CN108546252A - Triazinone compound and preparation method and application thereof - Google Patents
Triazinone compound and preparation method and application thereof Download PDFInfo
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- CN108546252A CN108546252A CN201810410175.8A CN201810410175A CN108546252A CN 108546252 A CN108546252 A CN 108546252A CN 201810410175 A CN201810410175 A CN 201810410175A CN 108546252 A CN108546252 A CN 108546252A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- -1 Triazinone compound Chemical class 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 201000008968 osteosarcoma Diseases 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract 9
- 229940079593 drug Drugs 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 31
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical class O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000001805 chlorine compounds Chemical class 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 8
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 238000013459 approach Methods 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- COHUUWHPQXYAII-UHFFFAOYSA-N C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=CC1 Chemical compound C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=CC1 COHUUWHPQXYAII-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 150000002170 ethers Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 150000003304 ruthenium compounds Chemical class 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
- 229930192474 thiophene Natural products 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- IFVXVYPDZQJILI-UHFFFAOYSA-N diaminomethylideneurea;hydrochloride Chemical compound [Cl-].NC(N)=[NH+]C(N)=O IFVXVYPDZQJILI-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 239000002547 new drug Substances 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000000523 sample Substances 0.000 description 6
- 150000003840 hydrochlorides Chemical class 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 4
- AVPVRXORILGHNM-UHFFFAOYSA-N chlorobenzene;methanol Chemical class OC.ClC1=CC=CC=C1 AVPVRXORILGHNM-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- GEZMEIHVFSWOCA-UHFFFAOYSA-N (4-fluorophenyl)methanol Chemical class OCC1=CC=C(F)C=C1 GEZMEIHVFSWOCA-UHFFFAOYSA-N 0.000 description 1
- PMJHHCWVYXUKFD-SNAWJCMRSA-N (E)-1,3-pentadiene Chemical compound C\C=C\C=C PMJHHCWVYXUKFD-SNAWJCMRSA-N 0.000 description 1
- 0 *NC(NC(N)=O)=N Chemical compound *NC(NC(N)=O)=N 0.000 description 1
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical class BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- 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)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a triazinone compound shown as a formula (III) and a preparation method and application thereof, wherein the method comprises the following steps: the alcohol compound shown in the formula (I) and guanylurea hydrochloride shown in the formula (II) are mixed and added into an organic solvent, the mixture is stirred and reacted for 15-27 hours at the temperature of 60-130 ℃ in the presence of an alkaline substance under the action of a metal ruthenium catalyst, a reaction liquid is obtained after the reaction is finished, and the triazinone compound shown in the formula (III) is prepared through post-treatment. The process has the advantages of mild reaction conditions, easily obtained raw materials and operation methodThe method has the advantages of convenience, low cost and wide industrial application prospect. The triazinone compound provided by the invention can be applied to preparation of drugs for treating osteosarcoma, lays a foundation for screening and developing new drugs, and has good practical value.
Description
(1) technical field
The present invention relates to a kind of triazinone compounds and its preparation method and application.
(2) background technology
Triazinone compounds are one of most common herbicides, are mainly used for preventing and kill off grassy weed and broad leaved weed,
In pesticide field using very extensive.1,3,5-triazines ketone is one of most important one kind compound in triazinone compounds,
The preparation method of such compound is less, mainly passes through S, S '-dimethyl-N-cyano carbimide di-sulfate amide derivatives
It is made under the conditions of sodium hydride, the preparation method complex steps, raw material is not easy to obtain, the structure list of prepared triazone derivatives
One, there is certain limitation.Therefore, the important reason of the preparation method of new, easy synthesis triazinone compounds is developed
By and practical significance.
(3) invention content
The present invention provides a new class of triazinone compounds and preparation method thereof in order to solve the problems existing in the prior art
And application.
The present invention adopts the following technical scheme that:
One kind triazinone compounds as shown in formula (III):
In formula (III), R1Or R2Respectively stand alone as C1~C10Alkyl, C4~C10Aryl, wherein aryl are heteroaromatic, phenyl
Or by C1~4Alkyl, C1~4Alkoxy or halogen substitution phenyl.
Further, the preferably described R1Or R2Respectively stand alone as methyl, thienyl, phenyl or by methyl, methoxyl group, 3,4-
The phenyl that methylene dimethoxy, fluorine, chlorine or bromine replace.
