CN105384702A - Tri-substituted sym-triazine compound and preparation method thereof - Google Patents

Tri-substituted sym-triazine compound and preparation method thereof Download PDF

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CN105384702A
CN105384702A CN201510920677.1A CN201510920677A CN105384702A CN 105384702 A CN105384702 A CN 105384702A CN 201510920677 A CN201510920677 A CN 201510920677A CN 105384702 A CN105384702 A CN 105384702A
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compound
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independently hydrogen
methyl
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CN105384702B (en
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张辰
郭顺娜
张立宇
李晓
崔冬梅
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a tri-substituted sym-triazine compound. The above target compound is prepared through the following steps: mixing hydrochloride of a biguanide compound with a 1,1-dibromoethylene compound, adding the obtained mixture to an organic solvent, stirring and reacting at 60-130DEG C for 2-25h in the presence of a ligand and an alkali under the catalysis of metallic copper, and processing. The invention also provides a preparation method of the tri-substituted sym-triazine compound with a novel structure. The method has the advantages of mild reaction conditions, convenient operation, low cost, and wide industrial application prospect. The tri-substituted sym-triazine compound has certain anti-breast cancer activity, lays a foundation for screening and exploiting new drugs, and has good practical values.

Description

Three replace s-triazine compound and preparation method thereof
Technical field
The invention belongs to chemical field, relate to three replacement s-triazine compound and the preparations thereof that a class is new.
Background technology
S-triazine compound is widely used in the industries such as medicine, weaving, rubber, as antiseptic-germicide, sterilant, reactive dyestuffs, white dyes, luminescent material, explosive and catalyzer etc., the ring of its route of synthesis mainly nitrile compounds gathers and the modification of s-triazine side chain. therefore, and novel three the replacing s-triazine compounds there is important theory significance and actual application value of preparation.
Summary of the invention
The object of this invention is to provide the three replacement s-triazine compounds that a class is new, general structure is as follows:
R in formula (III) 1, R 2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R 1, R 2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O; Preferred R 1, R 2respective is independently hydrogen or methyl, or R 1, R 2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring.R 3, R 4respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl; Preferred R 3, R 4respective is independently hydrogen or methyl.R 5for C6 ~ C10 aryl; Further R 5for substituted-phenyl; Preferred R 5be 3,4-Dimethoxyphenyl, rubigan or to bromophenyl.
Another object of the present invention is to provide the preparation method of described compound (III), is realized by following steps:
By the hydrochloride of the biguanide compound shown in formula (I) with by formula (II) Suo Shi 1, the mixing of 1-sym-dibromoethane compounds adds in organic solvent, under the katalysis of metallic copper, under the existence of part and alkali, stirring reaction 2 ~ 25 hours at 60 ~ 130 DEG C of temperature, after reaction terminates, reaction solution aftertreatment obtains three shown in formula (III) and replaces compound in triazine class.Reaction formula is as follows:
Described organic solvent is ethers; Described metallic copper catalyzer is the halogenide of copper or the oxide compound of copper; Described part is aromatic nitrogen heterocycle, carbonyl containing compound or amino acid; Described alkali is mineral alkali; The amount of substance of the hydrochloride (not comprising Metformin) of the biguanide compound shown in 1,1-sym-dibromoethane classization Yu formula (I) shown in formula (II), metallic copper catalyzer, part, alkaline matter is than being 1:0.5 ~ 3.0:0.05 ~ 0.5:0.3 ~ 0.1:8.0 ~ 4.0.
Wherein R 1, R 2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R 1, R 2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O; Preferred R 1, R 2respective is independently hydrogen, methyl (do not comprise R 1, R 2be methyl, R simultaneously 3, R 4it is hydrogen atom simultaneously; And R 1, R 2be hydrogen atom simultaneously, R 3, R 4be methyl simultaneously), or R 1, R 2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring.R 3, R 4respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl; Preferred R 3, R 4respective is independently hydrogen or methyl.R 5for C6 ~ C10 aryl; Preferred R 5for substituted-phenyl; Preferred R further 5be 3,4-Dimethoxyphenyl, rubigan or to bromophenyl.
