CN1563023A - 3,6-bi(2'-hydroxy-5'-chlorphenyl)-S-tetrazine and accessory ingredient of transition metal, preparation and application - Google Patents

3,6-bi(2'-hydroxy-5'-chlorphenyl)-S-tetrazine and accessory ingredient of transition metal, preparation and application Download PDF

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CN1563023A
CN1563023A CN 200410017445 CN200410017445A CN1563023A CN 1563023 A CN1563023 A CN 1563023A CN 200410017445 CN200410017445 CN 200410017445 CN 200410017445 A CN200410017445 A CN 200410017445A CN 1563023 A CN1563023 A CN 1563023A
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CN1279030C (en
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胡惟孝
杨忠愚
江银枝
饶国武
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Zhejiang University of Technology ZJUT
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Abstract

This invention relates to a novel anti-cancer drug-3,6-di(2-hydroxy-5-chlorophenyl)-5-tetrazine and transtion metal coordination compound, its prepn. method, and its application. Experiment shows that, this coordination compound of said terazine and transition metal has obvious anti-cancer activity. This invention prepn. of coordination compound is of simple process. This invention can help to select new medicines.

Description

3, title complex and the preparation and the application of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal
(1) technical field
The present invention relates to a kind of anticarcinogen 3, the title complex and the manufacture method thereof of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal, with and application in preparing cancer therapy drug.
(2) background technology
Tetrazine is the 6-membered heterocyclic compound that a class contains four nitrogen-atoms, and the S-tetrazine is the most stable in 3 kinds of isomerss.Germanization scholar Hantgsch had at first synthesized the S-tetrazine in 1900, and people find the S-tetrazine successively after the seventies in 20th century, although be aromatic hydrocarbons, (4+2) cycloaddition reaction can take place; The tetrazine derivatives of some special constructions has tangible antiviral activity, anti-tumor activity and can be as agricultural chemical insecticide, liquid crystal material and rocket fuel etc., thereby has caused people's extensive interest.
In the tetrazine analog derivative, filtered out some materials at present and had anti-tumor activity, N for example, N '-phenylbenzene-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-diformamide; 3, two (3-picoline-2 bases)-1,2,4 of 6-, the title complex of 5-tetrazine and transition metal, or the like.The S-tetrazine derivatives that contains the different structure of different substituents should have different biological activitys, screening by the tetrazine analog derivative, be expected to filter out the cancer therapy drug of high-efficiency low-toxicity, this will have very significant meaning, also will cause increasing scientific worker's concern.
(3) summary of the invention
The object of the invention provides a kind of new S-tetrazine kind anti-cancer drugs thing, and promptly 3, title complex of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal and preparation method thereof, and the application of this title complex in preparing cancer therapy drug.
For reaching the goal of the invention the technical solution adopted in the present invention be:
A kind of 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, described title complex has following general formula (I):
Wherein M is a transition-metal Fe 2+, Fe 3+, Co 2+, Ni 2+, Cu 2+, Pt 2+In a kind of, L is inorganic part Cl -, Br -, Ac -, I -, NO 3 -, SO 4 2-In a kind of, R is H or lone electron, x, y, z respectively are 1～5 number, a, b, c respectively are 0～10 number.
Preferably, described transition metal is Fe 3+, Co 2+, Ni 2+, Cu 2+In a kind of, described inorganic part is Cl -, NO 3 -, Ac -In a kind of.
A kind of preparation is described 3, the method for two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-, described method be with salicylic aldehyde and hydrazine hydrate in ethanolic soln, react the compound formula (II) that makes: 2,2 '-dihydroxy-benzene azine,
Reaction formula is shown in (A):
Figure A20041001744500083
Compound formula (II) feeds chlorine and makes compound formula (III): α in Glacial acetic acid/acid anhydrides solvent, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-,
Figure A20041001744500091
Reaction formula is shown in (B):
Figure A20041001744500092
Compound (III) in ethanolic soln with hydrazine hydrate reacting generating compound formula (IV): 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine,
Reaction formula is shown in (C):
Compound (IV) is oxidized to the compound formula V with nitrous acid: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, 5-tetrazine.
Described nitrous acid is made by Sodium Nitrite and acetic acid reaction.