Further, a kind of preparation method of the triazinone compounds as shown in formula (III) specifically in accordance with the following steps into
It is prepared by row:
Alcohol compound shown in formula (I) is mixed with dicyandiamidines hydrochloride shown in formula (II) and is added in organic solvent,
Under metal Ru catalyst effect, in the presence of alkaline matter, it is stirred to react 15~27 hours at a temperature of 60~130 DEG C, instead
After answering, reaction solution is obtained, triazinone compounds shown in post-treated obtained formula (III);Alcohol shown in the formula (I)
Class compound is 1: 0.5 with the ratio between dicyandiamidines hydrochloride, metal Ru catalyst, amount of substance of alkaline matter shown in formula (II)
~1.5: 0.01~0.04: 1.0~2.5;The organic solvent is ethers or substituted benzene;The alkaline matter is organic
Alkali;The metal Ru catalyst be divalent ruthenium or trivalent ruthenium compound,
Formula (I) R1With formula (II) R2It is such as above-mentioned.
Further, the organic solvent is preferably tetrahydrofuran, Isosorbide-5-Nitrae-dioxane or toluene.
Further, the volumetric usage of the organic solvent is usually in terms of the quality of alcohol compound shown in formula (I)
For 5~20mL/mmol.
Further, the metal Ru catalyst is preferably ten dicarbapentaborane rutheniums, triphenylphosphine ruthenic chloride, two (triphenylphosphine) rings
Pentadiene ruthenic chloride or 1,5- cyclo-octadiene ruthenous chlorides.
Further, the alkaline matter is preferably potassium tert-butoxide.
In preparation method of the present invention, the post-processing approach of the reaction solution is:The post-processing approach of the reaction solution
For:After reaction, water is added into the reaction solution, is extracted with ethyl acetate, organic layer is merged, it is dry with anhydrous sodium sulfate
It is dry, filtering, concentrate filtrate, column chromatography for separation, the mixed liquor of the dichloromethane and methanol that are 30: 1 using volume ratio as eluant, eluent,
The eluent containing target compound is collected, vacuum distillation is dried to obtain triazinone compounds shown in formula (III).
Triazinone compounds of the present invention can be applied to prepare treatment bone and flesh tumor medicine.
Further, the triazinone compounds are preferably
Compared with prior art, the beneficial effects of the present invention are:
The present invention develops a kind of preparation method of triazinone compounds, and the technological reaction mild condition, raw material is easy to get,
It is easy to operate, it is at low cost, there is extensive prospects for commercial application.Triazinone compounds provided by the present invention show certain
Anti-human osteosarcoma cell activity, lays a good foundation for new medicament screen and exploitation, has preferable practical value.
Specific implementation mode
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 (III-1):
In the reaction vessel plus N- phenyl dicyandiamidines hydrochlorides (107.3mg, 0.50mmol), P-methoxybenzyl alcohol
(93.3mg, 0.75mmol), 1,5- cyclo-octadiene ruthenous chloride (2.8mg, 0.01mmol), potassium tert-butoxide (167.3mg,
1.50mmol), the mixing in Isosorbide-5-Nitrae-dioxane (4mL), reacts 27 hours at 100 DEG C, after reaction, obtains reaction solution, to
Add water in the reaction solution, be extracted with ethyl acetate, merge organic layer, dried with anhydrous sodium sulfate, filter, concentrates filtrate,
Column chromatography (dichloromethane:Methanol=30:1) R, is collectedfThe eluent of value 0.3~0.35, vacuum distillation, is dried to obtain targeted
Close object (III-1), 96.6mg, yield 65%.
1H NMR(500MHz,DMSO-d6) δ 12.09 (br, 1H), 10.02 (br, 1H), 8.21 (d, J=8.9Hz, 2H),
7.85-7.67 (m, 2H), 7.34 (t, J=7.3Hz, 2H), 7.13 (d, J=8.9Hz, 2H), 7.07 (t, J=7.3Hz, 1H),
3.87(s,3H).
Embodiment 2:
1,5- cyclo-octadiene ruthenous chlorides are changed to ten dicarbapentaborane rutheniums (6.7g, 0.01mmol), other operate same embodiment
Isosorbide-5-Nitrae 0mg, yield 27%.
Embodiment 3:
1,5- cyclo-octadiene ruthenous chlorides are changed to three (triphenylphosphine) ruthenous chlorides (9.5mg, 0.01mmol), other behaviour
Make with embodiment 1,66.9mg, yield 45%.
Embodiment 4:
1,5- cyclo-octadiene ruthenous chlorides are changed to two (triphenylphosphine) cyclopentadiene ruthenic chlorides (7.0mg, 0.01mmol),
Other operations are the same as embodiment 1,52mg, yield 35%.
