CN108147996B - Synthetic method of arylmethylene bispyrazole ester monopotassium salt - Google Patents
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Abstract
A synthetic method of arylmethylene bispyrazole monopotassium salt relates to the technical field of chemical synthesis. In a solvent, phenylhydrazine, aromatic aldehyde, a potassium source and dimethyl butynedioate or diethyl butynedioate are mixed and reacted, cooling and suction filtration are carried out after the reaction is finished, a solid phase is obtained, and the solid phase is washed by ethanol and then recrystallized, so as to obtain the monopotassium arylmethylene bispyrazole ester. The invention solves the problems of difficult product separation of heterogeneous reaction, product pollution caused by organic micromolecule catalyst, and the defects of troublesome intermediate separation and purification, low yield and the like of multistep reaction.
Description
Technical Field
The invention relates to the technical field of chemical synthesis.
Background
The arylmethylidene bispyrazole derivative has important biological activity and is widely used as an anticancer agent for treating diseases such as cerebral ischemia and myocardial ischemia. It is also used as antipyretic analgesic, antidepressant, antifungal, antiinflammatory agent and Mycobacterium tuberculosis inhibitor. In addition, arylmethylidene bispyrazole derivatives have been used as pesticides and dyes, metal ion chelating agents.
Due to the important physiological activity and potential medicinal value of the arylmethylene-bis-pyrazole derivatives, research on the synthetic methods of the arylmethylene-bis-pyrazole derivatives is always concerned.
A series of synthetic methods have been reported, which are obtained by catalyzing the condensation of one molecule of aromatic aldehyde and two molecules of 3-methyl-1-phenyl-5-pyrazolone, and often use xanthic acid [ Kuarm, B.S.; Rajitha, B.Synth. Commun. 2012, 42, 2382-.
In recent years, aromatic aldehyde, phenylhydrazine and ethyl acetoacetate are used for direct condensation synthesis of arylmethylene bispyrazole derivatives, for example, 2012, Niknam and the like report that silica gel loaded N-propylpiperazine sulfamic acid is used for catalyzing the multi-component reaction [ Taybi S.; Niknam K. Iran. J. Catl. 2012, 2, 69-74 ]. In 2014, Zhou and Zhang reported the use of 2-hydroxyethylammonium propionate to catalyze this multi-component reaction to synthesize arylmethylidene bispyrazole derivatives [ Zhou, z. & Zhang, y. Green chem. lett. and rev., 2014, 7, 18-23 ]. In 2017, Lalitha et al reported the use of glycerol to catalyze this multicomponent reaction [ Ramesh1, R.; Nagasund aram1, N.; Meignasundar 1, D.; Vadivel, P.; Lalitha, A. Res Chem Intermed 2017, 43, 1767-.
The prior literature method uses a heterogeneous catalyst to promote the reaction, has the problems of difficult product separation and difficult product purification, and uses an organic small molecular catalyst to pollute the product and can not meet the use requirement of medicaments. The multi-step synthesis has the defects of long route, low total yield, use of a pyrazolone raw material which is not easy to obtain and the like. Although the arylmethylidene bispyrazole ester monopotassium salt can be directly prepared by a method reported in the literature, the arylmethylidene bispyrazole ester and a potassium source compound which are prepared by the method described in the literature can be synthesized theoretically, different potassium source compounds can form various potassium salt compounds such as multi-potassium salt and potassium salt at different positions, and obviously the requirement on the purity of the medicine cannot be met.
Disclosure of Invention
The invention aims to provide a synthetic method which can simply and efficiently obtain corresponding monopotassium arylmethylidene bispyrazole ester without additional catalysts or promoters aiming at the defects of the one-pot reaction.
The technical scheme of the invention is as follows: in a solvent, phenylhydrazine, aromatic aldehyde, a potassium source and dimethyl butynedioate or diethyl butynedioate are mixed and reacted, cooling and suction filtration are carried out after the reaction is finished, a solid phase is obtained, and the solid phase is washed by ethanol and then recrystallized, so as to obtain the monopotassium arylmethylene bispyrazole ester.
The invention does not use any extra catalyst or accelerant, directly uses phenylhydrazine, aromatic aldehyde and potassium carbonate as potassium source to synthesize the target compound through one-pot reaction with dimethyl butynedioate or diethyl butynedioate, and uses the potassium carbonate as both the potassium source and the alkaline reagent to promote the reaction, thereby simplifying the post-treatment procedure. The invention solves the problems of difficult product separation of heterogeneous reaction, product pollution caused by organic micromolecule catalyst, and the defects of troublesome intermediate separation and purification, low yield and the like of multistep reaction.
Furthermore, the feeding molar ratio of the phenylhydrazine, the aromatic aldehyde, the potassium source and the dimethyl butynedioate or diethyl butynedioate is 2: 1: 2-4: 2.
