CN1219772C - 1,3-aryl group substituted pyrazoline whose 5 position contains ester gruop and its liquid phase synthesis method - Google Patents

1,3-aryl group substituted pyrazoline whose 5 position contains ester gruop and its liquid phase synthesis method Download PDF

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CN1219772C
CN1219772C CN 03129682 CN03129682A CN1219772C CN 1219772 C CN1219772 C CN 1219772C CN 03129682 CN03129682 CN 03129682 CN 03129682 A CN03129682 A CN 03129682A CN 1219772 C CN1219772 C CN 1219772C
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pyrazoline
ester group
contain
phase synthesis
aryl replaces
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CN1515557A (en
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林旭锋
张健
王彦广
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Zhejiang University ZJU
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Abstract

The present invention discloses 1 3-aryl substituted pyrazoline with 5-position containing an ester group and a liquid phase synthesis method thereof. Namely, substituted acrylyl chloride is coupled to soluble resin in an organic solvent under the existence of alkali; equivalent aromatic alcohol and aromatic hydrazine hydrochloride are mixed to obtain corresponding hydrazone under the action of organic alkali, and then, substituted acrylic ester carried by the soluble resin and an oxidizer are added, namely that 1 3-aryl substituted pyrazoline with 5-position containing an ester group, which is carried by resin, is obtained by a one-kettle annelation method. The pyrazoline carried by a high molecular polymer can be disassociated from the soluble resin in an alcohol solvent under the catalytic action of corresponding sodium alcoholate to 1, 3-aryl substituted pyrazoline with 5-position containing an ester group in high yield and high purity. The compound can be developed into medicines, agricultural chemicals and photosensitive materials. The present invention has the advantages of convenient and rapid synthesis and low cost and has good application prospects.

