CN109053612A - A kind of phenethyl replaces 1,3,5- compound in triazine class and its preparation method and application - Google Patents

A kind of phenethyl replaces 1,3,5- compound in triazine class and its preparation method and application Download PDF

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Publication number
CN109053612A
CN109053612A CN201810701310.4A CN201810701310A CN109053612A CN 109053612 A CN109053612 A CN 109053612A CN 201810701310 A CN201810701310 A CN 201810701310A CN 109053612 A CN109053612 A CN 109053612A
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compound
phenethyl
formula
class
organic solvent
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崔冬梅
曾明
盛琦威
张辰
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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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
    • C07D251/26—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 only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses one kind phenethyls -1 as shown in formula (II), 3,5- compound in triazine class, the phenethyl -1,3,5- compound in triazine class is specifically prepared in accordance with the following steps: cinnamyl alcohol being mixed with biguanide hydrochloride shown in formula (I) and is added in organic solvent, under the action of metallic catalyst, in the presence of alkaline matter, it is stirred to react at a temperature of 80~140 DEG C 5~30 hours, after reaction, obtains phenethyl -1 shown in the post-treated obtained formula (II) of reaction solution, 3,5- compound in triazine class.Method reaction condition of the present invention is mild, and raw material is easy to get, easy to operate, at low cost, there is extensive prospects for commercial application.Phenethyl provided by the present invention -1,3,5-triazines class compound shows certain anti-human lung carcinoma cell activity, lays a good foundation for new medicament screen and exploitation, has preferable practical value.

