CN101407496B - Method for synthesizing 3,5-disubstituted pyrazole - Google Patents
Method for synthesizing 3,5-disubstituted pyrazole Download PDFInfo
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- CN101407496B CN101407496B CN2007100941378A CN200710094137A CN101407496B CN 101407496 B CN101407496 B CN 101407496B CN 2007100941378 A CN2007100941378 A CN 2007100941378A CN 200710094137 A CN200710094137 A CN 200710094137A CN 101407496 B CN101407496 B CN 101407496B
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- PPBRXRYQALVLMV-UHFFFAOYSA-N C=Cc1ccccc1 Chemical compound C=Cc1ccccc1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- LEFIXAQPASZFND-UHFFFAOYSA-N COc(cc1)ccc1-c1n[nH]c(-c2ccccc2)c1 Chemical compound COc(cc1)ccc1-c1n[nH]c(-c2ccccc2)c1 LEFIXAQPASZFND-UHFFFAOYSA-N 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N COc1ccc(C=O)cc1 Chemical compound COc1ccc(C=O)cc1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- LLPARVZCHDTYFP-XXFHCLJSSA-N Cc(cc1)ccc1S(NN/C(/C=C\COC)=C/CC=C)(=O)=O Chemical compound Cc(cc1)ccc1S(NN/C(/C=C\COC)=C/CC=C)(=O)=O LLPARVZCHDTYFP-XXFHCLJSSA-N 0.000 description 1
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Abstract
The invention relates to a practical synthetic method for 3, 5-disubstituted pyrazole, and the method solves the defects of long reaction time, large consumption of alkyne, low yield and being difficult to synthesize great amount of compounds of the existing method. The technical proposal is as follows: aldehyde compounds which are dissolved into a solvent react with sulfonyl hydrazine compounds, thus obtaining diazo compounds, then the diazo compounds react with alkyne under alkali and the 3, 5-disubstituted pyrazole is obtained. The method is characterized in that the solvent is toluene, the mol ratio of the aldehyde compounds and the sulfonyl hydrazine compounds in the first step of the reaction is 1; the alkali added in the second step is NaOH aqueous solution, the content of NaOH has the same valent weight with the hydrazine; 1.5 valent weight of diazo compounds are added in the third step, and pure target product is obtained by conventional processing after the reaction.
Description
Technical field:
The present invention relates to a kind of 3, the method for practical synthesizing of 5-disubstituted pyrazole, obtain by rational laboratory facilities synthetic 3, the optimization reaction conditions of 5-disubstituted pyrazole.
Technical background:
Pyrazole compound has extensive biological activity [Chinese Journal of Pesticides; 2005; 44; 491-495.].Aspect medicine and agricultural chemicals, its range of application is extremely extensive, involved weeding, desinsection, a plurality of fields [Modern Agrochemicals such as mite, sterilization and plant growth regulating extremely; 2006; 5; 6-12.].In recent years, 3, the research of 5-disubstituted pyrazole has obtained bigger progress, uses also more and more widely.3, the synthetic method of 5-disubstituted pyrazole has: 1) alpha, beta-unsaturated ketone and hydrazine [Bull.Chem.Soc.Jpn.; 1991,68,719-720.] or 1,3-diketone and hydrazine close cyclization established law [J.Organomet.Chem.; 2004,689,3265-3274.]; 2) aldehyde compound in the presence of hydrazine class compound with the synthesis method of alkyne reaction.The latter is comparatively emerging synthetic method.In the building-up reactions of above-mentioned aldehyde+hydrazine+alkynes, bibliographical information [J.Org.Chem.; 2003,68,5381-5383.] exist long reaction time, the consumption of alkynes to reach the not high shortcoming of yield greatly, make the synthetic problems that exist of this type of pyrazole compound, exist be difficult to realize synthetic a large amount of 3, the shortcoming of 5-disubstituted pyrazole compound.Report in the document that aldehyde obtains the diazonium compounds earlier with hydrazine reaction, this compound can obtain 3 with alkyne reaction in the presence of alkali, the 5-disubstituted pyrazole.The method that this employing is treated different things alike method has before had bigger improvement, for carrying out a large amount of synthetic certain basis of having established of pyrazole compound.But in the work that repeats document, we have found problems.In Bao Dao several routine pyrazole compounds synthetic, yield is between 20-60% in the literature; Simultaneously the reaction times reached 48 hours and the consumption of acetylene compound up to 5 equivalents.These problems make that the separation and purification difficulty is big, and synthetic cost height is less economical, thereby are unfavorable for a large amount of synthetic of pyrazole compound.