Embodiment 5:
Solvent Isosorbide-5-Nitrae-dioxane is changed to tetrahydrofuran (15mL), is 60 DEG C by reaction temperature, other operations are the same as implementation
Example 1,31.2mg, yield 21%.
Embodiment 6:
Reaction temperature is increased to 130 DEG C, other operations are the same as embodiment 1,89.1mg, yield 60%.
Embodiment 7:
The amount of 1,5- cyclo-octadiene ruthenous chlorides is changed to 7.8mg, with embodiment 1,52mg, yield is for other operations
35%.
Embodiment 8:
The amount of 1,5- cyclo-octadiene ruthenous chlorides is changed to 2.7mg, with embodiment 1,22.3mg, yield is for other operations
15%.
Embodiment 9:
The amount of potassium tert-butoxide is changed to 83.6mg, other operations are the same as embodiment 1,53.5mg, yield 36%.
Embodiment 10:
The amount of potassium tert-butoxide is changed to 209.1mg, other operations are the same as embodiment 1,29.7mg, yield 20%.
Embodiment 11:
It will be changed in reaction time 15 hours, other operations are the same as embodiment Isosorbide-5-Nitrae 3.1mg, yield 29%.
Embodiment 12:
The amount of N- phenyl dicyandiamidines hydrochlorides is changed to 80.5mg, with embodiment 1,26.7mg, yield is for other operations
18%.
Embodiment 13:
The amount of N- phenyl dicyandiamidines hydrochlorides is changed to 241.4mg, 1.1mmol, other are operated with embodiment 1,37.2mg,
Yield is 25%.
Embodiment 14:The preparation of compound (III-2)
Operation only changes P-methoxybenzyl alcohol into 4- chlorobenzene methanols (107.2mg, 0.75mmol) with embodiment 1, makes
Obtain target compound (III-2), 91.0mg, yield 60%.1H NMR(500MHz,DMSO-d6)δ12.31(br,1H),
10.14 (br, 1H), 8.20 (d, J=6.9Hz, 2H), 7.95-7.54 (m, 4H), 7.41-7.24 (m, 2H), 7.17-7.01 (m,
1H).
Embodiment 15:The preparation of compound (III-3)
Operation with embodiment 1, only by P-methoxybenzyl alcohol change into 3,4- 3,5-dimethoxybenzoic alcohols (123.0mg,
0.75mmol), target compound (III-3), 135.3mg, yield 82% is made.
1H NMR(500MHz,DMSO-d6)δ12.11(br,1H),10.02(br,1H),8.26-7.69(m,4H),7.41-
7.25 (m, 2H), 7.16 (d, J=8.3Hz, 1H), 7.10-7.05 (m, 1H), 3.87 (s, 6H)
Embodiment 16:The preparation of compound (III-4)
Operation with embodiment 1, only by P-methoxybenzyl alcohol change into 2,3- 3,5-dimethoxybenzoic alcohols (126.5mg,
0.75mmol), target compound (III-4), 134.0mg, yield 87% is made.
1H NMR(500MHz,DMSO-d6) δ 11.86 (br, 1H), 10.12 (br, 1H), 7.84 (d, J=7.2Hz, 2H),
7.34 (t, J=7.2Hz, 2H), 7.29 (dd, J=7.0,2.8Hz, 1H), 7.24-7.21 (m, 2H), 7.07 (t, J=7.0Hz,
1H),3.88(s,3H),3.82(s,3H).
Embodiment 17:The preparation of compound (III-5)
Operation only changes P-methoxybenzyl alcohol into 2- thenyl alcohols (89.2mg, 0.75mmol) with embodiment 1, makes
Obtain target compound (III-5), 95.8mg, yield 71%.1H NMR(500MHz,DMSO-d6)δ12.32(br,1H),
10.00 (br, 1H), 8.47-8.20 (m, 1H), 8.02 (d, J=4.6Hz, 1H), 7.89-7.62 (m, 2H), 7.34 (t, J=
7.5Hz, 2H), 7.30 (t, J=4.6Hz, 1H), 7.08 (t, J=7.5Hz, 1H)
Embodiment 18:The preparation of compound (III-6)
Operation with embodiment 1, only by P-methoxybenzyl alcohol change into 2- methoxy benzyl alcohols (126.2mg,
0.75mmol), target compound (III-6), 102.2mg, yield 69% is made.