Description

A kind of phenethyl replaces 1,3,5- compound in triazine class and its preparation method and application
(1) technical field
The present invention relates to phenethyl -1,3,5- compound in triazine class and its preparation method and application.
(2) background technique
Compound in triazine class is a kind of important heterocyclic nitrogen compound, is organic chemistry and pharmaceutical chemists research One of emphasis.1,3,5-triazines class compound has the multiple biological activities such as anticancer, antimalarial, weeding, is widely used and cures The fields such as medicine, pesticide.
(3) summary of the invention
Replace 1,3,5- compound in triazine class and preparation method thereof the purpose of the present invention is to provide a kind of phenethyl and answers With.
The present invention adopts the following technical scheme:
One kind phenethyl -1,3,5- compound in triazine class as shown in formula (II)
In formula (II),
R1、R2Respectively stand alone as hydrogen, C6~C10Aryl, C7~C12Aralkyl or the R1、R2And and R1、R2It is connected N formed containing N or containing the C of N, O4~C8Heterocycle.
Further, it is preferable that the R1、R2Respectively stand alone as hydrogen, phenyl or benzyl or the R1、R2And R1、R2 N between the two combines to form piperidine ring or morpholine ring.
Further, phenethyl of the present invention -1,3,5-triazines class compound it is specific the preparation method is as follows:
Cinnamyl alcohol is mixed with biguanide hydrochloride shown in formula (I) and is added in organic solvent, in the effect of metallic catalyst Under, in the presence of alkaline matter, it is stirred to react at a temperature of 80~140 DEG C 5~30 hours, after reaction, is reacted Phenethyl -1,3,5- compound in triazine class shown in the post-treated obtained formula (II) of liquid；It is double shown in the cinnamyl alcohol and formula (I) Guanidine hydrochloride, metallic catalyst, alkaline matter the mass ratio of the material be 1:0.5~1.5:0.01~0.04:1.0~3.0；It is described Metallic catalyst be ruthenium catalyst；The organic solvent is ethers；The alkaline matter is organic base；
In formula (I), R1、R2It is such as above-mentioned.
Further, the organic solvent is preferably Isosorbide-5-Nitrae-dioxane or 2- methyltetrahydrofuran.
Further, the volumetric usage of the organic solvent is usually with the substance of biguanide hydrochloride shown in formula (I) Amount is calculated as 5~20mL/mmol.
Further, the metallic catalyst is preferably three (triphenylphosphine) ruthenous chlorides, two (triphenylphosphine) cyclopentadiene Ruthenic chloride or dichloro (p -Methylisopropylbenzene base) ruthenium dimer.
Further, the alkaline matter is preferably potassium tert-butoxide or sodium methoxide.
In preparation method of the present invention, following method is can be used in the post-processing of the reaction solution: after reaction, Xiang get To reaction solution in plus water, be extracted with ethyl acetate, merge organic layer, dried, filtered with anhydrous sodium sulfate, be concentrated filtrate, warp Column chromatography for separation is the methylene chloride of 100:1 and the mixed liquor of methanol as eluant, eluent using volume ratio, is collected containing target compound Eluent, vacuum distillation, is dried to obtain phenethyl shown in target compounds of formula (II) -1,3,5-triazines class compound.
Phenethyl -1,3,5- compound in triazine class of the present invention is used to prepare anti-tumor drug.
Further, the tumour is preferably human lung cancer.
Compared with prior art, the beneficial effects of the present invention are:
The present invention develops a kind of phenethyl -1,3,5-triazines class compound and preparation method thereof, the technological reaction condition Mildly, raw material is easy to get, easy to operate, at low cost, there is extensive prospects for commercial application.Phenethyl -1 provided by the present invention, 3,5- compound in triazine class show certain anti-human lung carcinoma cell activity, lay a good foundation for new medicament screen and exploitation, have compared with Good practical value.
Specific embodiment
Below will by embodiment, the present invention is further illustrated, but the scope of the present invention is not limited thereto.
Embodiment 1: the preparation of compound (II -1)
In the reaction vessel plus abitilguanide hydrochloride (103.8mg, 0.50mmol), cinnamyl alcohol (67.2mg, 0.50mmol), three (triphenylphosphine) ruthenous chloride (9.0mg, 0.01mmol), potassium tert-butoxide (115.4mg, 1.03mmol), It mixes in Isosorbide-5-Nitrae-dioxane (4mL), is stirred to react 22 hours in 120 DEG C of oil baths；After reaction, add methanol and dichloromethane Filtrate is concentrated in alkane dissolution, filtering, and column chromatographs (methylene chloride: methanol=100:1), collects RfThe eluent of value 0.3~0.35, Vacuum distillation, is dried to obtain target compound (II -1), 95.2mg, yield 67%.
