CN107827834A - The formic acid ester compound of 5 aryl, 6 trifluoromethyl, 1,2,4 3 nitrogen piperazine 3 and preparation method - Google Patents
The formic acid ester compound of 5 aryl, 6 trifluoromethyl, 1,2,4 3 nitrogen piperazine 3 and preparation method Download PDFInfo
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- CN107827834A CN107827834A CN201711224389.8A CN201711224389A CN107827834A CN 107827834 A CN107827834 A CN 107827834A CN 201711224389 A CN201711224389 A CN 201711224389A CN 107827834 A CN107827834 A CN 107827834A
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- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention relates to the formic acid ester compound of 5 aryl, 6 trifluoromethyl, 1,2,4 3 nitrogen piperazine 3 and preparation method.By the tetrahydrochysene 1 of 5 aryl, 6 trifluoromethyl 1,2,5,6, the formic acid esters of 2,4 three nitrogen piperazine 3 is dissolved in organic solvent, after adding oxidant reaction completely, scrubbed, extraction, separation, obtain the formic acid ester compound of 5 aryl of target, 61,2,4 three nitrogen piperazine of trifluoromethyl 3.Gained target compound is 1 containing trifluoromethyl, 2,4 three nitrogen piperazine class heterocycle structures, as electron-deficient aromatic heterocycle, antielectron demand diels Alder cycloaddition reaction can be carried out with electron rich alkene, for bio-orthogonal click chemistry；The formic acid ester compound of 5 aryl, 61,2,4 three nitrogen piperazine of trifluoromethyl 3 can be used as medicine, or the core texture unit as pharmaceutical synthesis in itself, be screened for pharmaceutical activity.
Description
Technical field
The present invention provides a kind of 1,2,4- tri- nitrogen piperazine compounds containing trifluoromethyl and preparation method thereof, specifically public
A kind of 5- aryl-6s-Trifluoromethyl-1, the nitrogen piperazine -3- formic acid ester compounds of 2,4- tri- and preparation method are opened.
Background technology
Develop to the labeling method of intracellular biomolecule real-time visual for understanding that the molecular basis of life has
Important meaning.Bio-orthogonal connection chemical (bioorthogonal ligation) is increasingly becoming big to biology in vivo
Molecule and active small molecular carry out a kind of effective ways of specific mark.Mark based on bio-orthogonal reaction is, it is necessary in mesh
Mark and specific chemistry reading group (chemical reporter) is introduced in molecule, then by bio-orthogonal reaction with containing
The probe of complementation group is reacted, so as to realize the specific mark to target molecule.But this method is faced with very big choose
War because it needs corresponding chemical reaction to have very strong activity and selectivity in physiological conditions, and to surrounding other
The good inertia of bioactive molecule holding (K.Liang, J.W.Chin, Chem.Rev.2014,114,4764-4806 and P.Shieh,
C.R.Bertozzi,Org.Biomol.Chem.2014,12,9307–9320)。
Nearest U.S. J.A.Prescher, Britain M.E.Webb and Czech M.Vrabel attempt using the nitrogen piperazines of 1,2,4- tri- with
The antielectron demand diels of trans-cyclooctene class compound-Alder cycloaddition reaction (Inverse Electron-
Demand Diels-Alder Cycloaddition, IED-DA), develop new bio-orthogonal reaction (J.A.Prescher, et
al.,J.Am.Chem.Soc.2015,137,8388-8391&M.E.Webb,et al.,Chem.Eur.J.2015,21,
14376–14381&M.Vrabel,et al.,Chem.Sci.2017,8,3593–3598.).But these nitrogen piperazines of 1,2,4- tri- will
Electron rich, or being connected with double aryl substituent groups in 3, the 6- positions of ring, cause room temperature cycloaddition reation rate slow, in life
Lack practicality in the orthogonal chemical joint test of thing.Therefore there is an urgent need to design the nitrogen piperazine of synthesizing new 1,2,4- tri-, for biology
Orthogonal connection chemistry.
