CN107827834B - 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound and preparation method thereof - Google Patents
5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound and a preparation method thereof. Dissolving 5-aryl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-formate in an organic solvent, adding an oxidant to react completely, washing, extracting and separating to obtain the target 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound. The obtained target compound is a trifluoromethyl-containing 1,2, 4-triazine heterocyclic structure, is used as an electron-deficient aromatic heterocycle, can perform a reverse electron-requiring Diels-Alder cycloaddition reaction with electron-rich olefin, and is used for bioorthogonal linkage chemistry; the 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound can be used as a medicine or a core structural unit for medicine synthesis and is used for medicine activity screening.
Description
Technical Field
The invention provides a trifluoromethyl-containing 1,2, 4-triazazine compound and a preparation method thereof, and particularly discloses a 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound and a preparation method thereof.
Background
The development of a marking method for visualizing biomolecules in cells in real time is of great significance for understanding the molecular basis of life. Bioorthogonal ligation chemistry (bioorthogonal ligation) is increasingly becoming an effective method for specifically labeling biomacromolecules as well as small active molecules in vivo. Labeling based on bioorthogonal reaction requires introducing a specific chemical reading group (chemical reporter) into a target molecule, and then reacting with a probe containing a complementary group through bioorthogonal reaction, thereby realizing specific labeling of the target molecule. However, this method is very challenging because it requires the corresponding chemical reactions to be very active and selective under physiological conditions, and to keep good inertness to other surrounding active molecules (k.liang, j.w.chi, chem.rev.2014,114, 4764-4806 and p.shieh, c.r.bertozzi, org.biomol.chem.2014,12, 9307-.
More recently U.S. j.a. prescher, uk m.e.webb and czech m.vrabel attempted to develop new bioorthogonal reactions using the Inverse Electron-demanding Diels-Alder Cycloaddition reaction of 1,2, 4-triazazine with trans-cyclooctenes (Inverse Electron-Demand Diels-Alder Cycloaddition, IED-DA) (j.a. prescher, et al., j.am.chem.soc.2015,137,8388-8391& m.e.webb, et al., chem.eur.j.2015,21, 14376. f. v. 14381& m.vrabel, et al., chem.sci.2017,8, 3593. 3598). However, these 1,2, 4-triazazines are either electron rich or have biaryl substituents attached to the 3, 6-positions of the ring, resulting in slow rates of cycloaddition at room temperature and lack of utility in bio-orthogonal chemical ligation assays. There is therefore an urgent need to design and synthesize novel 1,2, 4-triazains for bioorthogonal ligation chemistry.
The invention provides a 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound and a preparation method thereof. The 1,2, 4-triazazine compounds contain formate and trifluoromethyl with strong electron at 3, 6-position, and the space volume of these substituent groups is smaller than that of aryl, so that 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate and trans-cyclooctenol compounds can react quickly at room temperature, and these compounds can be used in bioorthogonal linkage chemistry.
Disclosure of Invention
The object of the present invention is to provide a novel 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate compound, wherein Ar is an aromatic group, R is an aliphatic alkyl group and an aromatic group:
the aromatic group is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 3, 5-bis (trifluoromethyl) phenyl, 3,4, 5-trifluorophenyl, 1-naphthyl, 2-naphthyl, 9-anthracene, 9-phenanthrene or 1-pyrene, etc.
The aliphatic alkyl group is methyl, ethyl, propyl, butyl, tertiary butyl or benzyl and the like.
In another aspect, the present invention provides a method for preparing a 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate compound, comprising the steps of:
dissolving 5-aryl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-formate in an organic solvent, adding an oxidant to react completely, washing, extracting and separating to obtain the target 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound.
The oxidant is oxygen, hydrogen peroxide, dichloro dicyano benzoquinone, Oxone, m-chloroperoxybenzoic acid, manganese dioxide or tert-butyl peroxy alcohol.
The molar ratio of the 5-aryl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-formate to the oxidant is 1: 1-5.
The organic solvent is tetrahydrofuran, 1-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide DMF or dimethyl sulfoxide DMSO.
The invention provides a novel 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound and a preparation method thereof, wherein the obtained target compound is a trifluoromethyl-containing 1,2, 4-triazazine heterocyclic ring structure which is used as an electron-deficient aromatic heterocyclic ring and can perform a reverse electron demand Diels-Alder cycloaddition reaction with electron-rich olefin for bioorthogonal linkage chemistry; the 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound can be used as a medicine or a core structural unit for medicine synthesis and is used for medicine activity screening.