The method does not use any additional catalyst or accelerator, and the potassium source in the method is used as an alkaline reagent to promote the reaction, so that the molar ratio of the potassium source to the aromatic aldehyde is 2-4: 1, and the reaction is more sufficient.
The preferred potassium source of the present invention is K2CO3. Both strong alkaline potassium hydroxide and weak alkaline potassium bicarbonate are detrimental to the reaction, while the mild alkaline reagent potassium carbonate is not only effective in providing a source of potassium, but also effective in promoting the conversion of the reaction.
The preferred solvent for the present invention is ethanol. The polar protic solvent ethanol favors the conversion of the reaction.
The reaction temperature is 25-80 ℃. Experimental studies have shown that the conversion is influenced by changes in the reaction temperature, with the result that increasing the temperature is found to favor the conversion of this reaction and to shorten the reaction time to 5 hours.
Drawings
FIG. 1 is a molecular structural diagram of benzylene-4, 4' -bis (3-hydroxy-1-phenylpyrazole-5-carboxylic acid methyl ester) monopotassium (4a) synthesized by the present invention.
Detailed Description
A synthetic method of arylmethylene bis pyrazolone monopotassium salt comprises the following steps:
adding 2.0 mmol of dimethyl butynedioate or diethyl butynedioate, 552 mg (4.0 mmol) of potassium carbonate and 216 mg (2.0 mmol) of phenylhydrazine into 3 mL of ethanol solvent, stirring at normal temperature for 30 min, adding 1.0 mmol of aromatic aldehyde, heating in an oil bath to reflux (80 ℃), continuing stirring, tracking and detecting by thin-plate chromatography TLC (a developing agent is formed by mixing ethyl acetate and petroleum ether in a volume ratio of 1: 3), cooling to room temperature after 5h of reaction, performing suction filtration, washing twice by ethanol, and simply recrystallizing by 95% ethanol to obtain a pure product, wherein the corresponding compound is shown in Table 1.
The reaction formula is as follows:
table 1 synthesis results of arylmethylidene bispyrazolone monopotassium salt:
the molecular structural formula and the characterization experimental data of each product are as follows:
1. benzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid methyl ester) monopotassium (4 a):
experimental data: white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.92 (d, J = 7.6 Hz, 4H), 7.40 (dd, J= 7.6, 8.0 Hz, 4H), 7.29 (d, J = 7.6 Hz, 2H), 7.21 (dd, J= 7.2, 7.6 Hz, 2H), 7.17 (dd, J= 7.2, 7.6 Hz, 2H), 7.05 (dd, J= 7.2, 7.2 Hz, 1H), 6.72 (s, 1H), 3.80 (s, 6H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 164.2, 158.4, 146.0, 140.1, 139.6, 128.9, 127.9, 127.9, 125.6, 125.2, 121.2, 105.3, 51.4, 32.1; IR (KBr, cm-1): v 3418, 3032, 2948, 1657, 1589, 1478, 1018, 938, 750, 701。
single crystal characterization of compound 4 a:
(1) the molecular structure of potassium benzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylate) (4a) is shown in FIG. 1.
(2) Single crystal data for benzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid methyl ester) monopotassium (4 a):
the following table shows the crystal parameters of compound 4 a:
from FIG. 1 and the above table, the analysis of single crystal of compound 4a proves that the constructed arylmethylidene bispyrazole derivative has a potassium pyrazololate structural unit.