Summary of the invention:
The objective of the invention is: develop 3 of a kind of succinct convenient economy, the method for practical synthesizing of 5-disubstituted pyrazole, mainly solving existing synthetic method exists the separation and purification difficulty big, synthetic cost height, less economical technical problem, the present invention adopts rational solvent screening, by to the investigation of reactant consumption, reaction times and temperature of reaction to improve combined coefficient, reduce cost, thereby can carry out 3, a large amount of of 5-disubstituted pyrazole compounds synthesize.
Technical scheme of the present invention:
Among the present invention 3, the synthesis technique of 5-disubstituted pyrazole is as follows: the aldehyde compound that will be dissolved in the solvent obtains the diazonium compounds with the reaction of sulfonyl hydrazines compound earlier, and the diazonium compounds obtains 3 with alkyne reaction in the presence of alkali, the 5-disubstituted pyrazole.It is characterized in that: used solvent is a toluene; The mol ratio of aldehyde compound and sulfonyl hydrazines compound is 1 in the first step reaction; The alkali that second step added is the NaOH aqueous solution, the identical equivalent with hydrazine of NaOH content; The 3rd step added 1.5 normal acetylene compounds, and reaction is after conventional processing obtains pure target product, and chemical equation is:
R
1＝Me，p-MeC
6H
4
Ar in the reaction formula
1Represent the aromatic nucleus substituting group, R
1Be methyl or p-methylphenyl, Ar
2Be the aromatic nucleus substituting group.
Consider the many deficiencies in the document, we have carried out technical improvement to condition, in the hope of developing a kind of succinct, convenient, economical 3, the method for practical synthesizing of 5-disubstituted pyrazole, adopt rational solvent screening, by to the investigation of reactant consumption, reaction times and temperature of reaction to improve combined coefficient, reduce cost, thereby can carry out 3, a large amount of of 5-disubstituted pyrazole compounds synthesize.We are that example is carried out condition optimizing with a compound in the document, and reaction equation is as follows:
At first under the condition of bibliographical information, carry out the screening of solvent, seen Table 1; Under the similarity condition, obviously improve as the solvent yield with toluene, below we choose toluene as solvent.
Table 1: use the influence of different solvents to reaction result
| The solvent title | Reaction Separation yield (%) |
| Acetonitrile 1,4-dioxane toluene tetrahydrofuran (THF) | 49 67 89 72 |
| Other reaction conditions: 1) 1: 2=1 (mol ratio), room temperature, 3 hours; 2) room temperature, 20 minutes; 3) Ar 2C ≡ CH, 5 equivalents; 50 ℃, 48 hours. | |
Secondly, fixedly toluene is solvent, changes the temperature of reaction in the 3rd step, thus preferred reaction conditions.The selection and the reaction result of temperature see Table 2.As shown in Table 2, temperature of reaction reaction result the best in the time of 45 ℃.
Table 2: temperature of reaction is to the influence of reaction result in the 3rd step
| Temperature of reaction in the 3rd step (℃) | Reaction Separation yield (%) |
| Room temperature (25) 45 65 85 | 75 90 89 84 |
| Other reaction conditions: 1) 1: 2=1 (mol ratio), room temperature, 3 hours; 2) room temperature, 20 minutes; 3) Ar 2C ≡ CH, 5 equivalents; 48 hours. | |
The 3rd, we have investigated in the 3rd step the reaction times, and the result is as shown in table 3 to the influence of reaction result.As can be seen, reaction is carried out reacting completely after 12 hours in the table, continues to prolong the reaction times reaction yield is not further improved.Therefore we to choose optimum reacting time be 12 hours.
Table 3: the reaction times is to the influence of reaction result in the 3rd step
| Reaction times in the 3rd step (hour) | Reaction Separation yield (%) |
| 6 12 24 48 | 85 90 88 87 |
| Other reaction conditions: 1) 1: 2=1 (mol ratio), room temperature, 3 hours; 2) room temperature, 20 minutes; 3) Ar 2C ≡ CH, 5 equivalents, 45 ℃. | |
At last, we have carried out optimizing screening to the consumption of alkynes in the 3rd step, and the equivalent that we choose alkynes respectively is 1.5,2.5,3.5 and 5.Consumption is as shown in table 4 to the influence of reaction result.When the consumption of alkynes was 1.5 equivalents as can be seen, reaction was just very complete.And normal increase can not improve reaction yield significantly, considers economy for this reason, and the equivalents that we choose alkynes is 1.5.
