CN110256448A - A kind of 1,3,5- triazine -2- ketone spiro indole ketone compounds and preparation method - Google Patents
A kind of 1,3,5- triazine -2- ketone spiro indole ketone compounds and preparation method Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
A kind of 1,3,5-triazines -2- ketone spiro indole ketone compounds and preparation method, belong to the preparation technical field of compound.Specific experiment method are as follows: weigh N, the isatin -3- imines that the urea and trifluoroethyl that N '-dialkoxy replaces replace is dissolved in DME, and the TFP solution dissolved with NaH is added at 0 DEG C.Then oxidant is weighed, after being dissolved in DME, then is added dropwise to reaction system, at 0 DEG C under room temperature, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines that trifluoroethyl replaces completely consumes；It is concentrated under reduced pressure, 1,3,5-triazines -2- ketone spiro indole ketone compounds can be obtained by column chromatography in crude product.The synthetic method non-enantiomer selectivity reaches outstanding, is a kind of method that completely new efficient succinct synthesis has the active 1,3,5-triazines -2- ketone spiro indole ketone compounds of potential source biomolecule more than chemical yield is medium.
Description
Technical field
Present invention relates particularly to a kind of preparation methods of novel 1,3,5-triazines -2- ketone spiro indole ketone compounds, belong to
In the preparation technical field of compound.
Background technique
Spiro indole ketone compounds have unique space structure and chemical structure, have extensive bioactivity, such as
Antitumor, treatment diabetes, antibacterial, treating tuberculosis etc. have important application value in field of pharmaceutical chemistry research.Currently, closing
Still there is biggish development at the method for building structure diversity and the spiro indole ketone compounds of complexity and strategy
Space.Therefore, design and the mild methodology of organic synthesis easy to operate of Development of Novel, efficient, environmental-friendly, reaction condition, stand
Body selectively constructs the spiro indole ketone compounds containing all kinds of different spiroheterocyclic skeleton structures, is not only greatly enriched spiral shell
The research of ring indole ketone compound methodology of organic synthesis, and for developing and developing spiro indole ketone drug candidate tool
It is of great significance.
The urea that N, N '-dialkoxy replace is a kind of important building block, is mainly used for building structure and contains urea structure
All kinds of heterocyclic systems of unit.In general, the urea that N, N '-dialkoxy replace is oxidized under the synergistic effect of alkali and oxidant
At diaza allyl cation, this generated in-situ diaza allyl cation can be used as ternary synthon and participate in difference
Cycloaddition reaction.Up to now, the document report about N, the urea that N '-dialkoxy the replaces cycloaddition reaction participated in
Also seldom, there is very big development space.The indigo that the present invention is replaced with N, N '-dialkoxy the oxygroup urea replaced and trifluoroethyl
Red -3- imines is as reaction building block, under the existence condition of alkali and oxidant, by constructing novel and efficiently succinct [3+3]
Cycloaddition reaction realizes the stereoselective syntheses of novel 1,3,5-triazines -2- ketone spiro indole ketone compounds for the first time.
Class spiro indole ketone compounds have indolone skeleton structure, and have spirane structure, and indolone structure itself has very
The skeleton (prior art has this many substance) of strong pharmaceutical activity, along with spirane structure activity can generally enhance, such spiral shell
The advantageous drug matrices structure of ring indole ketone compound, quasi-medicated property is extremely strong, has potential medical value and biology living
Property.
Summary of the invention
It is an object of that present invention to provide a kind of 1,3,5- triazine -2- ketone spiro indole ketone compounds and preparation methods.
To achieve the above object of the invention, the technical solution adopted by the present invention is that:
A kind of structural formula of 1,3,5- triazine -2- ketone spiro indole ketone compounds are as follows:
Wherein, R1For benzyl, the fluoro- benzyl of 4-, the chloro- benzyl of 4-, the bromo- benzyl of 4-, 4- Nitro-benzyl, 4- Methyl-benzvl,
4- methyoxy-benzyl, phenyl, vinyl, methyl, ethyl etc.；R2For fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxyl group, amino,
Acetylamino, nitro etc.；R3For methyl, benzyl, phenyl, allyl, tertbutyloxycarbonyl, methoxy etc..