Figure A20041001744500095
Reaction formula is shown in (D):
Figure A20041001744500101
A kind of preparation is described 3, and the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal makes compound (IV) by preceding method: 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4,5-tetrazine, the salt M of compound (IV) and transition metal eL fCompound formula (I) is made in reaction in alcohol solvent: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal, wherein e, f respectively are 1～5 number.
Reaction formula is shown in (E):
Concrete, described method is carried out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-dihydroxy-benzene azine (II);
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, down feeds chlorine about 1 hour at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and in 10～20 ℃ of following chlorine 1.5～2 hours, with TLC point plate, observes the raw material spot and disappears and end, and stops logical chlorine, and placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines (III) of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4,5-tetrazine (IV);
(4) at normal temperatures, with 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV) are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF) eL fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number; Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour, with the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal.
A kind of preparation is described 3, and the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal makes compound (V) 3 by preceding method, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, the 5-tetrazine, the salt M of compound (V) and transition metal eL fCompound formula (I) is made in reaction in alcohol solvent: 3, and the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, wherein e, f respectively are 1～5 number.
Reaction formula is shown in (F):
Figure A20041001744500111
Concrete, described method is carried out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-the dihydroxy-benzene azine;
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, feeds chlorine about 1 hour down at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and logical chlorine is 1.5～2 hours under 10～20 ℃; With TLC point plate, observe the raw material spot and only disappear, stop logical chlorine, placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine;
(4) compound (IV) and sodium nitrite in aqueous solution stir into suspension, add acetic acid, and in stirring at room 3 hours, solid filtering, washing obtained red crystals 3 with ethyl alcohol recrystallization, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-s-tetrazines (V) of 6-again;
(5) at normal temperatures, with 3, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines (V) of 6-are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF) eL fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number.Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour; With the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal.
Described 3, the title complex of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal is treated application in the medicine of leukemia, lung cancer or other tumour in preparation.
Of the present invention 3, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-are mainly reflected in the title complex of transition metal and the beneficial effect of preparation and application: (1) provides a kind of cancer therapy drug newly, that obvious antitumour activity is arranged; (2) preparation flow is simple, for new medicament screen provides the research basis.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment:
Embodiment 1: preparation 2,2 '-dihydroxy-benzene azine (II)
2.4g NH (85%) 2NH 2H 2The O aqueous solution (0.04mol) joins in the 24ml water, adds 5ml ethanol, stirs evenly into solution A, 9.8g salicylic aldehyde (0.08mol) is dissolved in the 4ml ethanol become solution B.B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours.Add 20ml water, suction filtration, with big water gaging flushing after drying get 2,2 '-dihydroxy-benzene azine 9.1 restrains, productive rate 95%, m.p.214～216 ℃.
Embodiment 2: preparation α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines (III) of α '-two chloro-
With 5.5g2,2 '-dihydroxy-benzene azine (0.023mol), be added in the mixed solution of 40ml Glacial acetic acid and 4.5ml acetic anhydride.Stirring makes suspension preferably.Fed chlorine about 1 hour down at 10～20 ℃, solution retrogradation this moment, but solid does not disappear.Add 40ml Glacial acetic acid and 4.5ml aceticanhydride.In 10～20 ℃ of following chlorine 1.5～2 hours.With TLC point plate, observe the raw material spot and only disappear, stop logical chlorine, placement is spent the night.Suction filtration, solid washing with alcohol, dry α, two (2 '-hydroxyl-5 '-chloro-phenyl-)-azines 5 grams of α '-two chloro-, yield 58%, m.p.175～178 ℃.