The present invention provides 5- aryl-6s-Trifluoromethyl-1, the nitrogen piperazine -3- formic acid ester compounds of 2,4- tri- and preparation method thereof.
This kind of 1,2,4- tri- nitrogen piperazine compounds contain the formic acid esters and trifluoromethyl for haling electronics in 3,6- positions, these substituted radical spaces
Volume is again smaller than aromatic radical, therefore 5- aryl-6s-Trifluoromethyl-1,2,4- tri- nitrogen piperazine -3- formic acid esters and trans-cyclooctene alcohols
Compound room temperature can fast reaction, therefore these compounds can be used for bio-orthogonal click chemistry.
The content of the invention
It is an object of the present invention to provide a kind of new 5- aryl-6s-Trifluoromethyl-1, the nitrogen piperazine -3- formic acid esters chemical combination of 2,4- tri-
Thing, wherein Ar are that aromatic group, R are fatty alkyl and aromatic group：
Described aromatic group is phenyl, 4- aminomethyl phenyls, 4- methoxyphenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromobenzenes
Double (the fluoroforms of base, 4- iodophenyls, 4- cyano-phenyls, 4- nitrobenzophenones, 4- trifluoromethyls, 4- methoxycarbonyl groups phenyl, 3,5-
Base) phenyl, 3,4,5- trifluorophenyls, 1- naphthyls, 2- naphthyls, 9- anthracenes, 9- phenanthrene or 1- pyrenes etc..
Described fatty alkyl group is methyl, ethyl, propyl group, butyl, the tert-butyl group or benzyl etc..
On the other hand, 5- aryl-6s-Trifluoromethyl-1 proposed by the present invention, 2,4- tri- nitrogen piperazine -3- formic acid ester compounds
Preparation method, including step are as follows：
By 5- aryl-6s-Trifluoromethyl-1,2,5,6- tetrahydrochysenes -1,2, the nitrogen piperazine -3- formic acid esters of 4- tri- is dissolved in organic solvent,
After adding oxidant reaction completely, scrubbed, extraction, separation, target 5- aryl-6s-Trifluoromethyl-1 is obtained, 2,4- tri- nitrogen piperazines-
3- formic acid ester compounds.
Described oxidant is oxygen, hydrogen peroxide, DDQ, ammonium persulfate-sodium bisulfate Oxone, m-chloro mistake
Oxybenzoic acid, manganese dioxide or tert-Butanol peroxide.
5- aryl-6s-the Trifluoromethyl-1, the nitrogen piperazine -3- formic acid esters of 2,5,6- tetrahydrochysenes -1,2,4- three and oxidant rub
Your proportioning is 1:1~5.
Described organic solvent is tetrahydrofuran, 1- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxane, acetonitrile, N, N- dimethyl
Formamide DMF or dimethyl sulfoxide DMSO.
The present invention provides a kind of new 5- aryl-6s-Trifluoromethyl-1, the nitrogen piperazine -3- formic acid ester compounds of 2,4- tri- and its
Preparation method, gained target compound are 1 containing trifluoromethyl, 2,4- tri- nitrogen piperazine class heterocycle structures, as electron-deficient aromatic
Heterocycle, antielectron demand diels-Alder cycloaddition reaction can be carried out with electron rich alkene, for bio-orthogonal linkization
Learn；5- aryl-6s-Trifluoromethyl-1,2,4- tri- nitrogen piperazine -3- formic acid ester compounds can be used as medicine in itself, or as pharmaceutical synthesis
Core texture unit, for pharmaceutical activity screen.
Embodiment
Contribute to further understand the present invention by following examples, but be not intended to limit the present invention.