Described organic solvent is ethers; Be preferably tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane; More preferably Isosorbide-5-Nitrae-dioxane.The volumetric usage of described organic solvent counts 10 ~ 50mL/g with the quality of 1,1-sym-dibromoethane compounds shown in formula (II) usually.
Described metallic copper catalyzer is the halogenide of copper or the oxide compound of copper; Be preferably cuprous iodide or Red copper oxide.
Described part is aromatic nitrogen heterocycle, carbonyl containing compound or amino acid; Be preferably 2,2 '-dipyridyl, triketohydrindene hydrate or glycine.
Described alkali is mineral alkali; Be preferably potassiumphosphate.
In preparation method of the present invention, described aftertreatment can be adopted with the following method: after reaction terminates, reacting liquid filtering, filter residue methanol wash, concentrated filtrate, column chromatography (methylene dichloride: methyl alcohol=50:1, V:V), collect the elutriant containing target compound, underpressure distillation, drying obtains target compound (III).
Another object of the present invention is to provide the application of described compound (III) in preparation treatment breast cancer medicines.
The preparation method developing three of novel structure and replace s-triazine compound of the present invention, this technological reaction mild condition, easy to operate, cost is low, has prospects for commercial application widely.Provided by the present invention three replace s-triazine compound shows certain anti-breast cancer activity, for new medicament screen and exploitation are laid a good foundation, has good practical value.
Embodiment
Below will the present invention is further illustrated by embodiment, but protection scope of the present invention is not limited thereto.
Embodiment 1: the preparation of compound (III-1)
Piperidines biguanide hydrochloride (0.2057g) is added in reaction vessel, 1,1-dibromo (3,4-dimethoxy) vinylbenzene (0.1286g), cuprous iodide (0.0076g), 2,2 '-dipyridyl (0.0125g), potassiumphosphate (0.5094g), 1, mixing in 4-dioxane (5mL), stirring reaction 13 hours in 110 DEG C of oil baths; After reaction terminates, filter, filter residue methanol wash, concentrated filtrate, column chromatography (methylene dichloride: methyl alcohol=50:1), collect R fthe elutriant of value 0.3 ~ 0.35, underpressure distillation, drying obtains target compound III-1 (0.1067g, yield is 81%).
1HNMR(500MHz,CDCl 3):δ6.99(d,J＝1.8Hz,1H),6.90(dd,J＝8.2,1.8Hz,1H),6.80(d,J＝8.2Hz,1H),5.16(s,2H),3.87(s,3H),3.86(s,3H),3.75–3.73(m,6H),1.66(t,J＝5.4Hz2H),1.61–1.49(m,4H)。
Embodiment 2:
Change the amount of cuprous iodide into 0.0048g, other operations are with embodiment 1, and the amount of obtaining 0.013g, yield is 10%.
Embodiment 3:
Change the amount of cuprous iodide into 0.0189g, other operations are with embodiment 1, and the amount of obtaining 0.0988g, yield is 75%.
Embodiment 4:
Change the amount of piperidines biguanide hydrochloride into 0.308g, other operations are with embodiment 1, and the amount of obtaining 0.079g, yield is 60%.
Embodiment 5:
Change the amount of piperidines biguanide hydrochloride into 0.103g, other operations are with embodiment 1, and the amount of obtaining 0.0105g, yield is 8%.
Embodiment 6:
Change the amount of 2,2 '-dipyridyl into 0.0076g, other operations are with embodiment 1, and the amount of obtaining 0.0527g, yield is 40%.
Embodiment 7:
Change the amount of 2,2 '-dipyridyl into 0.0234g, other operations are with embodiment 1, and the amount of obtaining 0.0724g, yield is 55%.
Embodiment 8:
Change the amount of potassiumphosphate into 0.4246g, other operations are with embodiment 1, and the amount of obtaining 0.0803g, yield is 61%.
Embodiment 9:
Change the amount of potassiumphosphate into 0.8491g, other operations are with embodiment 1, and the amount of obtaining 0.1001g, yield is 76%.
