Disclosure of Invention
The invention aims to provide a synthesis method of a polysubstituted pyrazole compound, which takes cheap and easily available commodity as a raw material, and can simultaneously construct the 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted polysubstituted pyrazole compound by only normal-temperature reaction under the action of very cheap alkali catalysis and environment-friendly solvents; solves the problems of long route, uneconomical atom, unfriendly environment, complex operation and the like of the compound skeleton in the synthesis process.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention discloses a synthesis method of polysubstituted pyrazole compounds, wherein a compound in a formula I and a compound in a formula II react under an alkaline condition to generate a compound in a formula III and a compound in a formula IV, and the reaction formula is as follows:
the method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 1 Selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl;
R 2 selected from substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl;
R 3 selected from the group consisting of substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl, or thienyl.
The method can simultaneously synthesize two pyrazole compounds of 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted pyrazoles. For the synthesized product 1,3,4, 5-tetra-substituted pyrazole compound, the 4-aldehyde group can be subjected to structural modification, so that target functional groups are introduced to have different biological activities.
In some embodiments of the invention, R 1 Is selected from halogen or methoxy; preferably, at least one selected from chlorine, fluorine, bromine, methoxy; more preferably, R 1 Is different from the substituent of the (B).
In some embodiments of the invention, R 2 Is selected from halogen, methyl or methoxy; preferably, at least one selected from chlorine, fluorine, methyl, methoxy; more preferably, R 2 Is different from the substituent of the (B).
In some embodiments of the invention, R 3 Is selected from halogen or methoxy; preferably, at least one selected from chlorine, bromine and methoxy; more preferably, R 3 The substituent of (a) is para-position substitution.
In some embodiments of the present invention, the organic solvent is selected from at least one of tetrahydrofuran, ethyl acetate, acetonitrile, dichloromethane, ethanol; ethanol is preferred.
In some embodiments of the invention, the base is selected from Et 3 N、Cs 2 CO 3 、K 2 CO 3 Any one of DBU and DIPEA; preferably K 2 CO 3 。
In some embodiments of the present invention, the mass ratio of the compound of formula I, the compound of formula II, and the base is 1:1.2:0.5-1:1.2:2.5; preferably 1:1.2:2.5.
In some embodiments of the invention, the reaction temperature is from 10 to 40 ℃, preferably room temperature.
In some embodiments of the invention, a refining step is further included, preferably comprising column chromatography, recrystallization.
The room temperature of the invention is 10-30 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the invention has scientific design, ingenious conception, simple method and convenient operation. The method can synthesize pyrazole compounds containing various substituents, has fewer byproducts and is easy to purify. The method can synthesize two pyrazole compounds of 1,3, 4-trisubstituted and 1,3,4, 5-tetrasubstituted pyrazole at the same time, solves the limit that only one pyrazole compound can be synthesized in the known production method, and increases the application range of the method.
For the synthesized product 1,3,4, 5-tetra-substituted pyrazole compound, the 4-aldehyde group can be subjected to structural modification, so that target functional groups are introduced to have different biological activities.
The raw materials are cheap and easy to obtain, the reaction cost is effectively reduced, and the solvent is nontoxic and harmless, does not need a metal catalyst, and is environment-friendly; the reaction condition is simple, the target compound can be obtained in high yield in normal temperature air without heating or inert gas protection, a new route selection is provided for synthesizing active molecules containing the skeleton, and the method has good industrial application prospect.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
In the embodiment, the compound of formula I-1N-phenylbenzohydrazone acyl chloride and the compound of formula II-1 cinnamaldehyde are used as standard substrates to prepare the compound of formula III-1, 3, 4-triphenyl-1H-pyrazole and the compound of formula IV-1, 3, 5-triphenyl-1H-pyrazole-4-formaldehyde, wherein the reaction formula is as follows:
the specific operation is as follows: 10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of N-phenylbenzohydrazone acyl chloride (0.435 mmol) and 150.2mg of K were then added to the reaction tube, respectively 2 CO 3 (1.087 mmol), then adding 2.2mL of ethanol solvent, finally adding 69.00mg of cinnamaldehyde (0.522 mmol), reacting at normal temperature, monitoring the whole reaction progress by TLC, concentrating the solvent after the reaction is finished, and separating the obtained crude product by column chromatography with petroleum ether and ethyl acetate mixed solution (30/1, v/v) as eluent and 300-400 meshes of silica gel as separating resin to obtain 1,3, 4-triphenyl-1H-pyrazole (59.18 mg, light yellow oily) and 1,3, 5-triphenyl-1H-pyrazole-4-formaldehyde (74.64 mg, yellow solid), wherein the yield of the compound of the formula III-1 is 45.99%, and the yield of the compound of the formula IV-1 is 53.00%.