Example 1：5- phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
5- phenyl -6- Trifluoromethyl-1s, 2,5,6- tetrahydrochysenes -1,2,4- are added in a drying 15mLSchlenk reaction bulbs
Three nitrogen piperazine -3- methyl formates (115mg, 0.4mmol) and DDQ (363mg, 1.6mmol), 4mL tetrahydrofurans are added into system,
It is heated to 50 DEG C of stirring reactions 20 hours.After TLC detection reactions completely, depressurize solvent removal；Then 10mL is added to system
Ethyl acetate and saturated sodium bicarbonate solution 5mL, liquid separation, aqueous phase are extracted with ethyl acetate (10mL x 2), merge organic phase simultaneously
Washed twice with water (10mL), anhydrous MgSO4Dry, column chromatography (leacheate：Petrol ether/ethyl acetate=20/1to 10/1)
It can obtain target product 5- phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formate 94mg, yield 83%.1H NMR
(600MHz,CDCl3)δ7.78(d,2H),7.62(t,1H),7.55(t,2H),4.13(s,3H)；19F NMR(565MHz,
CDCl3)δ-61.30(s,3F)。
Example 2：5- p-methylphenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using oxygen as oxidant, 1- methyltetrahydrofurans are solvent, 5- p-methylphenyls -6-
The mol ratio of Trifluoromethyl-1, the nitrogen piperazine -3- methyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:5, closed 70 DEG C anti-
Answer 24 hours, synthesize 5- p-methylphenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 86%.1H NMR
(400MHz,CDCl3)δ7.71(d,2H),7.34(d,2H),4.10(s,3H),2.43(s,3H)；19F NMR(376MHz,
CDCl3)δ-61.45(s,3F)。
Example 3：5- p-methoxyphenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using hydrogen peroxide as oxidant, Isosorbide-5-Nitrae-dioxane is solvent, 5- p-methoxyphenyls-
The mol ratio of 6- Trifluoromethyl-1s, the nitrogen piperazine -3- methyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:4, heat 60 DEG C
Reaction 12 hours, synthesize 5- p-methoxyphenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 71%.1H
NMR(600MHz,CDCl3)δ7.83(d,2H),7.02(d,2H),4.09(s,3H),3.86(s,3H)；19F NMR(565MHz,
CDCl3)δ-61.71(s,3F)。
Example 4：5- p-fluorophenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using metachloroperbenzoic acid as oxidant, acetonitrile is solvent, 5- p-fluorophenyls -6- three
The mol ratio of the nitrogen piperazine -3- methyl formates of methyl fluoride -1,2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:3, heat 80 DEG C of reactions
8 hours, synthesize 5- p-fluorophenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 87%.1H NMR
(600MHz,CDCl3)δ7.31–7.25(m,2H),7.10–7.04(m,2H),3.89(s,3H)；19F NMR(565MHz,
CDCl3)δ-61.85(s,3F),-113.03–-113.35(m,1F)。
Example 5：5- rubigan -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using tert-Butanol peroxide as oxidant, DMF is solvent, 5- rubigan -6- fluoroforms
The mol ratio of the nitrogen piperazine -3- methyl formates of base -1,2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:2, it is small to heat 60 DEG C of reactions 8
When, synthesize 5- rubigan -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 80%.1H NMR(600MHz,
CDCl3)δ7.72(d,2H),7.49(d,2H),4.07(s,3H)；19F NMR(565MHz,CDCl3)δ-61.44(s,3F)。
Example 6：5- p-bromophenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using manganese dioxide as oxidant, DMSO is solvent, 5- p-bromophenyl -6- fluoroforms
The mol ratio of the nitrogen piperazine -3- methyl formates of base -1,2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:4, it is small to heat 60 DEG C of reactions 24
When, synthesize 5- p-bromophenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 76%.1H NMR(600MHz,
CDCl3)δ7.70(d,2H),7.54(d,2H),4.05(s,3H)；19F NMR(565MHz,CDCl3)δ-61.38(s,3F)。