Embodiment 10:
Temperature of reaction is reduced to 60 DEG C, other operations are with embodiment 1, and the amount of obtaining 0.0206g, yield is 10%.
Embodiment 11:
Temperature of reaction is elevated to 130 DEG C, other operations are with embodiment 1, and the amount of obtaining 0.0658g, yield is 50%.
Embodiment 12: the preparation of compound (III-2)
Operation is with embodiment 1, just change piperidines biguanide hydrochloride into Pyrrolidine biguanide hydrochloride (0.1917g, 1.00mmol), 2,2 '-dipyridyl changes triketohydrindene hydrate (0.0128g into, 0.08mmol), obtained target compound III-2 (0.0946g, yield is 75%). 1HNMR(500MHz,CDCl 3):δ6.99(d,J＝1.8Hz,1H),6.91(dd,J＝8.1,1.8Hz,1H),6.79(d,J＝8.1Hz,1H),5.28(s,2H),3.87(s,3H),3.85(s,3H),3.74(s,2H),3.58(t,J＝6.4Hz,2H),3.47(t,J＝6.4Hz,2H),2.02–1.83(m,4H)。
Embodiment 13: the preparation of compound (III-3)
Operation is with embodiment 1, and just piperidines biguanide hydrochloride changes Wirumin hydrochloride (0.2077g, 1.00mmol) into, 2,2 '-dipyridyl changes triketohydrindene hydrate (0.0128g, 0.08mmol) into, obtained target compound III-3 (0.1087g, yield is 82%). 1HNMR(500MHz,CDCl 3):δ6.93(d,J＝1.6Hz,1H),6.88(dd,J＝8.2,1.6Hz,1H),6.80(d,J＝8.2Hz,1H),5.26(s,2H),3.86(s,3H),3.86(s,3H),3.84-3.74(m,4H),3.74(s,2H),3.72–3.69(m,4H)。
Embodiment 14: the preparation of compound (III-4)
Operation is with embodiment 1, just change piperidines biguanide hydrochloride into N, N, N ', N '-tetramethyl-biguanide hydrochloride (0.1937g, 1.00mmol), 2,2 '-dipyridyl changes glycine (0.0060g, 0.08mmol) into, obtained target compound III-5 (0.0546g, yield is 43%).
1HNMR(500MHz,CDCl 3):δ7.07(d,J＝1.8Hz,1H),6.94(dd,J＝8.1,1.8Hz,1H),6.79(d,J＝8.1Hz,1H),3.88(s,3H),3.86(s,3H),3.76(s,2H),3.13(s,12H)。
Embodiment 15: the preparation of compound (III-5)
Operation is with embodiment 1, be 1,1-dibromo (3 ', 4 '-dimethoxy) vinylbenzene changes the bromo-vinylbenzene (0.1048g, 0.40mmol) of 1,1-bis-into, piperidines biguanide hydrochloride is changed into Wirumin hydrochloride (0.2077g, 1.00mmol), obtained target compound III-7 (0.0847g, yield is 78%).
1HNMR(500MHz,CDCl 3):δ7.35(d,J＝7.3Hz,2H),7.31(t,J＝7.3Hz,2H),7.23(t,J＝7.2Hz,1H),5.24(s,2H),3.81-3.79(m,6H),3.72–3.69(m,4H)。
Embodiment 16: the preparation of compound (III-6)
Operation is with embodiment 1, be 1,1-dibromo (3 ', 4 '-dimethoxy) vinylbenzene changes 1,1-dibromo (4 '-chlorine) vinylbenzene (0.1186g, 0.40mmol) into, piperidines biguanide hydrochloride is changed into Wirumin hydrochloride (0.2077g, 1.00mmol), obtained target compound III-8 (0.0929g, yield is 76%).