Table 4: the consumption of alkynes is to the influence of reaction result in the 3rd step
| The consumption of alkynes (equivalents) | Reaction yield (%) |
| 1 1.5 35 | 78 88 90 91 |
| Other reaction conditions: 1) 1: 2=1 (mol ratio), room temperature, 3 hours; 2) room temperature, 20 minutes; 3) Ar 2C ≡ CH, 45 ℃, 12 hours. | |
By the optimization to above condition, we obtain preferable reaction conditions.Promptly ought be with toluene as solvent, about 45 ℃ of temperature of reaction, about 12 hours reaction times, the equivalents of alkynes is 1.5 o'clock in the 3rd step, reaction result is good especially.Simultaneously, we replace p-toluene sulfonyl hydrazide to carry out same test with the sulfonyloxy methyl hydrazine, find that test-results is good.Chemical equation is as follows:
Above-mentioned 3, in the synthesis technique of 5-disubstituted pyrazole, the mol ratio of aldehyde compound and p-toluene sulfonyl hydrazide or sulfonyloxy methyl hydrazine is 1 in the first step reaction, temperature of reaction normal temperature, 3 hours reaction times; Second step add with hydrazine with the normal NaOH aqueous solution, temperature of reaction normal temperature, 20 minutes reaction times; The 3rd step added 1.5 normal acetylene compounds, was warming up to about 45 ℃, stirred 12 hours.Obtain product after the aftertreatment, purity is up to 95%, about yield 80-90%.
Beneficial effect of the present invention:
Synthetic method of the present invention is succinct, economical, significantly reduce the consumption of alkynes and shorten the reaction times, and yield improves than bibliographical information.The present invention can apply to synthetic a large amount of 3,5-disubstituted pyrazole compounds.
Embodiment:
Embodiment one
The first step, (136mg 1mmol) is dissolved in the 6mL toluene, and (186mg 1mmol), stirred 3 hours under the room temperature to add p-toluene sulfonyl hydrazide then with aubepine; Second step, and the aqueous sodium hydroxide solution of adding 5mol/L (0.2mL, 1mmol), stirring at room 20 minutes; In the 3rd step, (153mg 1.5mmol), is warmed up to 45 ℃, reacts 12 hours afterreactions and finishes to add phenylacetylene.Cool to room temperature revolves and uses ethyl acetate stripping organic phase after solvent and little water are fallen in steaming, and LCMS shows thick product purity 85%.
Above thick product is separated by the preparation plate, obtain 220 mg products, proton nmr spectra [
1H NMR (400MHz, CDCl
3): δ=7.72 (d, 2H), 7.63 (d, 2H), 7.38 (t, 2H), 7.32 (t, 1H), 6.90 (d, 2H), 6.75 (s, 1H), 3.82 (s, 3H)] display structure is correct; M/z=251 (M+H
+).Calculate yield: 88% by aubepine.
Embodiment two
The first step, (186mg 1mmol) is dissolved in the 6 mL toluene, and (186mg 1mmol), stirred 3 hours under the room temperature to add p-toluene sulfonyl hydrazide then with 5-bromopyridine-3-formaldehyde; Second step, and the aqueous sodium hydroxide solution of adding 5mol/L (0.2mL, 1mmol), stirring at room 20 minutes; In the 3rd step, (153mg 1.5mmol), is warmed up to 45 ℃, reacts 12 hours afterreactions and finishes to add phenylacetylene.Cool to room temperature revolves and uses ethyl acetate stripping organic phase after solvent and little water are fallen in steaming, and LCMS shows thick product purity 96%.
Above thick product is separated by the preparation plate, obtain the 260mg product, proton nmr spectra [
1H NMR (400MHz, CDCl
3): δ=9.15 (s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.72 (d, 2H), 7.38 (t, 2H), 7.32 (t, 1H) ,=6.75 (s, 1H)] display structure is correct; M/z=301 (M+H
+).Calculate yield: 86% by 5-bromopyridine-3-formaldehyde.