2. P-methoxybenzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid methyl ester) monopotassium salt (4 b):
experimental data: a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.92 (d, J = 8.0 Hz, 4H), 7.40 (dd, J= 7.6, 8.0 Hz, 4H), 7.22-7.19 (m, 4H), 6.74 (d, J= 8.8 Hz, 2H), 6.65 (s, 1H), 3.80 (s, 6H), 3.67 (s, 3H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 164.2, 158.3, 157.2, 140.2, 139.6, 138.1, 128.9, 128.7, 125.5, 121.1, 113.3, 105.6, 55.3, 51.4, 51.3; IR (KBr, cm-1): v 3423, 3037, 2948, 1663, 1593, 1486, 1018, 938, 832, 766。
3. benzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid ethyl ester) monopotassium (4 c):
experimental data: a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.91 (d, J = 8.0 Hz, 4H), 7.40 (dd, J= 7.6, 7.6 Hz, 4H), 7.32 (d, J = 8.0 Hz, 2H), 7.21 (dd, J= 7.2, 8.0 Hz, 2H), 7.17 (dd, J= 8.0, 7.6 Hz, 2H), 7.04 (dd, J= 7.2, 7.6 Hz, 1H), 6.70 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 163.8, 158.3, 146.2, 140.1, 139.9, 128.9, 127.9, 127.8, 125.5, 125.1, 121.2, 105.1, 60.0, 32.3, 14.6; IR (KBr, cm-1): v 3433, 3033, 2949, 1659, 1585, 1472, 1015, 938, 748, 701。
4. p-chlorobenzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid methyl ester) monopotassium salt (4 d):
experimental data: a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.93 (d, J = 8.0 Hz, 4H), 7.41 (dd, J= 8.0, 7.6 Hz, 4H), 7.30 (d, J = 8.4 Hz, 2H), 7.24 (dd, J= 7.2 Hz, 2H), 7.20 (dd, J= 6.4, 7.2 Hz, 2H), 6.73 (s, 1H), 3.81 (s, 6H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 164.1, 158.4, 144.9, 140.1, 139.5, 129.9, 129.7, 128.9, 127.9, 125.6, 121.2, 104.9, 51.4, 31.8; IR (KBr, cm-1): v 3422, 3031, 2947, 1666, 1593, 1487, 1013, 939, 832, 767。
5. m-chlorobenzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid methyl ester) monopotassium (4 e):
experimental data: a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.94 (d, J = 8.4 Hz, 4H), 7.42 (dd, J= 7.6, 8.0 Hz, 4H), 7.31 (s, 1H), 7.28-7.21 (m, 4H), 7.15 (d, J= 7.6 Hz, 1H), 6.77 (s, 1H), 3.83 (s, 6H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 164.1, 158.4, 148.7, 140.0, 139.5, 132.7, 129.9, 129.0, 127.5, 126.7, 125.7, 125.3, 121.3, 104.7, 51.5, 32.1; IR (KBr, cm-1): v 3417, 3032, 2949, 1667, 1599, 1482, 1018, 934, 793, 765。
6. o-bromobenzylmethylene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid methyl ester) monopotassium (4 f):
experimental data: a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.93 (d, J = 7.6 Hz, 4H), 7.40 (dd, J= 7.6, 8.0 Hz, 4H), 7.78 (d, J = 7.2 Hz, 1H), 7.45-7.38 (m, 5H), 7.27-7.19 (m, 3H), 7.03 (dd, J= 7.6, 7.2 Hz, 1H), 6.61 (s, 1H), 3.80 (s, 6H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 164.1, 158.8, 143.7, 140.3, 140.1, 132.7, 131.2, 128.9, 127.6, 127.0, 125.5, 123.8, 121.1, 103.8, 51.5, 33.7,; IR (KBr, cm-1): v 3423, 3028, 2947, 1662, 1594, 1486, 1017, 934, 768, 748。
7. m-methylbenzylidene-4, 4' -bis (1-phenyl-5-hydroxypyrazole-3-carboxylic acid methyl ester) monopotassium salt (4 g):
experimental data: a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.93 (d, J = 8.0 Hz, 4H), 7.40 (dd, J= 8.0, 7.6 Hz, 4H), 7.21 (dd, J= 7.2, 7.2 Hz, 2H), 7.12-7.04 (m, 3H), 6.87 (d, J= 6.8 Hz, 1H), 6.68 (s, 1H), 3.80 (s, 6H) , 2.20 (s, 3H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 164.2, 158.4, 146.0, 140.2, 139.7, 136.5, 128.9, 128.5, 127.8, 125.9, 125.5, 125.1, 121.2, 105.4, 51.4, 32.1, 21.8; IR (KBr, cm-1): v 3414, 3031, 2950, 1668, 1599, 1484, 1019, 933, 792, 765。
8. p-fluorobenzylidene-4, 4' -bis (ethyl 1-phenyl-5-hydroxypyrazole-3-carboxylate) monopotassium (4 h):
experimental data: a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.93 (d, J = 7.6 Hz, 4H), 7.42 (dd, J= 7.2, 7.6 Hz, 4H), 7.36 (dd, J= 6.4, 7.6 Hz, 2H), 7.22 (dd, J= 6.8, 7.6 Hz, 2H), 7.01 (dd, J= 8.4, 8.4 Hz, 2H), 7.05 (dd, J= 7.2, 7.2 Hz, 1H), 6.72 (s, 1H), 4.29 (q, J = 6.8 Hz, 4H), 1.32 (t, J = 6.8 Hz, 6H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 163.8, 159.3, 158.3, 142.3 (d, J= 3.0 Hz), 140.1, 139.8, 129.5, 129.5, 128.9, 125.6, 121.3, 114.4 (d, J = 10.7 Hz), 105.1, 60.0, 31.7, 14.6; IR (KBr, cm-1): v 3425, 3031, 2949, 1667, 1598, 1488, 1012, 940, 831, 767。
9. p-bromobenzylmethylene-4, 4' -bis (ethyl 1-phenyl-5-hydroxypyrazole-3-carboxylate) monopotassium (4 i):
experimental data:a white solid;1H NMR (DMSO-d 6, 400 MHz ) δ (ppm): 7.85 (d, J = 8.0 Hz, 4H), 7.45-7.39 (m, 6H), 7.28-7.22 (m, 4H), 6.72 (s, 1H), 4.30 (q, J = 6.8 Hz, 4H), 1.31 (t, J = 6.8 Hz, 6H); 13C NMR (DMSO-d 6, 100 MHz) δ (ppm): 163.7, 158.3, 145.6, 140.1, 139.8, 130.7, 130.2, 128.9, 125.6, 121.3, 118.3, 104.7, 60.0, 31.9, 14.6; IR (KBr, cm-1): v 3433, 3032, 2943, 1666, 1599, 1487, 1013, 940, 831, 769。
optimization test of synthesis reaction conditions of arylmethylene bis pyrazolone monopotassium salt:
using 284mg (2.0 mmol) of dimethyl butynedioate, 216 mg (2.0 mmol) of phenylhydrazine and 106 mg (1.0 mmol) of benzaldehyde as model reaction, potassium sources (K) of different molar equivalents were used for the study2CO3、KHCO3Or KOH), different solvents (THF, CH)2Cl2MeCN or EtOH) and different reaction temperatures.