Detailed Description
The following examples are included to aid in a further understanding of the invention, but are not intended to limit the invention thereto.
Example 1: preparation of 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
5-phenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylic acid methyl ester (115mg,0.4mmol) and DDQ (363mg,1.6mmol) were added to a dry 15mL Schlenk reaction flask, 4mL of tetrahydrofuran was added to the system, and the reaction was stirred at 50 ℃ for 20 hours. After TLC detection reaction is completed, removing the solvent by decompression; then 10mL ethyl acetate and 5mL saturated sodium bicarbonate solution were added to the system, the layers were separated, the aqueous layer was extracted with ethyl acetate (10mL x 2), the organic layers were combined and washed twice with water (10mL), anhydrous MgSO4Drying, column chromatography (eluent: petroleum ether/ethyl acetate 20/1to 10/1) to obtain the target product 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate 94mg, 83% yield.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: preparation of 5-p-methylphenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
Similar to the experiment 1, the method comprises the steps of using oxygen as an oxidant, using 1-methyltetrahydrofuran as a solvent, using 5-p-methylphenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate and oxygen in a molar ratio of 1:5, and reacting at 70 ℃ in a sealed environment for 24 hours to synthesize 5-p-methylphenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate with a yield of 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: preparation of 5-p-methoxyphenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
Similar to the experiment 1, hydrogen peroxide is used as an oxidant, 1, 4-dioxane is used as a solvent, the molar ratio of 5-p-methoxyphenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:4, and the mixture is heated to 60 ℃ for reaction for 12 hours to synthesize 5-p-methoxyphenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate with the yield of 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: preparation of methyl 5-p-fluorophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate
Similar to the method of experiment 1, m-chloroperoxybenzoic acid is used as an oxidant, acetonitrile is used as a solvent, the molar ratio of 5-p-fluorophenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:3, the mixture is heated to 80 ℃ to react for 8 hours, and 5-p-fluorophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate is synthesized, and the yield is 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: preparation of 5-p-chlorophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
Similar to experiment 1, the molar ratio of 5-p-chlorophenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylic acid methyl ester to oxygen was 1:2 using t-butanol peroxide as oxidant and DMF as solventHeating to 60 ℃ for reaction for 8 hours to synthesize the 5-p-chlorophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate with the yield of 80 percent.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: preparation of 5-p-bromophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
Similar to the experiment 1, manganese dioxide is used as an oxidant, DMSO is used as a solvent, the molar ratio of 5-p-bromophenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:4, and the mixture is heated to 60 ℃ for reaction for 24 hours to synthesize 5-p-bromophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate, wherein the yield is 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: preparation of 5-p-iodophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
Similar to experiment 1, DDQ is used as an oxidant, 1-methyltetrahydrofuran is used as a solvent, the molar ratio of 5-p-iodophenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:3, and the mixture is heated to 50 ℃ for reaction for 24 hours to synthesize 5-p-iodophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate with the yield of 82%.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: preparation of methyl 5-p-trifluoromethylphenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate
Similar to the method of experiment 1, potassium hydrogen persulfate complex salt Oxone is used as an oxidant, acetonitrile is used as a solvent, the molar ratio of 5-p-trifluoromethylphenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:3, and the reaction is carried out for 20 hours by heating at 70 ℃ to synthesize 5-p-trifluoromethylphenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate, wherein the yield is 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: preparation of methyl 5-p-cyanophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate
In a similar way to experiment 1, DDQ is used as an oxidant, tetrahydrofuran is used as a solvent, the molar ratio of 5-p-cyanophenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:2, and the mixture is heated to 50 ℃ to react for 12 hours to synthesize the 5-p-cyanophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate with the yield of 77%.1H NMR(600MHz,CDCl3)δ7.88(q,4H),4.15(s,3H)；19F NMR(565MHz,CDCl3)δ-61.14(s,3F)。