A compound of formula iii-1: 1 H NMR(600MHz,CDCl 3 )δ8.02(s,1H),7.82–7.78(m,2H),7.64–7.57(m,2H),7.50–7.45(m,2H),7.38–7.31(m,7H),7.31–7.27(m,2H). 13 C NMR(151MHz,CDCl 3 )δ150.26,139.70,132.89,132.63,129.25,128.48,128.32,128.24,128.11,127.70,126.73,126.44,126.25,122.71,118.74.HRMS-ESI(m/z):[M+H] + calcd for C 21 H 17 N 2 297.1392;found,297.1385.
a compound of formula iv-1: 1 H NMR(600MHz,CDCl 3 )δ9.87(s,1H),7.97–7.92(m,2H),7.50–7.39(m,6H),7.37–7.34(m,2H),7.34–7.28(m,5H). 13 C NMR(151MHz,CDCl 3 )δ185.66,153.84,149.15,138.73,131.52,130.63,129.84,129.27,129.17,129.03,128.65,128.36,128.27,127.72,125.39,118.73.HRMS-ESI(m/z):[M+H] + calcd for C 22 H 17 N 2 O 325.1341;found,325.1333.
example 2
In the embodiment, the reaction conditions of the synthesis of the base-catalyzed polysubstituted pyrazole compound are researched by taking N-phenylbenzohydrazone acyl chloride of the formula I-1 and cinnamaldehyde of the formula II-1 as standard substrates, wherein the reaction formula is as follows:
the reaction conditions and results are shown in Table 1:
TABLE 1
In table 1, "equiv" represents equivalent; the temperature "rt" is room temperature; a is that 2.5 equivalents of DDQ is added into a reaction system; b is anhydrous and anaerobic condition.
Example 3
This example discloses the preparation of the compound of formula III-2 (4-bromophenyl) -1, 3-diphenyl-1H-pyrazole and the compound of formula IV-2 5- (4-bromophenyl) -3- (cyclohex-1, 3-dien-1-yl) -1-phenyl-1H-pyrazole-4-carbaldehyde:
10mL reaction tube and magnetThe stirred mixture was dried in advance, and then 100 mgN-phenylbenzohydrazone acid chloride (0.435 mmol) and 150.2mg K were added to the reaction tube, respectively 2 CO 3 (1.087 mmol), 2.2mL of ethanol solvent was added, 110.17mg of p-bromocinnamaldehyde (0.522 mmol) was added, the whole reaction was allowed to react at room temperature, TLC was used to monitor the whole reaction progress, after the completion of the reaction, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to give (4-bromophenyl) -1, 3-diphenyl-1H-pyrazole (47.4 mg, pale yellow oil) and 5- (4-bromophenyl) -3- (cyclohex-1, 3-dien-1-yl) -1-phenyl-1H-pyrazole-4-carbaldehyde (75.7 mg, yellow solid), yield: formula III-2 is 29.15% and formula IV-2 is 43.51%.