Example 7：5- is to iodophenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, 1- methyltetrahydrofurans are solvent, and 5- is to iodophenyl -6- three
The mol ratio of the nitrogen piperazine -3- methyl formates of methyl fluoride -1,2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:3, heat 50 DEG C of reactions
24 hours, 5- was to iodophenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 82% for synthesis.1H NMR
(600MHz,CDCl3)δ7.68(d,2H),7.46(d,2H),4.06(s,3H)；19F NMR(565MHz,CDCl3)δ-66.49
(s,3F)。
Example 8：5- is to fluoroform phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using ammonium persulfate-sodium bisulfate Oxone as oxidant, acetonitrile is solvent, and 5- is to trifluoro
The mol ratio of aminomethyl phenyl -6- Trifluoromethyl-1s, the nitrogen piperazine -3- methyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:
3, to heat 70 DEG C and react 20 hours, 5- is to fluoroform phenyl -6- Trifluoromethyl-1s for synthesis, 2,5,6- tetrahydrochysenes -1,2, the nitrogen piperazines of 4- tri- -
3- methyl formates, yield 73%.1H NMR(600MHz,CDCl3)δ7.77(d,2H),7.57(d,2H),4.04(s,3H)；19F
NMR(565MHz,CDCl3)δ-62.84(s,3F),-61.79(s,3F)。
Example 9：5- is to cyano-phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, and 5- is to cyano-phenyl -6- fluoroforms
The mol ratio of the nitrogen piperazine -3- methyl formates of base -1,2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:2, it is small to heat 50 DEG C of reactions 12
When, 5- is to cyano-phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 77% for synthesis.1H NMR
(600MHz,CDCl3)δ7.88(q,4H),4.15(s,3H)；19F NMR(565MHz,CDCl3)δ-61.14(s,3F)。
Example 10：5- (4- methoxycarbonyl groups) phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- (4- methoxycarbonyl groups) phenyl -6-
The mol ratio of Trifluoromethyl-1, the nitrogen piperazine -3- methyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:3, heat 50 DEG C instead
Answer 16 hours, synthesize 5- (4- methoxycarbonyl groups) phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 63%.1H NMR(600MHz,CDCl3)δ8.19(d,2H),7.82(d,2H),4.12(s,3H),3.94(s,3H)；19F NMR
(565MHz,CDCl3)δ-61.25(s,3F)。
Example 11：5- p-nitrophenyl -6- Trifluoromethyl-1s, the nitrogen piperazine -3- Ethyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three
Prepare
With testing 1 similar method, using DDQ as oxidant, acetonitrile is solvent, 5- p-nitrophenyl -6- Trifluoromethyl-1s,
The mol ratio of the nitrogen piperazine -3- methyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and oxygen is 1:5, heat 50 DEG C and react 20 hours, close
Into 5- p-nitrophenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 68%.1H NMR(600MHz,
CDCl3)δ7.89(q,4H),4.17(s,3H)；19F NMR(565MHz,CDCl3)δ-61.22(s,3F)。
Example 12：5- phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- propyl formates of 2,4- tri-
With testing 1 similar method, using metachloroperbenzoic acid as oxidant, DMF is solvent, 5- phenyl -6- fluoroforms
The mol ratio of the nitrogen piperazine -3- propyl formates of base -1,2,5,6- tetrahydrochysenes -1,2,4- three and metachloroperbenzoic acid is 1:5, heating 50
DEG C reaction 20 hours, synthesize 5- phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- propyl formates, yield 55%.1H NMR
(600MHz,CDCl3)δ7.78-7.82(m,2H),7.41-7.50(m,3H),3.76(t,2H),1.77(m,2H),0.95(t,
3H)；19F NMR(565MHz,CDCl3)δ-61.72(s,3F)。
Example 13：5- phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- butyl formates of 2,4- tri-
With testing 1 similar method, using hydrogen peroxide as oxidant, DMSO is solvent, 5- phenyl -6- Trifluoromethyl-1s, 2,