The preparation method of above-mentioned 1,3,5-triazines -2- ketone spiro indole ketone compounds, the preparation method is that: 0 DEG C -
At room temperature, alkali is added for building block in the isatin -3- imines replaced with N, N '-the dialkoxy urea replaced and trifluoroethyl
Additive and oxidant obtain product 1,3,5-triazines -2- ketone spiro indole ketone compounds in aprotic organic solvent.
It is preferred that the molar ratio for the isatin -3- imines that urea and trifluoroethyl that the N, N '-dialkoxy replace replace is 1:2.
In above-mentioned technical proposal, the alkali additive is selected from: sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide, the tert-butyl alcohol
Potassium, lithium diisopropylamine (LDA), bis- (trimethyl silicon substrate) Sodamides (NaHMDS), diazabicylo (DBU), 1,5- phenodiazine
One of miscellaneous bicyclic [4.3.0] nonyl- 5- alkene (DBN), four fluoro- 1- sodium propoxides (NaTFP), sodium hydride etc. or two kinds.
In above-mentioned technical proposal, the oxidant is selected from: iodobenzene diacetate, [bis- (trifluoroacetyl oxygroup) iodine] benzene, 2- iodine
Acyl group benzoic acid, hydroxy-methylbenzene sulphonyl iodobenzene, bis- (tert-butyl carbonyl oxygen) iodobenzenes etc..
In above-mentioned technical proposal, the reaction time is 2~16 hours.
In above-mentioned technical proposal, the dosage of the alkali additive is N, the carbamide compound molal quantity that N '-dialkoxy replaces
Three times, the dosage of the oxidant is N, twice of the carbamide compound molal quantity that N '-dialkoxy replaces.
In above-mentioned technical proposal, reaction process includes: to weigh N, what the urea and trifluoroethyl that N '-dialkoxy replaces replaced
Isatin -3- imines is dissolved in organic solvent 1, is slowly added to (be initiated with 60% dissolved with NaH and be dispersed in kerosene at 0 DEG C
In) organic solvent 2 solution；Then weigh appropriate oxidant, after being dissolved in organic solvent 3, then by its in one minute slowly
It is added dropwise to reaction system, at 0 DEG C under room temperature, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until trifluoro
Isatin -3- the imines that ethyl replaces completely consumes.Finally, reaction mixture is concentrated under reduced pressure, crude product passes through simple column
Target product 1,3,5- triazine -2- ketone spiro indole ketone compounds can be obtained in chromatography.
Organic solvent 1 described above, organic solvent 2, organic solvent 3 are selected from methylene chloride, chloroform, 1,2- bis-
Chloroethanes, toluene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, n,N-Dimethylformamide, benzotrifluoride, 1,3,5- trifluoro-benzenes,
One of glycol dimethyl ether (DME), methyl tertiary butyl ether(MTBE), the fluoro- 1- propyl alcohol (TFP) of 2,2,3,3- tetra- and hexafluoroisopropanol etc.
Or two kinds.
In the present invention, the preparation method for the carbamide compound that N, N '-dialkoxy replace belongs to the prior art, and structural formula is such as
Shown in lower:R1For benzyl, the fluoro- benzyl of 4-, the chloro- benzyl of 4-, the bromo- benzyl of 4-, 4- Nitro-benzyl, 4- methyl-benzyl
Base, 4- methyoxy-benzyl, phenyl, vinyl, methyl, ethyl etc.；
In the present invention, the preparation method for the isatin -3- group with imine moiety that trifluoroethyl replaces belongs to the prior art, structure
Formula is as follows:R2For fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxyl group, amino, acetylamino, nitro
Deng；
R3For methyl, benzyl, phenyl, allyl, tertbutyloxycarbonyl, methoxy etc.；
Shown in one kind of reaction process disclosed by the invention is expressed as follows:
The petrol ether/ethyl acetate mixed solution of volume ratio 4:1~6:1 is selected as in column chromatographic elution agent.