A compound of formula iii-2: 1 H NMR(600MHz,CDCl 3 )δ8.01(s,1H),7.81–7.77(m,2H),7.60–7.54(m,2H),7.51–7.44(m,4H),7.38–7.33(m,3H),7.33–7.29(m,1H),7.24–7.19(m,2H). 13 C NMR(151MHz,CDCl 3 )δ149.11,138.46,131.46,130.48,130.37,128.89,128.17,127.12,126.78,125.31,125.24,120.39,119.60,117.68.HRMS-ESI(m/z):[M+H] + calcd for C 21 H 16 BrN 2 375.0497;found,375.0489.
a compound of formula iv-2: 1 H NMR(600MHz,CDCl 3 )δ9.90(s,1H),7.90–7.86(m,2H),7.55–7.52(m,2H),7.51–7.44(m,3H),7.38–7.34(m,3H),7.32–7.28(m,2H),7.25–7.22(m,2H). 13 C NMR(151MHz,CDCl 3 )δ185.49,154.56,146.93,138.47,132.14,131.89,131.23,129.30,129.23,128.56,128.51,126.69,125.47,124.50,118.62.HRMS-ESI(m/z):[M+Na] + calcd for C 22 H 15 BrN 2 NaO 425.0265;found,425.0258.
example 4
This example discloses the preparation of the compound 1, 4-diphenyl-3- (thiophen-2-yl) -1H-pyrazole of formula III-3 and the compound 1, 5-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carbaldehyde of formula IV-3:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of N-phenylthiophene-2-carbazone chloride (0.42 mmol) and 145.18mg of K were added to the reaction tube, respectively 2 CO 3 (1.05 mmol), then 2.1mL of ethanol solvent was added, finally 66.61mg of cinnamaldehyde (0.504 mmol) was added, the whole reaction was allowed to react at normal temperature, TLC was used to monitor the whole reaction progress, after the reaction was completed, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to obtain 1, 4-diphenyl-3- (thiophen-2-yl) -1H-pyrazole (21.7 mg, orange solid) and 1, 5-diphenyl-3- (thiophen-2-yl) -1H-pyrazole-4-carbaldehyde (56.2 mg, tan) as yields: formula III-3 is 16.96% and formula IV-3 is 40.43%.
A compound of formula iii-3: 1 H NMR(600MHz,CDCl 3 )δ7.95(s,1H),7.80–7.75(m,2H),7.52–7.43(m,4H),7.43–7.38(m,2H),7.38–7.34(m,1H),7.33–7.28(m,1H),7.27–7.24(m,1H),7.08(dd,J=3.6,1.2Hz,1H),6.95(dd,J=5.1,3.6Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ145.21,139.72,135.29,132.48,129.49,129.29,128.57,127.49,127.27,126.96,126.56,125.98,125.31,122.71,118.96.HRMS-ESI(m/z):[M+H] + calcd for C 19 H 15 N 2 S 303.0956;found,303.0949.
a compound of formula iv-3: 1 H NMR(600MHz,CDCl 3 )δ9.83(s,1H),8.29(dd,J=3.7,1.2Hz,1H),7.48–7.44(m,1H),7.44–7.38(m,3H),7.35–7.30(m,5H),7.29(dt,J=7.1,2.2Hz,2H),7.15(dd,J=5.1,3.7Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ185.27,150.34,147.37,138.44,133.82,130.63,130.01,129.70,129.05,128.81,128.35,127.70,127.43,127.06,125.34,118.35.HRMS-ESI(m/z):[M+H] + calcd for C 20 H 15 N 2 OS 331.0905;found,331.0897.
example 5
This example discloses the preparation of the compound 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -4-phenyl-1H-pyrazole of formula iii-4 and the compound 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -5-phenyl-1H-pyrazole-4-carbaldehyde of formula iv-4:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and then 100mg of N- (4-methoxyphenyl) -2-naphthylhydrazone chloride (0.323 mmol) and 111.46mg of K were added to the reaction tube, respectively 2 CO 3 (0.806 mmol) and then 2.1mL of ethanol solvent were added, and finally 51.23mg of cinnamaldehyde (0.39 mmol) was added, the whole reaction was allowed to react at room temperature, TLC was monitored for the progress of the whole reaction, after the completion of the reaction, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to give 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -4-phenyl-1H-pyrazole (46.7 mg, yellow oil) and 1- (4-methoxyphenyl) -3- (naphthalen-2-yl) -5-phenyl-1H-pyrazole-4-carbaldehyde (63.9 mg, red solid), yield: formula III-4 is 38.50% and formula IV-4 is 49.15%.