Embodiment 3: preparation 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV)
(3.8 grams 0.01mol) are dissolved in (20ml) in the ethanol, are heated to backflow, and (0.8 restrains, 0.012mol) to drip 80% hydrazine hydrate with III.Back flow reaction 45 minutes again after adding.Cool to room temperature with the solid filtering of separating out, is used washing with alcohol, dries to such an extent that yellow solid IV1.2 restrains yield 35%, m.p.250 ℃ (dec.).
Embodiment 4: preparation 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, 5-tetrazine (V)
(3.37 grams 0.01mol) add 25ml 10% sodium nitrite in aqueous solution (0.036mol) and stir into suspension compound IV, add 15ml acetic acid, again in stirring at room 3 hours.Solid filtering, washing obtain red crystals 1.1 grams with ethyl alcohol recrystallization.Yield 33%, m.p.238.5～240.5 ℃.IR(KBr)3443，3126，1613，1569，1477，1417，1303，1224，1140，1088，1046，941，898cm -1；NMR(CDCl 3)：δ7.1(d，2H，Ar-H)，7.5(d，2H，Ar-H)，8.6(s，2H，Ar-H)，10.8(s，2H，OH)；M/Z(％)：334(M +，7.55)，153(100.00)，125(56.36)，98(21.06)，63(61.50)。
Embodiment 5:3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the complex compound of 2-dihydro-S-tetrazine IV and transition metal.
At normal temperatures, with 0.5 gram 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV) are dissolved in and become solution A, 1.0g nickelous nitrate (Ni (NO in the 30ml tetrahydrofuran (THF) (THF) 3) 2) be dissolved in the 30ml ethanol and become solution B.Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour.With the solid filtering that generates, the washing of ethanol/water mixed solution obtains nickel-IV complex compound (VI).
CoCl is used in same operation 2Solution obtains cobalt-IV complex compound (VII);
Same operation is with Ni (OAc) 2Solution obtains nickel-IV complex compound (VIII);
Complex compound VI, VII, VIII molecular conductivity (s) and results of elemental analyses are as follows:
Complex compound Molecular formula Molecular conductivity S.cm 2.mol -1 Ultimate analysis (%) experimental value/calculated value
????C ????H ????N
VI Ni(NO 3) 2·IV 2·THF·1.5EtOH ????33 ????42.09/42.11 ????3.12/3.74 ????14.07/14.03
VII Co 2Cl·IV·EtOH·7H 2O ????150 ????25.13/24.99 ????3.8/3.94 ????7.23/7.29
VIII Ni(AcO) 2IV 2·4H 2O ????43 ????38.83/39.00 ????3.13/3.72 ????12.10/12.14
Embodiment 6:3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, the complex compound of 5-tetrazine (V) and transition metal
0.5 gram V is suspended in 1: 1 the ethanol/water mixture solution of 30ml.Slowly the aqueous sodium hydroxide solution of Dropwise 5 % to solid dissolves fully.This moment, solution PH was 6.5～7, was solution A; The 1g nickelous nitrate is dissolved in and is solution B in the water of 30ml.Under stirring at normal temperature, the A drips of solution is added in the B liquid, added the back restir 1.5 hours.With the solid filtering that generates, with behind ethanol/water (1: the 1) solvent wash the complex compound (IX) of nickel-(V);
Same operation gets the complex compound (X) of iron-(V) with liquor ferri trichloridi;
Same operation gets the complex compound (XI) of cobalt-(V) with cobalt chloride solution;
Complex compound VIII, IX, molecular conductivity and the results of elemental analyses of X are as follows:
Complex compound Molecular formula Molecular conductivity S.cm 2.mol -1 Ultimate analysis (%) experimental value/calculated value
??C ??H ??N
IX ????Ni 2(NO 3) 2·V·8H 2O ????10 ??28.66/28.62 ??4.22/4.09 ??9.30/9.55
X ????FeCl 3·(V) 3 ????430 ??43.61/43.20 ??2.08/1.93 ??14.83/14.40
XI ????Co 2Cl 2·V·3.5EtOH，4·H 2O ????33 ??32.98/33.39 ??4.15/4.68 ??-/7.42
To above-claimed cpd IV, V, and complex compound VI, IX, X, XI has measured compound respectively to P-388 mouse leukemia cell and the A-549 human lung carcinoma cell inhibiting rate in growth in vitro with tetrazolium enzyme reduction method (mtt assay) and sulphonyl rhodamine β protein staining method (srb assay).Its result is as follows:
Partly compound under different concns to the inhibiting rate of growth of cancer cells
Complex compound Mtt assay P-388 cell Srb assay A-549 cell
??10 -4 ??10 -5 ??10 -6 ??10 -7 ??10 -8 ??10 -4 ??10 -5 ??10 -6 ??10 -7 ??10 -8
??IV ??89.0 ??0 ??0 ??0 ??0 ??65.3 ??80.3 ??0 ??0 ??0
??V ??92.5 ??90.7 ??91.2 ??88.0 ??82.8 ??57.6 ??62.3 ??16.4 ??0 ??0
??VI ??95.5 ??96.3 ??94.4 ??/ ??94.0 ??57.6 ??69.0 ??74.3 ??71.5 ??74.6
??IX ??94.0 ??95.9 ??95.4 ??93.2 ??88.7 ??79.1 ??90.2 ??79.8 ??79.9 ??77.5
??X ??50.4 ??95.6 ??94.7 ??93.7 ??97.8 ??96.8 ??97.6 ??91.2 ??79.8 ??77.5
??XI ??91.7 ??73.6 ??92.4 ??92.6 ??87.2 ??100 ??100 ??98.9 ??97.2 ??90.7
It is generally acknowledged that in concentration be 10-6mol/l, inhibiting rate reaches that to think then more than 50% that this compounds has potent.By this standard, ligand i V is invalid and part V has potent to P-388; No matter and 4 kinds of title complexs all have potent to P-388 or A-549.