Due to the above technical solutions, the present invention has the following advantages over the prior art:
1. the present invention provides the isatin-replaced with N, N '-the dialkoxy carbamide compound replaced and trifluoroethyl for the first time
3- group with imine moiety is building block, under the action of alkali and oxidant, prepares a kind of novel 1,3,5-triazines -2- ketone loop coil
The method of indole ketone compound；The synthetic method have efficiently succinct, easy to operate, reaction condition is mild, chemical yield compared with
The advantages that high and non-enantiomer selectivity is outstanding.
2. being isolated and purified simple using alkali as additive in preparation method disclosed in this invention.
3. the method disclosed in the present substrate universality is good, more than chemical yield is medium.
4. starting material according to the present invention is easy preparation, at low cost, pollution-free.
5, the advantageous drug matrices structure of class spiro indole ketone compounds of the present invention, quasi-medicated property is extremely strong, has latent
Medical value and bioactivity.
Specific embodiment
The present invention will be further described below with reference to examples, but the present invention is not limited to following embodiments.
Embodiment 1:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2a (48.4mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2a that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3aa (33.3mg), yield 65% can be obtained.
The characterization and analysis of object: white solid；M.P.=176.2-177.0 DEG C；1H NMR(400MHz,CDCl3):δ
7.56-7.49 (m, 3H), 7.42-7.35 (m, 4H), 7.26-7.22 (m, 1H), 7.21-7.16 (m, 3H), 6.93 (d, J=
8.0Hz, 1H), 6.84 (d, J=6.8Hz, 2H), 5.62-5.56 (m, 1H), 5.34 (d, J=8.8Hz, 1H), 5.03-4.97
(m, 2H), 4.49 (d, J=9.6Hz, 1H), 3.18 (s, 3H), 3.14 (d, J=12.4Hz, 1H) ppm；13C NMR(100MHz,
CDCl3):δ171.4,161.9,144.4,134.9,134.5,131.7,129.7,129.4,128.7,128.5,128.4,
128.2,124.4,123.5,123.1,122.5(q,JC,F=280.0Hz), 109.4,78.8,77.9,75.7,68.3 (q, JC,F
=32.0Hz), 26.4ppm；HRMS(ESI)m/z:C26H23F3N4O4[M+H]+Calculated value: 513.1744, measured value:
513.1730.
Embodiment 2:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2b (64.0mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2b that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3ab (47.2mg), yield 80% can be obtained.
The characterization and analysis of object: white solid；M.P.=205.9-207.0 DEG C；1H NMR(400MHz,CDCl3):δ
7.60-7.54(m,3H),7.43-7.38(m,4H),7.30-7.28(m,1H),7.25-7.21(m,2H),6.95-6.93(m,
2H), 6.78 (d, J=8.4Hz, 1H), 5.58-5.53 (m, 1H), 5.33 (d, J=8.8Hz, 1H), 5.02 (d, J=10.0Hz,
1H), 4.99 (d, J=8.8Hz, 1H), 4.59 (d, J=10Hz, 1H), 3.14 (s, 3H), 3.12 (d, J=12.4Hz, 1H)
ppm；13C NMR(100MHz,CDCl3):δ170.8,161.7,143.4,134.7,134.4,129.7,129.4,128.8,
128.7,128.4,128.3,127.9,126.4,126.2,122.3(q,JC,F=280Hz), 115.9,110.8,78.8,
78.0,75.5,68.2(q,JC,F=32.0Hz), 26.6ppm；HRMS(ESI)m/z:C26H22BrF3N4O4[M+H]+Theoretical calculation
Value: 591.0849, measured value: 591.0846.
Embodiment 3:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2c (55.2mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2c that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3ac (37.1mg), yield 68% can be obtained.