Formula III-4: 1 H NMR(600MHz,CDCl 3 )δ8.12–8.09(m,1H),7.97(s,1H),7.87–7.81(m,1H),7.81–7.75(m,2H),7.77–7.71(m,2H),7.69(dd,J=8.5,1.7Hz,1H),7.49–7.42(m,2H),7.40–7.35(m,2H),7.35–7.27(m,3H),7.05–6.99(m,2H),3.87(s,3H). 13 C NMR(151MHz,CDCl 3 )δ158.35,149.93,133.76,133.41,132.97,132.95,130.77,128.73,128.58,128.35,127.80,127.66,127.33,126.97,126.94,126.58,126.01,125.99,122.77,120.80,114.60,55.63.HRMS-ESI(m/z):[M+H] + calcd for C 26 H 21 N 2 O 377.1654;found,377.1648.
formula IV-4: 1 H NMR(600MHz,CDCl 3 )δ9.91(s,1H),8.52(d,J=1.7Hz,1H),8.06(dd,J=8.5,1.8Hz,1H),7.98–7.91(m,2H),7.89–7.82(m,1H),7.54–7.48(m,2H),7.46–7.38(m,3H),7.37–7.32(m,2H),7.31–7.21(m,2H),6.85–6.78(m,2H),3.77(s,3H). 13 C NMR(151MHz,CDCl 3 )δ184.10,157.73,151.85,147.77,132.04,131.62,130.15,129.06,128.17,127.42,127.28,127.10,127.03,126.28,126.14,126.11,125.17,125.10,124.97,124.61,117.07,112.60,53.90.HRMS-ESI(m/z):[M+H] + calcd for C 27 H 21 N 2 O 2 405.1603;found,405.1600.
example 6
This example discloses the preparation of the compound 4- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole of formula III-5 and the compound 5- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole-4-carbaldehyde of formula IV-5:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of 3-fluoro-N-mesityl benzohydrazone chloride (0.344 mmol) and 118.74mg of K were then added to the reaction tube, respectively 2 CO 3 (0.859 mmol), 1.7mL of ethanol solvent was added, 68.78mg of p-chlorocinnamaldehyde (0.413 mmol) was added, the whole reaction was allowed to react at normal temperature, TLC was used to monitor the whole reaction progress, after the completion of the reaction, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to obtain 4- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole (35.00 mg, yellow oily) and 5- (4-chlorophenyl) -3- (3-fluorophenyl) -1-mesityl-1H-pyrazole-4-carbaldehyde (95.7 mg, yellow solid), yield: formula III-5 is 26.12% and formula IV-5 is 66.64%.
A compound of formula iii-5: 1 H NMR(600MHz,CDCl 3 )δ7.52(s,1H),7.35–7.26(m,7H),7.03–6.97(m,3H),2.34(s,3H),2.11(s,6H). 13 C NMR(151MHz,CDCl 3 )δ161.99(d,J=245.1Hz),147.22(d,J=2.4Hz),138.39,135.67,134.86,134.57(d,J=8.1Hz),132.01,130.56,130.53,129.20,129.02(d,J=8.4Hz),128.17,128.02,123.26(d,J=2.8Hz),119.26,114.41(d,J=22.5Hz),113.84(d,J=21.0Hz),20.34,16.69.HRMS-ESI(m/z):[M+H] + calcd for C 24 H 21 ClFN 2 391.1377;found,391.1373.