Example 10: preparation of 5- (4-methoxycarbonyl) phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
Similar to the experiment 1, DDQ is used as an oxidant, tetrahydrofuran is used as a solvent, the molar ratio of 5- (4-methoxycarbonyl) phenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:3, the mixture is heated to 50 ℃ for reaction for 16 hours, and the 5- (4-methoxycarbonyl) phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate is synthesizedEster, 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: preparation of ethyl 5-p-nitrophenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylate
Similar to the experiment 1, DDQ is used as an oxidant, acetonitrile is used as a solvent, the molar ratio of 5-p-nitrophenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to oxygen is 1:5, and the mixture is heated to 50 ℃ to react for 20 hours to synthesize 5-p-nitrophenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate, wherein the yield is 68%.1H NMR(600MHz,CDCl3)δ7.89(q,4H),4.17(s,3H)；19F NMR(565MHz,CDCl3)δ-61.22(s,3F)。
Example 12: preparation of propyl 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate
Similar to experiment 1, m-chloroperoxybenzoic acid was used as an oxidant, DMF was used as a solvent, the molar ratio of 5-phenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylic acid propyl ester to m-chloroperoxybenzoic acid was 1:5, and 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid propyl ester was synthesized with a yield of 55% by heating at 50 ℃ for 20 hours.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: preparation of 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid butyl ester
Similar to the experiment 1, the method comprises the steps of taking hydrogen peroxide as an oxidant, taking DMSO as a solvent, reacting 5-phenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-butyl formate with hydrogen peroxide in a molar ratio of 1:5 at 60 ℃ for 24 hours to synthesize 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-butyl formate with a yield of 71%.1H NMR(600MHz,CDCl3)δ7.68-7.73(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: preparation of 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid tert-butyl ester
Similar to experiment 1, DDQ is used as an oxidant, tetrahydrofuran is used as a solvent, the molar ratio of 5-phenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylic acid tert-butyl ester to DDQ is 1:3, and the mixture is heated to 50 ℃ for reaction for 18 hours to synthesize the 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid tert-butyl ester with the yield of 59%.1H NMR(600MHz,CDCl3)δ7.66-7.71(m,2H),7.39-7.42(m,3H),1.38(s,9H)；19F NMR(565MHz,CDCl3)δ-61.72(s,3F)。
Example 15: preparation of benzyl 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate
In a similar way to experiment 1, DDQ is used as an oxidant, tetrahydrofuran is used as a solvent, the molar ratio of 5-phenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-benzyl formate to DDQ is 1:5, and the mixture is heated to 50 ℃ for reaction for 10 hours to synthesize 5-phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-benzyl formate with the yield of 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: preparation of 5- (1-naphthyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
In a similar manner to experiment 1, DDQ is used as an oxidant, tetrahydrofuran is used as a solvent, the molar ratio of 5- (1-naphthyl) -6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to DDQ is 1:5, and the mixture is heated to 50 ℃ for reaction for 10 hours to synthesize 5- (1-naphthyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate, wherein the yield is 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: preparation of 5- (2-naphthyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
In a similar manner to experiment 1, DDQ is used as an oxidant, tetrahydrofuran is used as a solvent, the molar ratio of 5- (2-naphthyl) -6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to DDQ is 1:4, and the mixture is heated to 50 ℃ for reaction for 20 hours to synthesize 5- (2-naphthyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate with the yield of 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: preparation of 5- (9-anthracenyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
Similar to experiment 1, DDQ was used as an oxidizing agent, methyltetrahydrofuranThe pyran is used as a solvent, the molar ratio of the 5- (9-anthryl) -6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to the DDQ is 1:4, the mixture is heated to 50 ℃ to react for 20 hours, and the 5- (9-anthryl) -6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate is synthesized, and the yield is 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: preparation of 5- (9-phenanthryl) -6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester
In a similar way to experiment 1, DDQ is used as an oxidant, tetrahydrofuran is used as a solvent, the molar ratio of 5- (9-phenanthryl) -6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-methyl formate to DDQ is 1:3, and the mixture is heated to 50 ℃ for 24 hours to synthesize 5- (9-phenanthryl) -6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate with the yield of 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: preparation of 5- (1-pyrenyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-methyl formate