1H NMR(500MHz,CDCl3) δ 7.31-7.24 (m, 4H), 7.20 (t, J=7.1Hz, 1H), 5.07 (s, 2H), 3.87-3.77(m,4H),3.73-3.66(m,4H),3.01-3.04(m,2H),2.85-2.80(m,2H)。
Embodiment 2:
Potassium tert-butoxide is changed to sodium methoxide (51.5mg, 1.00mmol), temperature is reduced to 80 DEG C, the time extends to 40h, Isosorbide-5-Nitrae-dioxane is changed to 2- methyltetrahydrofuran (2.5mL), and other are operated with embodiment 1, obtain target compound (II -1), 27mg, yield 19%.
Embodiment 3:
The amount of abitilguanide hydrochloride is changed to (51.9mg, 0.25mmol), the amount of potassium tert-butoxide be changed to (168.9mg, 1.50mmol), 140 DEG C are raised the temperature to, the reaction time is changed to 5 hours, other operations obtain target chemical combination with embodiment 1 Object (II -1), 85.3mg, yield 60%.
Embodiment 6:
The amount of abitilguanide hydrochloride is changed to (155.7mg, 0.75mmol), three (triphenylphosphine) ruthenous chlorides are changed to Two (triphenylphosphine) cyclopentadiene ruthenic chlorides (7.5mg, 0.01mmol), are changed to 10ml for the amount of solvent, other operations are the same as implementation Example 1 obtains target compound (II -1), 48.3mg, yield 34%.
Embodiment 10:
By three (triphenylphosphine) ruthenous chlorides be changed to dichloro (p -Methylisopropylbenzene base) ruthenium dimer (6.8mg, 0.01mmol), the amount of potassium tert-butoxide is changed to (56.8mg, 0.50mmol), other operations obtain target compound with embodiment 1 (II -1), 17.1mg, yield 12%.
Embodiment 37: the preparation of compound (II -2)
Operation with embodiment 1, only by abitilguanide hydrochloride change into N- benzyl biguanide hydrochloride (113.8mg, 0.50mmol), target compound (II -2) are made, 82.4mg, yield 54%.
1H NMR(500MHz,CDCl3)δ7.50-7.13(m,10H),5.26(br,1H),5.26(br,1H),5.14(br, 1H),4.64-4.61(m,2H),3.08-3.01(m,2H),2.90-2.68(m,2H)。
Embodiment 38: the preparation of compound (II -3)
Operation with embodiment 1, only by abitilguanide hydrochloride change into N- phenyl biguanide hydrochloride (107.1mg, 0.50mmol), target compound (II -3) are made, 101.3mg, yield 71%.
1H NMR(500MHz,CDCl3) δ 7.57 (dd, J=8.6,0.9Hz, 2H), 7.41-7.33 (m, 3H), 7.33- 7.28(m,2H),7.26-7.22(m,2H),7.21-7.19(m,1H),7.13-7.07(m,1H),5.50(br,2H),3.11- 3.01(m,2H),2.89-2.86(m,2H)。
Embodiment 38: the preparation of compound (II -4)
Operation with embodiment 1, only by Metformin change into N- piperidines biguanide hydrochloride (102.8mg, 0.50mmol), target compound (II -4) are made, 76.3mg, yield 54%.
1H NMR(500MHz,CDCl3)δ7.33-7.22(m,4H),7.24-7.14(m,1H),5.19(br,2H),3.97- 3.59(m,4H),3.11-3.02(m,2H),2.95-2.76(m,2H),1.72-1.64(m,2H),1.62-1.55(m,4H).
Embodiment 31: anti-lung cancer cell NCI-H460 biological activity test
External anti-lung cancer cell NCI-H460 activity test method: mtt assay
Experimental procedure:
1) preparation of sample: for solvable sample, every 1mg is dissolved with 20 μ L DMSO, takes 2uL dilute with 1000 μ L culture solutions It releases, makes 100 μ g/mL of concentration, then with culture solution serial dilution to using concentration.
2) culture of cell
2.1) preparation of culture medium: contain 800,000 units of Penicillin, 1.0g streptomysin, 10% inactivation in every 1000mL culture medium Fetal calf serum.
2.2) culture of cell: by tumor cell inoculation in culture medium, 37 DEG C are set, 5%CO2It is cultivated in incubator, 3~ 5d passage.
3) inhibiting effect of the measurement sample to growth of tumour cell
Cell EDTA- pancreatin digestive juice is digested, and is diluted to 1 × 10 with culture medium5/ mL is added to the training of 96 hole cells It supports in plate, every hole 100uL sets 37 DEG C, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is added and uses the diluted sample of culture medium, Every 100 μ L of hole, each concentration add 3 holes, set 37 DEG C, 5%CO2It is cultivated in incubator, 5mg/ is added after 72h in cell culture well The MTT of mL, every 10 μ L of hole set 37 DEG C of incubation 4h, and DMSO is added, and every 150 μ L of hole is vibrated with oscillator, and Shi formazan is completely dissolved, With microplate reader under 570nm wavelength colorimetric.With similarity condition use be free of sample, the culture medium culture containing same concentration DMSO it is thin Born of the same parents calculate sample to the inhibiting rate of growth of tumour cell, the results are shown in Table 1 as control.
Using lung carcinoma cell NCI-H460 as model, the two amido-s- compound in triazine class samples prepared in embodiment are determined Product are in vitro to the inhibiting effect of lung cancer cell growth (see Table 1 for details for result).
Inhibiting rate of each compound of table 1 to lung carcinoma cell NCI-H460
Compound Inhibiting rate %
(II-1) 59
(II-2) 57
(II-3) 31
(II-4) 61