a compound of formula iv-5: 1 H NMR(600MHz,CDCl 3 )δ9.92(s,1H),7.75(dt,J=7.7,1.2Hz,1H),7.72–7.67(m,1H),7.44(td,J=8.0,5.8Hz,1H),7.34–7.29(m,2H),7.24–7.18(m,2H),7.17–7.11(m,1H),6.89(s,2H),2.29(s,3H),1.98(s,6H). 13 C NMR(151MHz,CDCl 3 )δ185.22,162.70(d,J=245.7Hz),152.99(d,J=2.7Hz),149.23,139.87,136.25,135.36,134.03,133.62(d,J=8.4Hz),131.12,129.87(d,J=8.3Hz),129.28,128.82,125.55,125.05(d,J=2.9Hz),117.28,116.22(d,J=22.6Hz),116.08(d,J=20.7Hz),21.15,17.78.HRMS-ESI(m/z):[M+H] + calcd for C 25 H 21 ClFN 2 O 419.1326;found,419.1321.
example 7
This example discloses the preparation of the compound 3- (3-chlorophenyl) -1, 4-bis (4-methoxyphenyl) -1H-pyrazole of formula III-6 and the compound 3- (3-chlorophenyl) -1, 5-bis (4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde of formula IV-6:
10mL of the reaction tube and the magnetic stirrer were dried in advance, and 100mg of 3-chloro-N- (4-methoxyphenyl) benzohydrazone chloride (0.340 mmol) and 117.53mg of K were then added to the reaction tube, respectively 2 CO 3 (0.850 mmol) and then 1.7mL of ethanol solvent were added, and finally 66.18mg of p-methoxycinnamaldehyde (0.41 mmol) was added, the whole reaction was allowed to react at normal temperature, TLC was monitored for the whole reaction progress, after the reaction was completed, the solvent was concentrated, and the obtained crude product was separated by column chromatography using a mixture of petroleum ether and ethyl acetate (30/1, v/v) as an eluent and 300-400 mesh silica gel as a separation resin to obtain 3- (3-chlorophenyl) -1, 4-bis (4-methoxyphenyl) -1H-pyrazole (38.80 mg, pale yellow oil) and 3- (3-chlorophenyl) -1, 5-bis (4-methoxyphenyl) -1H-pyrazole-4-carbaldehyde (74.30 mg, red solid) as preparation, yield: formula III-6 is 29.24%, formula IV-6 is 52.25%;
a compound of formula iii-6: 1 H NMR(600MHz,CDCl 3 )δ7.86(d,J=1.5Hz,1H),7.71–7.65(m,3H),7.40(dq,J=7.6,1.5Hz,1H),7.33–7.16(m,4H),6.99(dd,J=8.9,1.6Hz,2H),6.89(dd,J=8.6,1.7Hz,2H),3.86(d,J=1.4Hz,3H),3.84(d,J=1.5Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ158.82,158.37,148.39,135.21,134.24,133.62,129.87,129.48,128.20,127.74,126.73,126.49,124.87,122.35,120.67,114.58,114.09,55.62,55.31.HRMS-ESI(m/z):[M+H] + calcd for C 23 H 20 ClN 2 O 2 391.1213;found,391.1205.
a compound of formula iv-6: 1 H NMR(600MHz,CDCl 3 )δ9.82(s,1H),7.98(dt,J=1.7,1.1Hz,1H),7.88(pd,J=4.5,1.6Hz,1H),7.43–7.37(m,2H),7.28–7.23(m,2H),7.25–7.19(m,2H),6.95–6.89(m,2H),6.88–6.82(m,2H),3.84(s,3H),3.80(s,3H). 13 C NMR(151MHz,CDCl 3 )δ185.53,160.69,159.32,151.87,149.69,134.19,133.51,132.05,131.73,129.50,129.09,129.07,127.52,126.70,119.38,118.28,114.24,114.19,55.53,55.37.HRMS-ESI(m/z):[M+Na] + calcd for C 24 H 19 ClN 2 NaO 3 441.0982;found,441.0980.
the embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the invention is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.