The characterization and analysis of object: white solid；M.P.=185.9-187.2 DEG C；1H NMR(400MHz,CDCl3):δ
7.56-7.54(m,2H),7.45-7.37(m,4H),7.31-7.27(m,1H),7.24-7.21(m,3H),6.94-6.92(m,
2H), 6.83 (d, J=8.0Hz, 1H), 5.57-5.53 (m, 1H), 5.33 (d, J=8.8Hz, 1H), 5.03-5.98 (m, 2H),
4.59 (d, J=10Hz, 1H), 3.16 (s, 3H), 3.10 (d, J=12.0Hz, 1H) ppm；13C NMR(100MHz,CDCl3):δ
170.88,161.79,142.90,134.67,134.42,131.46,129.65,129.38,128.81,128.77,128.70,
128.43,128.24,126.00,123.50,122.31(q,JC,F=280.0Hz), 110.29,78.72,77.93,75.50,
68.16(q,JC,F=32.0Hz), 26.61ppm；HRMS(ESI)m/z:C26H22ClF3N4O4[M+H]+Calculated value:
547.1354 measured value: 547.1352.
Embodiment 4:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2d (52.2mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2d that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3ad (29.1mg), yield 55% can be obtained.
The characterization and analysis of object: white solid；M.P.=164.7-166.0 DEG C；1H NMR(400MHz,CDCl3):δ
7.56-7.53(m,2H),7.43-7.37(m,3H),7.30-7.26(m,1H),7.23-7.20(m,2H),7.19-7.14(m,
1H), 6.97 (dd, J=7.2,2.4Hz, 1H), 6.94-6.91 (m, 2H), 6.84 (dd, J=8.4,4.0Hz, 1H), 5.58-
5.52 (m, 1H), 5.32 (d, J=8.8Hz, 1H), 5.00 (d, J=7.2Hz, 1H), 4.98 (d, J=6.0Hz, 1H), 4.59
(d, J=10.0Hz, 1H), 3.18 (s, 3H), 3.06 (d, J=12.0Hz, 1H) ppm；13C NMR(100MHz,CDCl3):δ
171.1,161.8,159.2(d,JC,F=242.0Hz), 140.3 (d, JC,F=3.0Hz), 134.7,134.5,129.6,
129.4,128.7(d,JC,F=2.0Hz), 128.4,128.2,125.8 (d, JC,F=8.0Hz), 122.3 (q, JC,F=
280.0Hz),117.8(d,JC,F=23.0Hz), 111.4 (d, JC,F=24.0Hz), 110.0,109.9,78.6,77.9,
75.6,68.2(q,JC,F=32.0Hz), 26.7ppm；HRMS(ESI)m/z:C26H22F4N4O4[M+H]+Calculated value:
531.1650 measured value: 531.1639.
Embodiment 5:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2e (51.2mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2e that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3ae (34.7mg), yield 66% can be obtained.
The characterization and analysis of object: white solid；M.P.=187.6-188.4 DEG C；1H NMR(400MHz,CDCl3):δ
7.57-7.54(m,2H),7.42-7.36(m,3H),7.30-7.23(m,2H),7.21-7.16(m,3H),6.87-6.84(m,
2H), 6.82 (d, J=8.0Hz, 1H), 5.63-5.59 (m, 1H), 5.34 (d, J=8.8Hz, 1H), 5.02 (d, J=5.6Hz,
1H), 4.99 (d, J=4.4Hz, 1H), 4.54 (d, J=9.6Hz, 1H), 3.15-3.12 (m, 4H), 2.39 (s, 3H) ppm；13C
NMR(100MHz,CDCl3):δ171.3,161.9,142.1,134.9,134.6,133.1,131.8,129.6,129.3,
128.6,128.5,128.4 128.1,124.5,123.6,122.4(q,JC,F=280.0Hz), 109.1,78.7,77.8,
75.7,68.2(q,JC,F=32.0Hz), 26.5,21.1ppm；HRMS(ESI)m/z:C27H25F3N4O4[M+H]+Calculated value:
527.1901 measured value: 527.1888.
Embodiment 6:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2f (54.4mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2f that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3af (28.1mg), yield 52% can be obtained.