1H NMR(500MHz,DMSO-d6) δ 11.69 (br, 1H), 10.12 (br, 1H), 7.84 (d, J=7.8Hz, 2H),
7.75 (d, J=7.4Hz, 1H), 7.60 (t, J=7.8,1H), 7.34 (t, J=7.8Hz, 2H), 7.22 (d, J=7.4Hz,
1H), 7.12 (t, J=7.4Hz, 1H), 7.07 (t, J=7.4Hz, 1H), 3.89 (s, 3H)
Embodiment 19:The preparation of compound (III-7)
Operation only changes P-methoxybenzyl alcohol into 4- bromobenzenes methanol (140.5mg, 0.75mmol) with embodiment 1, makes
Obtain target compound (III-7), 113.0mg, yield 66%.1H NMR(500MHz,DMSO-d6)δ12.60(br,1H),
10.19 (br, 1H), 8.15 (d, J=7.2Hz, 2H), 7.92-7.53 (m, 4H), 7.36 (t, J=7.2Hz, 2H), 7.09 (t, J
=7.2Hz, 1H)
Embodiment 20:The preparation of compound (III-8)
Operation only changes P-methoxybenzyl alcohol into 3- chlorobenzene methanols (106.9mg, 0.75mmol) with embodiment 1, makes
Obtain target compound (III-8), 79.8mg, yield 53%.1H NMR(500MHz,DMSO-d6)δ12.33(br,1H),
10.16 (br, 1H), 8.34-8.21 (m, 1H), 8.15 (d, J=7.1Hz, 1H), 7.85-7.45 (m, 3H), 7.63 (t, J=
7.5Hz,1H),7.46-7.24(m,2H),7.17-7.01(m,1H).
Embodiment 21:The preparation of compound (III-9)
Operation only changes P-methoxybenzyl alcohol into 4- fluorophenyl methanols (91.4mg, 0.75mmol) with embodiment 1, makes
Obtain target compound (III-9), 106.1mg, yield 53%.1H NMR(500MHz,DMSO-d6)δ12.25(br,1H),
10.12 (br, 1H), 8.33-8.21 (m, 2H), 7.94-7.69 (m, 2H), 7.44 (t, J=7.8Hz, 2H), 7.36 (t, J=
7.2Hz, 2H), 7.09 (t, J=7.2Hz, 1H)
Embodiment 22:The preparation of compound (III-10)
Operation with embodiment 1, only by P-methoxybenzyl alcohol change into the sub- methoxy benzyl alcohol of 2,3- bis- (113.6mg,
0.75mmol), target compound (III-10), 122.3mg, yield 84% is made.
1H NMR(500MHz,DMSO-d6)δ12.07(br,1H),10.01(br,1H),8.06-7.58(m,4H),7.48-
7.24(m,2H),7.21-7.00(m,2H),6.18(s,2H).
Embodiment 23:The preparation of compound (III-11)
Operation with embodiment 1, only by N- phenyl dicyandiamidines hydrochlorides change into N- methyl amidino ureas hydrochloride (77.6mg,
0.50mmol), target compound (III-11), 45.5mg, yield 46% is made.
1H NMR(500MHz,DMSO-d6)δ11.85(br,1H),8.26(br,1H),8.1-7.93(m,2H),7.63-
7.53 (m, 3H), 2.79 (d, J=4.1Hz 3H)
Embodiment 24:The preparation of compound (III-12)
Operation only changes N- phenyl dicyandiamidines hydrochlorides into N- (4- aminomethyl phenyls) dicyandiamidines hydrochloride with embodiment 1
(77.6mg, 0.50mmol), P-methoxybenzyl alcohol are changed to 3- chlorobenzene methanols (109.9mg, 0.75mmol), and target chemical combination is made
Object (III-12), 74.5mg, yield 50%.
1H NMR(500MHz,DMSO-d6)δ12.29(br,1H),10.10(br,1H),8.34-8.21(m,1H),8.14
(d, J=8.9Hz, 1H), 7.73-7.60 (m, 4H), 7.16 (d, J=7.5Hz, 2H), 2.29 (s, 3H)
Embodiment 25:Anti-human osteosarcoma U 2OS biological activity test
External anti-human osteosarcoma cell (U2OS) activity test method:Mtt assay
Experimental procedure:
1) preparation of sample:For solvable sample, per 1mg with 20 μ L DMSO dissolvings, take 2uL dilute with 1000 μ L culture solutions
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
2) culture of cell
2.1) preparation of culture medium:Contain 800,000 units of Penicillin, 1.0g streptomysins, 10% inactivation in per 1000mL culture mediums
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 is passed on.
