | 2018-07-06 | 浙江工业大学 | A kind of preparation method of naphthylamine derivative |
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| WO2004063156A1 (en) * | 2003-01-08 | 2004-07-29 | Biovitrum Ab | Novel indole derivates as fabp-4 inhibitors |
| 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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| CN108250135A (en) * | 2018-01-19 | 2018-07-06 | 浙江工业大学 | A kind of preparation method of naphthylamine derivative |
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Application publication date: 20160323 |