The reaction formula is as follows:
the results of the reaction conditions optimization are shown in Table 2.
TABLE 2 comparison of the results of the synthesis of arylmethylidene bispyrazolone monopotassium salt
The results from table 2 show that:
different potassium source reagents have a large influence on the reaction, strong alkali potassium hydroxide and weak alkali potassium bicarbonate are not beneficial to the reaction, and a mild alkaline reagent potassium carbonate can effectively provide a potassium source and can effectively promote the conversion of the reaction (compare with serial numbers 1-3 in table 2).
Among the common solvents studied, tetrahydrofuran, dichloromethane, acetonitrile and ethanol, the polar protic solvent, ethanol, favours the conversion of the reaction (compare numbers 1, 4-6 in table 2).
The effect on the reaction was examined by varying the amount of potassium carbonate used as solvent, and the results showed that twice the equivalent of potassium carbonate gave the best results (compare numbers 1, 6-10 in Table 2). While when the reaction temperature was changed, it was found that the conversion of this reaction was facilitated by increasing the temperature, and the reaction time was also shortened to 5 hours.
Claims (3)
1. A synthetic method of arylmethylene bispyrazole monopotassium salt is characterized in that phenylhydrazine, aromatic aldehyde, a potassium source and dimethyl butynedioate or diethyl butynedioate are mixed and reacted in a solvent, cooling and suction filtration are carried out after the reaction is finished, a solid phase is obtained, and the solid phase is washed by ethanol and then recrystallized to obtain the arylmethylene bispyrazole monopotassium salt; the potassium source is K2CO3(ii) a The solvent is ethanol; the aromatic aldehyde is benzaldehyde, p-methoxybenzaldehyde, p-chlorobenzaldehyde, m-chlorobenzaldehyde, o-bromobenzaldehyde, m-methylbenzaldehyde, p-fluorobenzaldehyde or p-bromobenzaldehyde;
the reaction formula of the mixing reaction is as follows:
2. the method for synthesizing the monopotassium arylmethylidene bispyrazole ester according to claim 1, wherein the feeding molar ratio of the phenylhydrazine, the aromatic aldehyde, the potassium source and the dimethyl butynedioate or the diethyl butynedioate is 2: 1: 2-4: 2.
3. The method for synthesizing the monopotassium arylmethylidene bispyrazole ester according to claim 2, wherein the reaction temperature is 25-80 ℃.
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| WO2014159214A1 (en) * | 2013-03-14 | 2014-10-02 | Chdi Foundation, Inc. | Histone deacetylase inhibitors and compositions and methods of use thereof |
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| WO2008121861A2 (en) * | 2007-03-28 | 2008-10-09 | Xenon Pharmaceuticals Inc. | Pyrazole and pyrrole compounds useful in treating iron disorders |
| WO2014159214A1 (en) * | 2013-03-14 | 2014-10-02 | Chdi Foundation, Inc. | Histone deacetylase inhibitors and compositions and methods of use thereof |
Non-Patent Citations (3)
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| "A Green and Efficient One-Pot Pseudo-Five-Component Reaction for Synthesis of Bis(pyrazol-5-ol) Derivatives via Tandem Cyclocondensation-Knoevenagel–Michael Reaction";Cheng Yang, et al.,;《ChemistrySelect》;20170130;第2卷(第3期);1232–1236 * |
| "Development of the next generation of HIV-1 integrase inhibitors: Pyrazolone as a novel inhibitor scaffold";Victor Hadi，et al.,;《Bioorganic & Medicinal Chemistry Letters》;20100917;第20卷;6854-6857 * |
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