The mol ratio of the nitrogen piperazine -3- butyl formates of 5,6- tetrahydrochysenes -1,2,4- three and hydrogen peroxide is 1:5, heat 60 DEG C and react 24 hours, close
Into 5- phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- butyl formates, yield 71%.1H NMR(600MHz,CDCl3)δ
7.68-7.73(m,2H),7.40-7.48(m,3H),3.75(t,2H),1.63-1.66(m,2H),1.40-1.44(m,2H),
0.92(t,3H)；19F NMR(565MHz,CDCl3)δ-61.32(s,3F)。
Example 14：5- phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- t-butyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- phenyl -6- Trifluoromethyl-1s, 2,
Nitrogen piperazine -3- the t-butyl formates of 5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:3, heat 50 DEG C and react 18 hours, close
Into 5- phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- t-butyl formates, yield 59%.1H NMR(600MHz,CDCl3)δ
7.66-7.71(m,2H),7.39-7.42(m,3H),1.38(s,9H)；19F NMR(565MHz,CDCl3)δ-61.72(s,3F)。
Example 15：5- phenyl -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- benzyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- phenyl -6- Trifluoromethyl-1s, 2,
Nitrogen piperazine -3- the benzyl formates of 5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:5, heat 50 DEG C and react 10 hours, synthesis
5- phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- benzyl formates, yield 71%.1H NMR(600MHz,CDCl3)δ7.40-
7.49(m,7H),7.31-7.38(d,3H),5.27(s,2H)；19F NMR(565MHz,CDCl3)δ-61.30(s,3F)。
Example 16：5- (1- naphthyls) -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- (1- naphthyls) -6- trifluoromethyls -
Nitrogen piperazine -3- the methyl formates of 1,2,5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:5, heat 50 DEG C and react 10 hours,
Synthesize 5- (1- naphthyls) -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 64%.1H NMR(400MHz,
CDCl3)δ8.05(d,1H),7.95(d,1H),7.57(dd,2H),7.49(dd,2H),7.37(d,1H),4.13(s,3H)；19F
NMR(377MHz,CDCl3)δ-62.33(s,3F)。
Example 17：5- (2- naphthyls) -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- (2- naphthyls) -6- trifluoromethyls -
Nitrogen piperazine -3- the methyl formates of 1,2,5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:4, heat 50 DEG C and react 20 hours,
Synthesize 5- (2- naphthyls) -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 66%.1H NMR(400MHz,
CDCl3)δ8.35(s,1H),7.98(dd,2H),7.88(dd,2H),7.66–7.54(m,2H),4.15(s,3H)；19F NMR
(377MHz,CDCl3)δ-61.20(s,3F)。
Example 18：5- (9- anthryls) -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, methyltetrahydrofuran is solvent, 5- (9- anthryls) -6- trifluoros
Methyl isophthalic acid, the nitrogen piperazine -3- methyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:4, heat 50 DEG C of reactions 20
Hour, synthesize 5- (9- anthryls) -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 67%.1H NMR
(600MHz,CDCl3)δ8.25(s,1H),7.86–7.97(m,4H),7.36-7.41(m,4H),3.94(s,3H)；19F NMR
(565MHz,CDCl3)δ-62.00(s,3F)。
Example 19：5- (9- phenanthryl) -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- (9- phenanthryl) -6- trifluoromethyls -
Nitrogen piperazine -3- the methyl formates of 1,2,5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:3, heat 50 DEG C and react 24 hours,
Synthesize 5- (9- phenanthryl) -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 55%.1H NMR(600MHz,
CDCl3)δ8.98(d,2H),8.17(d,2H),7.82–7.89(m,4H),7.64(s,1H),3.94(s,3H)；19F NMR
(565MHz,CDCl3)δ-62.06(s,3F)。
Example 20：5- (1- pyrenyls) -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- methyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, acetonitrile is solvent, 5- (1- pyrenyls) -6- Trifluoromethyl-1s, 2,
Nitrogen piperazine -3- the methyl formates of 5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:4, heat 50 DEG C and react 24 hours, synthesis