Claims (10)

1. one kind 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described title complex has following general formula (I):
Wherein M is a transition-metal Fe 2+, Fe 3+, Co 2+, Ni 2+, Cu 2+, Pt 2+In a kind of, L is inorganic part Cl -, Br -, Ac -, I -, NO 3 -, SO 4 2-In a kind of, R is H or lone electron, x, y, z respectively are 1～5 number, a, b, c respectively are 0～10 number.
2. as claimed in claim 13, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described transition metal is Fe 3+, Co 2+, Ni 2+, Cu 2+In a kind of.
3. as claimed in claim 23, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described inorganic part is Cl -, NO 3 -, Ac -In a kind of.
4. one kind prepares as claimed in claim 13, the method of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-, it is characterized in that described method be with salicylic aldehyde and hydrazine hydrate in ethanolic soln, react the compound formula (II) that makes: 2,2 '-dihydroxy-benzene azine
Figure A2004100174450002C2
Compound formula (II) feeds chlorine and makes compound formula (III): α in Glacial acetic acid/acid anhydrides solvent, two (2 '-hydroxyl-5-the chloro-phenyl-)-azines of α '-two chloro-,
Compound (III) in ethanolic soln with hydrazine hydrate reacting generating compound formula (IV): 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine,
Compound (IV) is oxidized to the compound formula V with nitrous acid: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1,2,4 of 6-, 5-tetrazine.
5. as claimed in claim 43, the preparation method of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-is characterized in that described nitrous acid is made by Sodium Nitrite and acetic acid reaction.
6. one kind prepares as claimed in claim 13, the method of the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, it is characterized in that making compound (IV): 3 by method as claimed in claim 4, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine, the salt M of compound (IV) and transition metal eL fCompound formula (I) is made in reaction in alcohol solvent: 3, and two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal, wherein e, f respectively are 1～5 number.
7. as claimed in claim 63, the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described method carries out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-the dihydroxy-benzene azine;
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, down feeds chlorine about 1 hour at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and in 10～20 ℃ of following chlorine 1.5～2 hours, with TLC point plate, observes the raw material spot and disappears and end, and stops logical chlorine, and placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine;
(4) at normal temperatures, with 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-S-tetrazine (IV) are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF) eL fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number; Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour, with the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, the title complex of 2-dihydro-S-tetrazine and transition metal.
8. one kind prepares as claimed in claim 13, the method of the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, it is characterized in that making compound (V) 3 by method as claimed in claim 5, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2,4,5-tetrazine, the salt M of compound (V) and transition metal eL fCompound formula (I) is made in reaction in alcohol solvent: 3, and the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal, wherein e, f respectively are 1～5 number.
9. as claimed in claim 83, the method for the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal is characterized in that described method carries out as follows:
(1) hydrazine hydrate solution is added to the water, the adding small amount of ethanol stirs evenly into solution A, salicylic aldehyde is dissolved in become solution B in the ethanol, B solution is remained under 10～20 ℃ of stirrings, slowly be added dropwise to solution A, after adding in 1.5～2 hours, restir reaction 2 hours, add entry, suction filtration, with big water gaging flushing after drying get 2,2 '-the dihydroxy-benzene azine;
(2) with 2,2 '-the dihydroxy-benzene azine is added in the mixed solution of Glacial acetic acid and acetic anhydride.Stirring makes suspension preferably, feeds chlorine about 1 hour down at 10～20 ℃, and this adds Glacial acetic acid and aceticanhydride if solid does not disappear, and logical chlorine is 1.5～2 hours under 10～20 ℃; With TLC point plate, observe the raw material spot and only disappear, stop logical chlorine, placement is spent the night; Suction filtration, solid washing with alcohol, the dry α that gets, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-;
(3) with α, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-azines of α '-two chloro-are dissolved in the ethanol, are heated to backflow, drip 80% hydrazine hydrate, back flow reaction 45 minutes again after adding, cool to room temperature, with the solid filtering of separating out, use washing with alcohol, dry yellow solid 3, two (the 2 '-hydroxyls-5 '-chloro-phenyl-)-1 of 6-, 2-dihydro-1,2,4, the 5-tetrazine;
(4) compound (IV) and sodium nitrite in aqueous solution stir into suspension, add acetic acid, and in stirring at room 3 hours, solid filtering, washing obtained red crystals 3 with ethyl alcohol recrystallization, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-s-tetrazines of 6-again;
(5) at normal temperatures, with 3, two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines (V) of 6-are dissolved in and become solution A, the salt M of transition metal in the tetrahydrofuran (THF) (THF) eL fBe dissolved in and become solution B in the ethanol, wherein e, f respectively are 1～5 number.Under agitation, A is added drop-wise among the B, dripped off in 30 minutes, restir reaction 1 hour; With the solid filtering that generates, the washing of ethanol/water mixed solution obtains complex compound (I) 3, the title complex of two (2 '-hydroxyl-5 '-chloro-phenyl-)-S-tetrazines of 6-and transition metal.
10. described 3 as one of claim 1～3, the title complex of two (2 '-hydroxyl-5 '-the chloro-phenyl-)-S-tetrazines of 6-and transition metal is treated application in the medicine of leukemia, lung cancer or other tumour in preparation.
CN 200410017445 2004-03-31 2004-03-31 3,6-bi(2'-hydroxy-5'-chlorphenyl)-S-tetrazine and accessory ingredient of transition metal, preparation and application Expired - Fee Related CN1279030C (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702122A (en) * 2012-05-16 2012-10-03 南通大学 Method for preparing tetrazine by oxidizing dihydro tetrazine
CN102911189A (en) * 2012-10-16 2013-02-06 桂林理工大学 Salicylaldehyde azine schiff base transition metal compound and application thereof
CN109134301A (en) * 2018-10-12 2019-01-04 阜阳师范学院 A kind of fluorescence probe preparation method and applications based on salicylide azine
CN110818908A (en) * 2019-08-29 2020-02-21 杭州市富阳区浙工大银湖创新创业研究院 Preparation method of metal organic framework material for detecting oxidizing gas

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702122A (en) * 2012-05-16 2012-10-03 南通大学 Method for preparing tetrazine by oxidizing dihydro tetrazine
CN102911189A (en) * 2012-10-16 2013-02-06 桂林理工大学 Salicylaldehyde azine schiff base transition metal compound and application thereof
CN109134301A (en) * 2018-10-12 2019-01-04 阜阳师范学院 A kind of fluorescence probe preparation method and applications based on salicylide azine
CN110818908A (en) * 2019-08-29 2020-02-21 杭州市富阳区浙工大银湖创新创业研究院 Preparation method of metal organic framework material for detecting oxidizing gas
CN110818908B (en) * 2019-08-29 2021-12-17 杭州市富阳区浙工大银湖创新创业研究院 Preparation method of metal organic framework material for detecting oxidizing gas

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