Claims (10)

1. a kind of phenethyl as shown in formula (II) -1,3,5-triazines class compound,
In formula (II),
R1、R2Respectively stand alone as hydrogen, C6~C10Aryl, C7~C12Aralkyl or the R1、R2And and R1、R2Connected N shape At containing N or containing the C of N, O4~C8Heterocycle.
2. phenethyl as described in claim 1-1,3,5-triazines class compound, it is characterised in that: the R1、R2Respectively solely It stands as hydrogen, phenyl or benzyl or the R1、R2And R1、R2N between the two combines to form piperidine ring or morpholine ring.
3. phenethyl as described in claim 1-1,3,5-triazines class compound preparation method, it is characterised in that: described Method carries out in accordance with the following steps:
Cinnamyl alcohol is mixed with biguanide hydrochloride shown in formula (I) and is added in organic solvent, under the action of metallic catalyst, In the presence of alkaline matter, it is stirred to react at a temperature of 80~140 DEG C 5~30 hours, after reaction, obtains reaction solution after It handles and phenethyl -1,3,5- compound in triazine class shown in formula (II) is made；The cinnamyl alcohol and biguanides hydrochloric acid shown in formula (I) The ratio between amount of substance of salt, metallic catalyst, alkaline matter is 1:0.5~1.5:0.01~0.04:1.0~3.0；The gold Metal catalyst is ruthenium catalyst；The organic solvent is ethers；The alkaline matter is organic base；
4. method as claimed in claim 3, it is characterised in that: the organic solvent is Isosorbide-5-Nitrae-dioxane or 2- methyl Tetrahydrofuran.
5. method as claimed in claim 3, it is characterised in that: the volumetric usage of the organic solvent is shown in formula (I) The amount of the substance of biguanide hydrochloride is calculated as 5~20mL/mmol.
6. method as claimed in claim 3, it is characterised in that: the metallic catalyst be three (triphenylphosphine) ruthenous chlorides, Two (triphenylphosphine) cyclopentadiene ruthenic chlorides or dichloro (p -Methylisopropylbenzene base) ruthenium dimer.
7. method as claimed in claim 3, it is characterised in that: the alkaline matter is potassium tert-butoxide or sodium methoxide.
8. method as claimed in claim 3, it is characterised in that: the post-processing approach of the reaction solution are as follows: after reaction, to Add water in obtained reaction solution, be extracted with ethyl acetate, merge organic layer, dried, filtered with anhydrous sodium sulfate, filtrate is concentrated, It is the methylene chloride of 100:1 and the mixed liquor of methanol as eluant, eluent using volume ratio through column chromatography for separation, collects and contain target compound Eluent, vacuum distillation, be dried to obtain phenethyl shown in target compounds of formula (II) -1,3,5-triazines class compound.
9. a kind of phenethyl -1,3,5- compound in triazine class as described in claim 1 is in preparation treatment anti-tumor drug Using.
10. application as claimed in claim 9, it is characterised in that: the tumour is human lung cancer.
CN201810701310.4A 2018-06-29 2018-06-29 A kind of phenethyl replaces 1,3,5- compound in triazine class and its preparation method and application Pending CN109053612A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110407761A (en) * 2019-06-28 2019-11-05 浙江工业大学 A kind of polysubstituted heterocyclic nitrogen compound and the preparation method and application thereof
CN110511214A (en) * 2019-06-28 2019-11-29 浙江工业大学 Two amidos replace heteroaromatic class compound and its preparation method and application
CN112250639A (en) * 2020-11-19 2021-01-22 浙江工业大学 Heterocyclic substituted arylamine compound and preparation method and application thereof
CN113387984A (en) * 2020-03-13 2021-09-14 九江学院 Symmetric binuclear ruthenium complex containing deprotonated metformin ligand and preparation method and application thereof

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110407761A (en) * 2019-06-28 2019-11-05 浙江工业大学 A kind of polysubstituted heterocyclic nitrogen compound and the preparation method and application thereof
CN110511214A (en) * 2019-06-28 2019-11-29 浙江工业大学 Two amidos replace heteroaromatic class compound and its preparation method and application
CN113387984A (en) * 2020-03-13 2021-09-14 九江学院 Symmetric binuclear ruthenium complex containing deprotonated metformin ligand and preparation method and application thereof
CN113387984B (en) * 2020-03-13 2023-05-23 九江学院 Symmetric binuclear ruthenium complex containing deprotonated metformin ligand, and preparation method and application thereof
CN112250639A (en) * 2020-11-19 2021-01-22 浙江工业大学 Heterocyclic substituted arylamine compound and preparation method and application thereof
CN112250639B (en) * 2020-11-19 2022-05-24 浙江工业大学 Heterocyclic substituted arylamine compound and preparation method and application thereof

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Application publication date: 20181221