1HNMR(500MHz,CDCl 3):δ7.31–7.23(m,4H),5.35(s,2H),3.78–3.76(m,6H),3.72–3.66(m,4H)。
Embodiment 17: the preparation of compound (III-7)
Operation is with embodiment 1, be 1,1-dibromo (3 ', 4 '-dimethoxy) vinylbenzene changes 1,1-dibromo (4 '-bromine) vinylbenzene (0.1363g, 0.40mmol) into, piperidines biguanide hydrochloride is changed into Wirumin hydrochloride (0.2077g, 1.00mmol), obtained target compound III-9 (0.0882g, yield is 63%).
1HNMR(500MHz,CDCl 3):δ7.41(d,J＝8.3Hz,2H),7.22(d,J＝8.3Hz,2H),5.20(s,2H),3.78-3.75(m,6H),3.72–3.68(m,4H)。
Embodiment 18: anti-breast cancer cell MDA-MB-231 biological activity test
In Vitro Anti breast cancer cell MDA-MB-231 activity test method: mtt assay
A principle: Thiazolyl blue (MTT) is decomposed into water-fast bluish voilet crystallization by plastosome lytic enzyme and is deposited in cell by cell, crystallisate can by dmso solution, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, indirectly reflect proliferative conditions and the number change of cell.
B cell: breast cancer cell MDA-MB-231 (purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank)
C experimental procedure:
1) preparation of sample: for solvable sample, every 1mg 20 μ LDMSO dissolve, and get 2uL 1000 μ L nutrient solutions and dilute, make concentration be 100 μ g/mL, then use nutrient solution serial dilution to working concentration.
2) cultivation of cell
2.1) preparation of substratum: containing 800,000 units of Penicillin in every 1000mL substratum, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum.
2.2) cultivation of cell: by tumor cell inoculation in substratum, puts 37 DEG C, 5%CO 2cultivate in incubator, 3 ~ 5d goes down to posterity.
3) working sample is to the restraining effect of growth of tumour cell
By cell EDTA-trysinization liquid digestion, and be diluted to 1 × 10 with substratum 5/ mL, be added in 96 porocyte culture plates, every hole 100uL, puts 37 DEG C, 5%CO 2cultivate in incubator.After inoculation 24h, add the sample with substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO 2cultivate in incubator, add the MTT of 5mg/mL after 72h in cell culture well, every hole 10 μ L, puts 37 DEG C and hatches 4h, add DMSO, every hole 150 μ L, and with oscillator vibrates, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.With similarity condition with containing sample, containing the culture medium culturing of same concentration DMSO cell in contrast, calculation sample is to the median lethal concentration (IC of growth of tumour cell 50), result is as shown in table 1.
With breast cancer cell MDA-MB-231 for model, be positive reference substance with cis-platinum, determine the external restraining effect to breast cancer cell growth of biphenol compound (III) sample prepared in embodiment.Result shows, and part of compounds (III) has certain restraining effect (the results detailed in Table 1) to experiment breast cancer cell MDA-MB-231 used.
Table 1 compound (III) is to the IC of MDA-MB-231 50(μM)
Test No. Compound IC 50
1 III-1 9.06
2 III-5 0.66
3 III-8 1.22
4 Contrast medicine (cis-platinum) 8.21

Claims (10)

1. three replace a s-triazine compound, and it is characterized in that, general structure is as follows:
Wherein R 1, R 2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R 1, R 2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O; R 3, R 4respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl; R 5for C6 ~ C10 aryl.
2. according to claim 1 a kind of three replace s-triazine compound, it is characterized in that, R 1, R 2respective is independently hydrogen or methyl, or R 1, R 2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring.
3. according to claim 1 a kind of three replace s-triazine compound, it is characterized in that, R 3, R 4respective is independently hydrogen or methyl.
4. according to claim 1 a kind of three replace s-triazine compound, it is characterized in that, R 5for substituted-phenyl, be selected from 3,4-Dimethoxyphenyl, rubigan or to bromophenyl.