5- (1- pyrenyls) -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- methyl formates, yield 56%.1H NMR(600MHz,CDCl3)δ
8.10-8.19(m,2H),7.85-7.89(m,2H),7.66-7.70(m,5H),3.93(s,3H)；19F NMR(565MHz,
CDCl3)δ-61.87(s,3F)。
Example 21：5- (3,5- bis trifluoromethyls) phenyl -6- Trifluoromethyl-1s, the system of the nitrogen piperazine -3- benzyl formates of 2,4- tri-
It is standby
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- (3,5- bis trifluoromethyl) benzene
Base -6- Trifluoromethyl-1s, the nitrogen piperazine -3- benzyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:4, heating 50
DEG C reaction 24 hours, synthesize 5- (3,5- bis trifluoromethyl) phenyl -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- benzyl formates, receive
Rate 68%.1H NMR(600MHz,CDCl3)δ7.90(s,1H),7.58(s,2H),7.47–7.52(m,2H),7.35–7.39(m,
3H),5.21(s,2H)；19F NMR(565MHz,CDCl3)δ-62.89(s,6F),-61.77(s,3F)。
Example 22：5- (3,4,5- trifluorophenyls) -6- Trifluoromethyl-1s, the preparation of the nitrogen piperazine -3- Ethyl formates of 2,4- tri-
With testing 1 similar method, using DDQ as oxidant, tetrahydrofuran is solvent, 5- (3,4,5- trifluorophenyl) -6-
Trifluoromethyl-1, the nitrogen piperazine -3- Ethyl formates of 2,5,6- tetrahydrochysenes -1,2,4- three and DDQ mol ratio are 1:3, heat 50 DEG C instead
Answer 24 hours, synthesize 5- (3,4,5- trifluorophenyl) -6- Trifluoromethyl-1s, 2,4- tri- nitrogen piperazine -3- Ethyl formates, yield 60%.1H NMR(600MHz,CDCl3)δ6.75(s,2H),4.34(q,2H),1.35(t,3H)；19F NMR(565MHz,CDCl3)δ-
62.02(s,3F),-113.03–-113.38(m,3F)。
Bio-orthogonal connects chemical test
5- aryl-6s-Trifluoromethyl-1, the nitrogen piperazine -3- formic acid esters of 2,4- tri- and addition-oxygen of trans-cyclooctene class compound
Change reaction second-order kinetics speed constant to use19F-NMR is determined, and as internal standard, every group of measuring takes for 3 times 4- 5 bromine benzotrifluorides
Average value.Concrete operations are as follows：0.2mL 50mM three nitrogen piperazine acetonitriles/deuterated water (1/1) solution is added into nuclear magnetic tube, wherein
The concentration of 4- 5 bromine benzotrifluorides is 25mM, adds 0.2mL 50mM trans cyclo-octene acetonitrile/deuterated water (1/1) solution afterwards,
Finally it is settled to 0.5mL.The ultimate density of reactant is 20mM, and wherein internal standard concentration is 10mM, determines second-order kinetics speed
Constant k2(×10-2M-1s-1) as follows：
Illustrated with data in upper table, 5- aryl-6s-Trifluoromethyl-1,2,4- tri- nitrogen piperazine -3- formic acid esters and trans-cyclooctene
Antielectron demand diels-Alder cycloaddition reaction (Inverse Electron-Demand can quickly occur for class compound
Diels-Alder Cycloaddition, IED-DA), it was demonstrated that this kind of compound can be used for bio-orthogonal connection chemical test,
There is very big potential using value in terms of chemical biology and bio-imaging.
The invention is not limited in the technology described in embodiment, its description be it is illustrative, and nonrestrictive,
The authority of the present invention is defined in the claims, and can be changed according to the present invention based on those skilled in the art, recombinated etc. just
The technology related to the present invention that method obtains, all within protection scope of the present invention.
Claims (7)
1. a kind of 5- aryl-6s-Trifluoromethyl-1, the nitrogen piperazine -3- formic acid ester compounds of 2,4- tri-；Change with following chemical constitution
Compound：
Wherein Ar is aromatic group, and R is fatty alkyl and aromatic group.