In a similar manner to experiment 1, DDQ was used as an oxidant, acetonitrile was used as a solvent, the molar ratio of 5- (1-pyrenyl) -6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylic acid methyl ester to DDQ was 1:4, and 5- (1-pyrenyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid methyl ester was synthesized with a yield of 56% by heating at 50 ℃ for 24 hours.1H NMR(600MHz,CDCl3)δ8.10-8.19(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: preparation of benzyl 5- (3, 5-bis-trifluoromethyl) phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate
In a similar manner to experiment 1, DDQ was used as an oxidant, tetrahydrofuran was used as a solvent, the molar ratio of 5- (3, 5-bis (trifluoromethyl) phenyl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylic acid benzyl ester to DDQ was 1:4, and 5- (3, 5-bis (trifluoromethyl) phenyl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylic acid benzyl ester was synthesized with a yield of 68% by heating at 50 ℃ for 24 hours.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: preparation of ethyl 5- (3,4, 5-trifluorophenyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate
In a similar manner to experiment 1, DDQ was used as an oxidizing agent, tetrahydrofuran was used as a solvent, the molar ratio of ethyl 5- (3,4, 5-trifluorophenyl) -6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-carboxylate to DDQ was 1:3, and the mixture was heated to 50 ℃ for 24 hours to synthesize ethyl 5- (3,4, 5-trifluorophenyl) -6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate with a yield of 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)。
Bioorthogonal ligation chemistry assay
The second-order kinetic rate constants of the addition-oxidation reaction of the 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate and the trans-cyclooctenes are all used19F-NMR measurements with 4-bromotrifluorotoluene as internal standard, 3 determinations per set of experiments were averaged. The specific operation is as follows: to the nuclear magnetic tube was added 0.2mL of a 50mM solution of triazazine acetonitrile/deuterated water (1/1),wherein the concentration of the 4-bromotrifluorotoluene is 25mM, then 0.2mL of 50mM trans-cyclooctene acetonitrile/deuterated water (1/1) solution is added, and finally the volume is made to be 0.5 mL. The final concentration of the reaction was 20mM with an internal standard concentration of 10mM, and the second order kinetic rate constant k was determined2(×10-2M-1s-1) The following were used:
the data in the table show that the 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate and the trans-cyclooctene compound can rapidly generate Inverse Electron Demand Diels-Alder Cycloaddition reaction (IED-DA), and the compound is proved to be used for bioorthogonal ligation chemical tests and has very large potential application value in the aspects of chemistry and biological imaging.
The present invention is not limited to the techniques described in the embodiments, which are described for illustrative purposes and not restrictive purposes, and the rights of the present invention are defined by the claims, and the technical matters related to the present invention, which are obtained by the methods of the present invention, such as changes, rearrangements, etc., may be made by those skilled in the art within the scope of the present invention.
Claims (2)
1. A 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate compound; a compound having the chemical structure:
wherein Ar is an aromatic group, and R is methyl, ethyl, propyl, butyl, tert-butyl or benzyl;
the aromatic group is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-methoxycarbonylphenyl, 3, 5-bis (trifluoromethyl) phenyl, 3,4, 5-trifluorophenyl, 1-naphthyl, 2-naphthyl, 9-anthracene, 9-phenanthrene or 1-pyrene.
2. A process for producing a 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-carboxylate compound according to claim 1; the method is characterized in that: dissolving 5-aryl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-formate in an organic solvent, adding an oxidant to react completely, washing, extracting and separating to obtain a target 5-aryl-6-trifluoromethyl-1, 2, 4-triazazine-3-formate compound;
the oxidant is oxygen, hydrogen peroxide, dichlorodicyano benzoquinone DDQ, Oxone, m-chloroperoxybenzoic acid, manganese dioxide or tert-butyl peroxy; the molar ratio of the 5-aryl-6-trifluoromethyl-1, 2,5, 6-tetrahydro-1, 2, 4-triazazine-3-formate to the oxidant is 1: 1-5; the organic solvent is tetrahydrofuran, 1-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide 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 |
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| Silver-Catalyzed [3 + 3] Dipolar Cycloaddition of Trifluorodiazoethane and Glycine Imines: Access to Highly Functionalized Trifluoromethyl-Substituted Triazines and Pyridines;Zhen Chen et al.;《ACS Catalysis》;20190412;第9卷;4600-4608 * |
| Strain-Promoted Reaction of 1,2,4-Triazines with Bicyclononynes;Katherine A. Horner et al.;《Chem. Eur. J.》;20150813;第21卷;14376-14381 * |
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