Embodiment three
The first step will (106mg 1mmol) be dissolved in the 6mL toluene, and (186mg 1mmol), stirred under the room temperature 3 hours to add p-toluene sulfonyl hydrazide then to phenyl aldehyde; Second step, and the aqueous sodium hydroxide solution of adding 5mol/L (0.2mL, 1mmol), stirring at room 20 minutes; In the 3rd step, (174mg 1.5mmol), is warmed up to 45 ℃, reacts 12 hours afterreactions and finishes to methylbenzene acetylene in adding.Cool to room temperature revolves and uses ethyl acetate stripping organic phase after solvent and little water are fallen in steaming, and LCMS shows thick product purity 91%.
Above thick product is separated by the preparation plate, obtain the 210mg product, proton nmr spectra [
1H NMR (400MHz, CDCl
3): δ=7.72 (d, 2H), 7.63 (d, 2H), 7.32 (t, 1H), 7.18 (d, 2H), 6.90 (d, 2H), 6.75 (s, 1H), 2.18 (s, 3H)] display structure is correct; M/z=235 (M+H
+).Calculate yield: 90% by phenyl aldehyde.
Embodiment four
The first step, (106mg 1mmol) is dissolved in the 6mL toluene, and (110mg 1mmol), stirred 3 hours under the room temperature to add the sulfonyloxy methyl hydrazine then with aubepine; Second step, and the aqueous sodium hydroxide solution of adding 5mol/L (0.2mL, 1mmol), stirring at room 20 minutes; In the 3rd step, (153mg 1.5mmol), is warmed up to 45 ℃, reacts 12 hours afterreactions and finishes to add phenylacetylene.Cool to room temperature revolves and uses ethyl acetate stripping organic phase after solvent and little water are fallen in steaming, and LCMS shows thick product purity 89%.
Above thick product is separated by the preparation plate, obtain the 212mg product, [
1HNMR (400MHz, CDCl
3): δ=7.72 (d, 2H), 7.63 (d, 2H), 7.38 (t, 2H), 7.32 (t, 1H), 6.90 (d, 2H), 6.75 (s, 1H), 3.82 (s, 3H)] display structure is correct; M/z=251 (M+H
+).Calculate yield: 85% by aubepine.
Claims (1)
1. one kind 3, the synthetic method of 5-disubstituted pyrazole, the aldehyde compound that will be dissolved in the solvent obtains the diazonium compounds with the reaction of sulfonyl hydrazines compound earlier, the diazonium compounds obtains 3 with alkyne reaction in the presence of alkali, the 5-disubstituted pyrazole, it is characterized in that used solvent is a toluene in the first step reaction, the mol ratio of aldehyde compound and sulfonyl hydrazines compound is 1; The alkali that second step added is the NaOH aqueous solution, the same equivalent of NaOH content and hydrazine; The 3rd step added acetylene compound, and the alkynes consumption is 1.5 equivalents, and reaction is warming up to 45 ℃, stirred 12 hours, and reaction is after conventional processing obtains pure target product, and chemical equation is:
R
1＝Me，p-MeC
6H
4
Ar in the reaction formula
1Represent the aromatic nucleus substituting group, R
1Be methyl or p-methylphenyl, Ar
2Be the aromatic nucleus substituting group.
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|---|---|---|---|
| CN2007100941378A CN101407496B (en) | 2007-10-12 | 2007-10-12 | Method for synthesizing 3,5-disubstituted pyrazole |
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| CN101407496B true CN101407496B (en) | 2011-08-17 |
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| CN102633721B (en) * | 2012-03-22 | 2014-10-29 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing pyrazol derivatives by utilizing gas diazomethane |
| CN102977027B (en) * | 2012-12-06 | 2015-05-13 | 天津大学 | Preparation method of 5-aryl-3-trifluoromethyl-1H-pyrazole compound |
| CN107162975A (en) * | 2017-06-08 | 2017-09-15 | 安顺学院 | A kind of method that pyrazole compound is prepared in solvent-recoverable |
| CN107056635B (en) * | 2017-06-09 | 2019-03-01 | 广西师范大学 | A kind of synthetic method of alkynyl amide class compound |
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Non-Patent Citations (1)
| Title |
|---|
| Varinder K. Aggarwal et al..A Novel One-Pot Method for the Preparation of Pyrazoles by 1，3－Dipolar Cycloadditions of Diazo Compounds Generated in Situ.《Journal of Organic Chemistry》.2003,第68卷(第13期),第5381-5383和S1-S13页. * |
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