3) inhibiting effect of the determination sample to growth of tumour cell
Cell EDTA- pancreatin digestive juices are digested, culture medium is used in combination to be diluted to 1 × 105/ mL is added to 96 hole cell trainings
It supports in plate, per hole 100uL, sets 37 DEG C, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, the diluted sample of addition culture medium,
Per 100 μ L of hole, each concentration adds 3 holes, sets 37 DEG C, 5%CO2It is cultivated in incubator, 5mg/ is added after 72h in cell culture well
The MTT of mL sets 37 DEG C of incubation 4h, DMSO is added, per 150 μ L of hole, is vibrated with oscillator per 10 μ L of hole, and Shi Jia Za is completely dissolved,
With microplate reader under 570nm wavelength colorimetric.With similarity condition use be free of sample, the medium culture containing same concentration DMSO it is thin
Born of the same parents as a contrast, calculate sample to the inhibiting rate of growth of tumour cell, the results are shown in Table 1.
Using human osteosarcoma cell U2OS as model, determine the triazinone compounds (III-1) that are prepared in embodiment~
(III-12) 12 samples are in vitro to the inhibiting effect of human osteosarcoma cell's growth.The results show that the sample that this experiment is tested
In, compound (III-2), (III-3), (III-5), (III-6), (III-10) have to testing osteosarcoma U 2OS used
Certain inhibiting effect (the results detailed in Table 1).
Inhibiting rate of the 1 each compound of table to human osteosarcoma cell U2OS
Compound | Inhibiting rate % | Compound | Inhibiting rate % |
(III-1) | 30 | (II1-7) | 31 |
(III-2) | 74 | (III-8) | 26 |
(III-3) | 65 | (III-9) | 32 |
(III-4) | 25 | (III-10) | 67 |
(III-5) | 64 | (III-11) | 22 |
(III-6) | 68 | (III-12) | 35 |
Claims (10)
1. a kind of triazinone compounds as shown in formula (III):
In formula (III), R1Or R2Respectively stand alone as C1~C10Alkyl, C4~C10Aryl, wherein aryl be heteroaromatic, phenyl or by
C1~4Alkyl, C1~4Alkoxy or halogen substitution phenyl.
2. triazinone compounds as described in claim 1, it is characterised in that:The R1Or R2Respectively stand alone as methyl, thiophene
Pheno, phenyl or the phenyl replaced by methyl, methoxyl group, 3,4- methylenes dimethoxy, fluorine, chlorine or bromine.
3. the preparation method of triazinone compounds as described in claim 1, it is characterised in that:The method is according to as follows
It is prepared by step:
Alcohol compound shown in formula (I) is mixed with dicyandiamidines hydrochloride shown in formula (II) and is added in organic solvent, in metal
It under ruthenium catalyst effect, in the presence of alkaline matter, is stirred to react at a temperature of 60~130 DEG C 15~27 hours, reaction knot
Shu Hou, obtains reaction solution, triazinone compounds shown in post-treated obtained formula (III);Alcohols shown in the formula (I)
It is 1 that object, which is closed, with the ratio between dicyandiamidines hydrochloride, metal Ru catalyst, amount of substance of alkaline matter shown in formula (II):0.5~
1.5:0.01~0.04:1.0~2.5;The organic solvent is ethers or or substituted benzene;The alkaline matter is organic
Alkali;The metal Ru catalyst be divalent ruthenium or trivalent ruthenium compound,
4. method as claimed in claim 3, it is characterised in that:The organic solvent is tetrahydrofuran, Isosorbide-5-Nitrae-dioxane
Or toluene.
5. method as claimed in claim 3, it is characterised in that:The volumetric usage of the organic solvent is with shown in formula (I)
The amount of the substance of alcohol compound is calculated as 5~20mL/mmol.
6. method as claimed in claim 3, it is characterised in that:The metal Ru catalyst is ten dicarbapentaborane rutheniums, triphenylphosphine
Ruthenic chloride, two (triphenylphosphine) cyclopentadiene ruthenic chlorides or 1,5- cyclo-octadiene ruthenous chlorides.
7. method as claimed in claim 3, it is characterised in that:The alkaline matter is potassium tert-butoxide.
8. method as claimed in claim 3, it is characterised in that:The post-processing approach of the reaction solution is:After reaction, to
Add water in the reaction solution, be extracted with ethyl acetate, merge organic layer, dried with anhydrous sodium sulfate, filter, concentrates filtrate,
Column chromatography for separation, with volume ratio for 30:1 dichloromethane and the mixed liquor of methanol are eluant, eluent, it collects containing target compound
Eluent, vacuum distillation, is dried to obtain triazinone compounds shown in formula (III).
9. a kind of triazinone compounds as described in claim 1 are preparing the application in treating human osteosarcoma drug.
10. application as claimed in claim 9, it is characterised in that:The triazinone compounds are
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