The characterization and analysis of object: white solid；M.P.=189.1-190.2 DEG C；1H NMR(400MHz,CDCl3):δ
7.54-7.42(m,2H),7.42-7.35(m,3H),7.27-7.17(m,3H),7.01-6.98(m,2H),6.89-6.87(m,
2H), 6.84 (d, J=9.2Hz, 1H), 5.63-5.57 (m, 1H), 5.33 (d, J=8.8Hz, 1H), 5.03 (d, J=9.6Hz,
1H), 4.99 (d, J=8.8Hz, 1H), 4.55 (d, J=9.6Hz, 1H), 3.84 (s, 3H), 3.15-3.12 (m, 4H) ppm；13C
NMR(100MHz,CDCl3):δ171.1,161.9,156.6,137.7,134.8,134.6,129.6,129.2,128.6,
128.4,128.3,128.1,125.6,121.4(q,JC,F=280.0Hz), 115.7,110.5,109.9,78.7,77.8,
75.8,68.3(q,JC,F=32.0Hz), 56.0,26.6ppm；HRMS(ESI)m/z:C27H25F3N4O5[M+H]+Calculated value:
543.1850 measured value: 543.1846.
Embodiment 7:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2g (53.6mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2g that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3ag (41.9mg), yield 78% can be obtained.
The characterization and analysis of object: colorless and transparent semisolid；1H NMR(400MHz,CDCl3):δ7.56-7.54(m,
2H), 7.51-7.46 (m, 2H), 7.40-7.38 (m, 3H), 7.25-7.14 (m, 4H), 6.90 (d, J=7.6Hz, 1H), 6.79-
6.77 (m, 2H), 5.68-5.60 (m, 2H), 5.33 (d, J=8.0Hz, 1H), 5.05 (d, J=9.2Hz, 1H), 5.01-4.95
(m, 3H), 4.58-4.40 (m, 2H), 4.17-4.11 (m, 1H), 3.16 (d, J=12.0Hz, 1H) ppm；13C NMR(100MHz,
CDCl3):δ171.2,161.9,143.7,134.8,134.3,131.5,129.7,129.6,129.4,128.6,128.5,
128.4,128.1,124.6,123.3,122.9,122.4(q,JC,F=280.0Hz), 117.7,110.4,78.9,77.8,
75.6,68.2(q,JC,F=32.0Hz), 42.3ppm；HRMS(ESI)m/z:C28H25F3N4O4[M+H]+Calculated value:
539.1901 measured value: 539.1896.
Embodiment 8:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2h (69.2mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2h that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3ah (49.7mg), yield 81% can be obtained.
The characterization and analysis of object: white solid；M.P.=56.4-57.5 DEG C；1H NMR(400MHz,CDCl3):δ
7.58-7.54 (m, 3H), 7.49 (d, J=1.6Hz, 1H), 7.41-7.38 (m, 3H), 7.30-7.27 (m, 1H), 7.23-7.19
(m, 2H), 6.89 (d, J=7.2Hz, 2H), 6.75 (d, J=8.4Hz, 1H), 5.67-5.54 (m, 2H), 5.32 (d, J=
8.8Hz, 1H), 5.07 (d, J=9.6Hz, 1H), 5.01-4.97 (m, 3H), 4.54 (d, J=9.6Hz, 1H), 4.44-4.38
(m, 1H), 4.11 (dd, J=16.8,5.2Hz, 1H), 3.15 (d, J=12.0Hz, 1H) ppm；13C NMR(100MHz,
CDCl3):δ170.7,161.8,142.6,134.7,134.3,134.2,129.6,129.4,129.2,128.8,128.7,
128.4,128.2,126.5,126.3,122.3(q,JC,F=280.0Hz), 118.0,115.8,111.9,79.0,78.0,
75.5,68.2(q,JC,F=32.0Hz), 42.4ppm；HRMS(ESI)m/z:C28H24BrF3N4O4[M+H]+Calculated value:
617.1006 measured value: 617.0992.
Embodiment 9:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2i (54.4mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2i that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3ai (36.3mg), yield 67% can be obtained.