2. compound as claimed in claim 1, it is characterized in that described aromatic group is phenyl, 4- aminomethyl phenyls, 4- methoxies
Base phenyl, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 4- iodophenyls, 4- cyano-phenyls, 4- nitrobenzophenones, 4- trifluoromethylbenzenes
Base, 4- methoxycarbonyl groups phenyl, 3,5- double (trifluoromethyl) phenyl, 3,4,5- trifluorophenyls, 1- naphthyls, 2- naphthyls, 9- anthracenes, 9-
Luxuriant and rich with fragrance or 1- pyrenes.
3. compound as claimed in claim 1, it is characterized in that described fatty alkyl group is methyl, ethyl, propyl group, butyl,
The tert-butyl group or benzyl.
4. 5- aryl-6s-Trifluoromethyl-1 of claim 1, the preparation method of the nitrogen piperazine -3- formic acid ester compounds of 2,4- tri-；It is special
Sign is：By 5- aryl-6s-Trifluoromethyl-1,2,5,6- tetrahydrochysenes -1,2, the nitrogen piperazine -3- formic acid esters of 4- tri- is dissolved in organic solvent, is added
After entering oxidant reaction completely, scrubbed, extraction, separation, target 5- aryl-6s-Trifluoromethyl-1,2,4- tri- nitrogen piperazine -3- are obtained
Formic acid ester compound.
5. method as claimed in claim 4, it is characterized in that described oxidant is oxygen, hydrogen peroxide, DDQ
DDQ, ammonium persulfate-sodium bisulfate Oxone, metachloroperbenzoic acid, manganese dioxide or tert-Butanol peroxide.
6. method as claimed in claim 4, it is characterized in that 5- aryl-6s-Trifluoromethyl-1,2,5,6- tetrahydrochysenes -1,2,4-
The mol ratio of three nitrogen piperazine -3- formic acid esters and oxidant is 1:1~5.
7. method as claimed in claim 4, it is characterized in that described organic solvent be tetrahydrofuran, 1- methyltetrahydrofurans,
Isosorbide-5-Nitrae-dioxane, acetonitrile, DMF or dimethyl sulfoxide.
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| US20100016545A1 (en) * | 2006-06-16 | 2010-01-21 | Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts | Process for the covalent coupling of two molecules by means of a diels-alder reaction with inverse electron requirement |
| WO2010147430A2 (en) * | 2009-06-19 | 2010-12-23 | Green Cross Corporation | Novel c-aryl glucoside sglt2 inhibitors and pharmaceutical composition comprising same |
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| US20100016545A1 (en) * | 2006-06-16 | 2010-01-21 | Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts | Process for the covalent coupling of two molecules by means of a diels-alder reaction with inverse electron requirement |
| WO2010147430A2 (en) * | 2009-06-19 | 2010-12-23 | Green Cross Corporation | Novel c-aryl glucoside sglt2 inhibitors and pharmaceutical composition comprising same |
Non-Patent Citations (4)
| Title |
|---|
| DAVID N. KAMBER ET AL.: "1,2,4-Triazines Are Versatile Bioorthogonal Reagents", 《J.AM.CHEM.SOC.》 * |
| KATHERINE A. HORNER ET AL.: "Strain-Promoted Reaction of 1,2,4-Triazines with Bicyclononynes", 《CHEM. EUR. J.》 * |
| SEBASTIAN J. SIEGL ET AL.: "The discovery of pyridinium 1,2,4-triazines with enhanced performance in bioconjugation reactions", 《CHEMICAL SCIENCE》 * |
| ZHEN CHEN ET AL.: "Silver-Catalyzed [3 + 3] Dipolar Cycloaddition of Trifluorodiazoethane and Glycine Imines: Access to Highly Functionalized Trifluoromethyl-Substituted Triazines and Pyridines", 《ACS CATALYSIS》 * |
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