5. the preparation method of a kind of three replacement s-triazine compounds according to claim 1, be is characterized in that, realized by following steps:
By the hydrochloride of the biguanide compound shown in formula (I) and by 1 shown in formula (II), the mixing of 1-sym-dibromoethane compounds adds in organic solvent, under the katalysis of metallic copper, under the existence of part and alkali, stirring reaction 2 ~ 25 hours at 60 ~ 130 DEG C of temperature, after reaction terminates, reaction solution aftertreatment obtains three shown in formula (III) and replaces compound in triazine class, and reaction formula is as follows:
Described organic solvent is ethers; Described metallic copper catalyzer is the halogenide of copper or the oxide compound of copper; Described part is aromatic nitrogen heterocycle, carbonyl containing compound or amino acid; Described alkali is mineral alkali; The mass ratio of the material of the hydrochloride of 1,1-sym-dibromoethane compounds shown in formula (II) and the biguanide compound shown in formula (I), metallic copper catalyzer, part, alkali is 1:0.5 ~ 3.0:0.05 ~ 0.5:0.3 ~ 0.1:8.0 ~ 4.0;
Wherein R 1, R 2respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl, or R 1, R 2n is between the two combined to form the heterocycle containing N or the C4 ~ C8 containing N, O; And R 1, R 2be hydrogen atom simultaneously, R 3, R 4be methyl simultaneously, or R 1, R 2n is between the two combined to form Pyrrolidine ring, piperidine ring or morpholine ring; R 3, R 4respective is independently hydrogen, C1 ~ C10 alkyl or C6 ~ C10 aryl; R 5for C6 ~ C10 aryl.
6. preparation method according to claim 5, is characterized in that, the hydrochloride of the biguanide compound shown in formula (I) does not comprise Metformin.
7. preparation method according to claim 5, is characterized in that, R 1, R 2respective is independently hydrogen, methyl, and does not comprise R 1, R 2be methyl, R simultaneously 3, R 4it is hydrogen atom simultaneously; R 3, R 4respective is independently hydrogen or methyl; R 5for substituted-phenyl, be selected from 3,4-Dimethoxyphenyl, rubigan or to bromophenyl.
8. preparation method according to claim 5, is characterized in that, described organic solvent is ethers; Be selected from tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane, the volumetric usage of organic solvent counts 10 ~ 50mL/g with the quality of 1,1-sym-dibromoethane compounds shown in formula (II) usually; Described metallic copper catalyzer is the halogenide of copper or the oxide compound of copper, is selected from cuprous iodide or Red copper oxide; Described part is aromatic nitrogen heterocycle, carbonyl containing compound or amino acid, is selected from 2,2 '-dipyridyl, triketohydrindene hydrate or glycine; Described alkali is mineral alkali, is selected from potassiumphosphate.
9. preparation method according to claim 5, it is characterized in that, described aftertreatment is adopted with the following method: after reaction terminates, reacting liquid filtering, filter residue methanol wash, concentrated filtrate, column chromatography, methylene dichloride: methyl alcohol=50:1, V:V, collect the elutriant containing target compound, underpressure distillation, drying obtains target compound (III).
10. according to claim 1 a kind of three replace the application of s-triazine compound in preparation treatment breast cancer medicines.
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CN105732528A (en) * 2016-03-25 2016-07-06 浙江工业大学 Preparation method of 2-arylamine-4-dimethylamine-1, 3, 5-triazine compound
CN105732528B (en) * 2016-03-25 2018-11-13 浙江工业大学 Preparation method of 2-arylamine-4-dimethylamine-1, 3, 5-triazine compound
CN108546252A (en) * 2018-05-02 2018-09-18 浙江工业大学 Triazinone compound and preparation method and application thereof
CN108840829A (en) * 2018-05-02 2018-11-20 浙江工业大学 Preparation method of 4-aryl-1, 3, 5-triazine-2-ketone compound
CN108752284A (en) * 2018-06-29 2018-11-06 浙江工业大学 Two amido-s- compound in triazine class of one kind and its preparation method and application
CN110511214A (en) * 2019-06-28 2019-11-29 浙江工业大学 Diamine substituted aromatic heterocyclic compound and preparation method and application thereof
CN113288899A (en) * 2021-05-17 2021-08-24 浙江工业大学 Application of heterocyclic thiol compound in preparation of antitumor drugs

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