The characterization and analysis of object: white solid；M.P.=141.0-142.3 DEG C；1H NMR(400MHz,CDCl3):δ
7.56-7.42(m,4H),7.41-7.37(m,3H),7.29-7.22(m,2H),7.18-7.14(m,3H),6.77-6.75(m,
2H), 5.60-5.55 (m, 1H), 5.34 (d, J=8.8Hz, 1H), 5.14 (d, J=11.2Hz, 1H), 5.06 (d, J=8.8Hz,
1H), 5.02 (d, J=11.2Hz, 1H), 4.99 (d, J=8.8Hz, 1H), 4.42 (d, J=8.8Hz, 1H), 3.21 (d, J=
12.0Hz,1H),2.93(s,3H)ppm；13C NMR(100MHz,CDCl3):δ172.0,161.9,142.7,134.7,134.1,
131.7,129.7,129.4,128.7,128.6,128.4,128.2,124.2,123.9,122.9,122.3(q,JC,F=
280.0Hz),111.2,79.0,77.9,76.0,71.3,68.3(q,JC,F=32.0Hz), 55.9ppm；HRMS(ESI)m/z:
C27H25F3N4O5[M+H]+Calculated value: 543.1850, measured value: 543.1830.
Embodiment 10:
N is weighed, the isatin -3- that the urea 1a (27.2mg, 0.1mmol) and trifluoroethyl that N '-dialkoxy replaces replace is sub-
Amine 2j (60.8mg, 0.2mmol) is dissolved in DME (0.5mL), be slowly added at 0 DEG C dissolved with NaH (12.0mg,
0.3mmol, 60% is dispersed in kerosene) TFP (0.5mL) solution.Then weigh oxidant PhI (OH) (OTs) (78.4mg,
0.2mmol), after being dissolved in DME (1.5mL), then it is slowly added dropwise into reaction system, at 0 DEG C to room temperature condition in one minute
Under, reaction mixture is sufficiently stirred and (is detected and reacted with TLC), until the isatin -3- imines 2j that trifluoroethyl replaces disappears completely
Consumption.Finally, reaction mixture is concentrated under reduced pressure, crude product by column chromatography (eluant, eluent be selected as the petroleum ether of volume ratio 5:1/
Ethyl acetate mixture) target product trans-3aj (39.0mg), yield 68% can be obtained.
The characterization and analysis of object: white solid；M.P.=68.2-69.5 DEG C；1H NMR(400MHz,CDCl3):δ
7.55-7.52(m,3H),7.49-7.45(m,3H),7.43-7.37(m,4H),7.29-7.24(m,4H),7.21-7.17(m,
2H), 6.90 (d, J=7.6Hz, 1H), 6.86-6.84 (m, 2H), 5.66-5.61 (m, 1H), 5.33 (d, J=8.8Hz, 1H),
5.09 (d, J=9.2Hz, 1H), 5.01 (d, J=8.4Hz, 1H), 4.50 (d, J=9.2Hz, 1H), 3.24 (d, J=12Hz,
1H)ppm；13C NMR(100MHz,CDCl3):δ171.0,166.7,144.8,134.8,134.5,133.3,131.6,129.7,
129.6,129.2,128.7,128.6,128.5,128.4,128.2,126.4,124.4,123.8,123.2,122.4(q,JC,F
=280.0Hz), 110.7,78.9,77.7,75.7,68.2 (q, JC,F=32.0Hz) ppm；HRMS(ESI)m/z:
C31H25F3N4O4[M+H]+Calculated value: 575.1901, measured value: 575.1891.
It is mild that result above can be seen that preparation method reaction condition disclosed by the invention, and post-processing is simple, solid selection
Property it is outstanding, and the most objects synthesized have the medium above chemical yield.
The advantageous drug matrices structure of the present invention, quasi-medicated property is extremely strong, has potential medical value and bioactivity.
Claims (9)
1. a kind of 1,3,5-triazines -2- ketone spiro indole ketone compounds, structural formula are
Wherein, R1For benzyl, the fluoro- benzyl of 4-, the chloro- benzyl of 4-, the bromo- benzyl of 4-, 4- Nitro-benzyl, 4- Methyl-benzvl, 4- methoxy
Base-benzyl, phenyl, vinyl, methyl, ethyl etc.；R2For fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxyl group, amino, acetyl ammonia
Base, nitro etc.；R3For methyl, benzyl, phenyl, allyl, tertbutyloxycarbonyl, methoxy etc..
2. a kind of preparation method of 1,3,5-triazines -2- ketone spiro indole ketone compounds described in claim 1 is prepared, it is special
Sign is, weighs N, and the isatin -3- imines that the urea and trifluoroethyl that N '-dialkoxy replaces replace is dissolved in organic solvent 1,
The solution of the organic solvent 2 dissolved with NaH is slowly added at 0 DEG C；Then appropriate oxidant is weighed, organic solvent 3 is dissolved in
Afterwards, then by it is slowly added dropwise in one minute into reaction system, at 0 DEG C under room temperature, reaction mixture is sufficiently stirred,
Until isatin -3- the imines that trifluoroethyl replaces completely consumes；Finally, reaction mixture is concentrated under reduced pressure, crude product passes through
Target product 1,3,5- triazine -2- ketone spiro indole ketone compounds can be obtained in simple column chromatography.
3. according to the method for claim 2, which is characterized in that the carbamide compound and three that the N, N '-dialkoxy replace
The molar ratio for the isatin -3- group with imine moiety that fluoro ethyl replaces is 1:2.
4. according to the method for claim 2, which is characterized in that organic solvent 1 described above, organic solvent 2, You Jirong
Agent 3 is selected from methylene chloride, chloroform, 1,2- dichloroethanes, toluene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N, N- bis-
Methylformamide, benzotrifluoride, 1,3,5- trifluoro-benzene, glycol dimethyl ether (DME), methyl tertiary butyl ether(MTBE), 2,2,3,3- tetra- are fluoro-
One of 1- propyl alcohol (TFP) and hexafluoroisopropanol etc. or two kinds.
5. according to the method for claim 2, which is characterized in that the alkali additive is selected from: sodium carbonate, potassium hydroxide, first
Sodium alkoxide, sodium ethoxide, potassium tert-butoxide, lithium diisopropylamine (LDA), bis- (trimethyl silicon substrate) Sodamides (NaHMDS), diaza
In two rings (DBU), 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), four fluoro- 1- sodium propoxides (NaTFP), sodium hydride etc.
It is one or two kinds of.
6. according to the method for claim 2, which is characterized in that the oxidant is selected from: iodobenzene diacetate, [bis- (trifluoro second
Acyloxy) iodine] benzene, 2- iodosobenzoic acid, hydroxy-methylbenzene sulphonyl iodobenzene, bis- (tert-butyl carbonyl oxygen) iodobenzenes etc..
7. according to the method for claim 2, which is characterized in that the reaction time is 2 hours~16 hours.
8. according to the method for claim 2, which is characterized in that the dosage of the alkali additive is N, and N '-dialkoxy takes
For three times of carbamide compound molal quantity, the dosage of the oxidant is N, and N '-dialkoxy replaces the two of carbamide compound molal quantity
Times.
9. a kind of preparation method of 1,3,5-triazines -2- ketone spiro indole ketone compounds according to claim 2, special
Sign is,
N, N '-dialkoxy replace carbamide compound, and structural formula is as follows:
Isatin -3- group with imine moiety the structural formula that trifluoroethyl replaces is as follows:
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| CN111303188A (en) * | 2020-04-08 | 2020-06-19 | 东莞暨南大学研究院 | Novel oxoindole spiro-compound and preparation method thereof |
| CN112574220A (en) * | 2020-12-08 | 2021-03-30 | 北京工业大学 | Chiral 1, 4-benzodiazepine-2-ketone spiroheterocyclic compound and preparation method thereof |
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| CN111303188A (en) * | 2020-04-08 | 2020-06-19 | 东莞暨南大学研究院 | Novel oxoindole spiro-compound and preparation method thereof |
| CN111303188B (en) * | 2020-04-08 | 2021-07-30 | 东莞暨南大学研究院 | Oxoindole spiro-compound and preparation method thereof |
| CN112574220A (en) * | 2020-12-08 | 2021-03-30 | 北京工业大学 | Chiral 1, 4-benzodiazepine-2-ketone spiroheterocyclic compound and preparation method thereof |
| CN112645958A (en) * | 2021-01-17 | 2021-04-13 | 北京工业大学 | Chiral spiro pyrazolone compound and preparation method thereof |
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