Description

5 contain 1 of ester group, the pyrazoline liquid phase synthesizing method that the 3-aryl replaces
Technical field
The present invention relates to pyrazoline and synthetic method thereof, relate in particular to a kind of 5 and contain 1 of ester group, the pyrazoline liquid phase synthesizing method that the 3-aryl replaces.
Background technology
Pyrazoline is one of modal structure component in natural product, sensitive materials, modern medicines and the agricultural chemicals, has multiple important physical activity.For example, antisepsis and anti-inflammation, antimycotic, antitumor, and regulate seed germination and plant-growth etc., at aspects such as sensitive materials, medicine and agricultural chemicals huge value of exploiting and utilizing is arranged.For a long time, people are imagining library of molecules how to set up this compounds always, thereby systematically carry out bioactive screening, determine structure activity relationship.how easy and 5 contain 1 of ester group, and the pyrazoline that the 3-aryl replaces has physiologically active uniquely, and synthetic in enormous quantities efficiently this compounds? can 1, the pyrazoline prior synthesizing method that the 3-aryl replaces all is based on the alternate reaction of solution.Solution alternate reaction for example, (a) document Tetrahedron letters1998,39,4887 reported the chloro hydrazone in the presence of alkali with the cycloaddition reaction of alkene; (b) synth.Comm., 1989,19,2799 have reported after hydrazone is by the chloramine-T oxidation reaction with different alkene; (c) Tetrahedron 1995,51, and 1631 have reported diazomethane and different alkene preparation 3,4, the reaction of 5-three pyrazoline-substitutings.However, tentatively do not put forward above some method and will use expensive reagent, some has provided unfavorable productive rate, and reaction branch multistep is carried out, and can not directly make full use of commercial available raw material; Even they may be effectively for synthetic certain or several compounds, but want obtain a large amount of highly purified different compounds with precursor structure rapidly easily, but are time-consuming, almost are impossible.We are diversion to 1, during the parallel liquid phase of the pyrazoline that the 3-aryl replaces is synthetic, and wish to utilize the cyclization of one kettle way, can directly make full use of the library of molecules that commercial available raw material is set up this compounds fast.
Summary of the invention
The purpose of this invention is to provide a kind of 5 and contain 1 of ester group, the pyrazoline liquid phase synthesizing method that the 3-aryl replaces.
Its general molecular formula is:
Figure C0312968200041
R wherein 1, R 2=H, alkyl, cyano group, halogen, nitro, methoxyl group, oxyethyl group, wherein alkyl is C nH 2n+1, n=1-5; R 3=methyl, ethyl; R 4=H, alkyl, aryl, wherein alkyl is C nH 2n+1, n=1-5.
Its liquid-phase synthesis process is in room temperature, in organic solvent, under the organic bases effect, mix the aromatic aldehyde of equivalent and the corresponding hydrazone that fragrant hydrazonium salt obtains, under 0--5 ℃, add soluble resin then and prop up the acrylate and the oxygenant of the replacement of carrying, promptly obtain resin-carried 5 at a certain temperature and contain 1 of ester group, the pyrazoline that the 3-aryl replaces with the annulation of one kettle way.Through simple crystallization, washing and drying, the pyrazoline of these polymer-supporteds is in alcoholic solvent, and under corresponding sodium alkoxide catalysis, the pyrazoline of these polymer-supporteds disintegrates down from soluble resin, obtain 5 and contain 1 of ester group, the pyrazoline that the 3-aryl replaces.Reaction formula is:
R wherein 1, R 2=H, alkyl, cyano group, halogen, nitro, methoxyl group, oxyethyl group, wherein alkyl is C nH 2n+1, n=1-5; R 3=methyl, ethyl; R 4=H, alkyl, aryl, wherein alkyl is C nH 2n+1, n=1-5.
The present invention compares with existing synthetic method, has the following advantages:
1) hydrogencarbonate aqueous solution is by the aromatic aldehyde that contains corresponding group and the condensation under the alkali effect of fragrant hydrazonium salt of equivalent, without purifying, just can be directly in cyclization as 1,3-dipole precursor uses, and uses one kettle way can produce a large amount of cyclisation product quickly and easily.
2) because the solubility of resin polyoxyethylene glycol, reaction is a homogeneous, as long as use 3-5 normal excessive 1, the 3-dipole just can make reaction yield improve widely, is higher than the productive rate of solution phase and solid phase synthesis.
3) use gentle oxygenant can obtain regiospecific pyrazoline derivative.
4) utilize liquid phase to synthesize segregative characteristics, simplified operation greatly, only need through simple crystallization, washing, the purity of crude product just can reach more than 90%, is enough to reach the purity requirement of bioactivity screening.
5) used cheap soluble resin polyoxyethylene glycol, alkali and solvent that some are commonly used, synthetic with low cost, good prospects for application is arranged; Employed polyoxyethylene glycol can dissolve well at organic solvent such as methylene dichloride, chloroform, toluene, methyl alcohol etc., and it is insoluble substantially in organic solvent such as ether, Virahol, utilize this character, promptly reach the purpose of the polyglycol supported product of purifying through simple crystallization, washing.
6) feed intake and aftertreatment all very simple, and similar, be easy to utilize the liquid phase synthesizer to realize automatization.
Specific implementation method
5 contain 1 of ester group, and the concrete reactions steps of the liquid phase synthesizing method of the pyrazoline that the 3-aryl replaces is as follows:
1) acrylate of Qu Daiing is resin-carried: in organic solvent, the acrylate chloride of replacement with soluble resin reaction 5-25 hour, can load on the acrylate that replaces on the resin under alkali existence and certain temperature condition, and recommended temperature is 0-35 ℃; Wherein soluble resin is that molecular-weight average is the polyoxyethylene glycol (MeOPEG) of the polyoxyethylene glycol (PEG) of 3000-5000 or the mono methoxy protection that molecular-weight average is 3000-5000.Organic solvent comprises methylene dichloride, chloroform.
2) 5 of the load of one kettle way synthetic resins contain 1 of ester group, the pyrazoline that the 3-aryl replaces: in organic solvent, the aromatic aldehyde that contains corresponding group of equivalent and fragrant hydrazonium salt be (20-80 ℃) at a certain temperature, under the organic bases effect, obtained hydrogencarbonate aqueous solution in condensation reaction 0.5-3 hour, without purifying, the acrylate and the oxygenant that directly add resin-carried replacement, reacted at a certain temperature 5-24 hour, annulation takes place, through simple crystallization and washing, obtain resin-carried 5 and contain 1 of ester group, the pyrazoline that the 3-aryl replaces; Oxygenant is p-methyl benzene sulfonic chloride amine sodium salt (chloramine-T), Chloramine B salt (chloramine B); Recommend to use chloramine-T.Organic solvent is methyl alcohol, ethanol.The cyclization temperature is 25-80 ℃.Organic bases is a diisopropyl ethyl amine, triethylamine, tripropyl amine, trioctylamine; Aldehyde and hydrazonium salt are the 3-5 equivalent; Alkali wherein: aldehyde: hydrazonium salt: oxygenant=1: 1: 1: 1.
3) resin cutting: under sodium alkoxide catalysis, resin-carried 5 contain 1 of ester group, and the pyrazoline that the 3-aryl replaces is in corresponding alcoholic solvent, at room temperature reaction 5-12 hour, by crystallization, washing, obtain 5 to high yield, high purity and contain 1 of ester group, the pyrazoline that the 3-aryl replaces.Sodium alkoxide comprises sodium methylate, sodium ethylate, and its consumption is the 0.5-3.0 equivalent; Alcoholic solvent is methyl alcohol, ethanol.
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1
Step 1: with the 15g molecular weight is that 4000 polyoxyethylene glycol (PEG4000) is dissolved in the 60ml methylene dichloride, adds the 4.16ml trioctylamine, and the ice bath cooling slowly dripped the 2.45ml acrylate chloride more than 2 hours.Dropwise, remove ice bath, room temperature reaction 24 hours.Reaction finishes, and add the 500ml anhydrous diethyl ether and rock to solution and be muddy, freezing 30 minutes, separate out crystal, suction filtration with anhydrous diethyl ether washing three times, is put into moisture eliminator, and vacuum-drying is spent the night and is obtained PEG4000 and prop up the acrylate 14.9g that carries.
Step 2: under the nitrogen protection, add hydrazinobenzene hydrochloride salt 185mg in the little flask of 10ml, add methyl alcohol 8ml, trioctylamine 0.5ml adds phenyl aldehyde 133mg, stirring at room 30 minutes; Add 281mg chloramine-T and PEG4000 then successively and prop up the 0.5g acrylate that carries, temperature control reacted 12 hours at 40 ℃.Reaction finishes, and adds anhydrous diethyl ether 50ml, freezing and crystallizing.Suction filtration, it is inferior to give a baby a bath on the third day after its birth with anhydrous diethyl ether.Vacuum-drying is spent the night, and promptly gets pure PEG4000 and props up the pyrazoline 0.49g that carries.
Step 3: under the nitrogen protection, above-mentioned PEG is propped up the pyrazoline 0.49g that carries put into the little flask of 10ml, add 5mg sodium methylate and anhydrous methanol 4ml, stirring at room 6 hours.Adding anhydrous diethyl ether 40ml, crystallisation by cooling is separated out PEG4000, and suction filtration is removed resin PEG, and the quick silica gel short column of crossing of filtrate is removed remaining PEG and sodium methylate, concentrates and does, and vacuum-drying is spent the night, and gets product 1-phenyl-3-phenyl-5-methyl-formiate pyrazoline.Purity 93%, productive rate 88%.
Figure C0312968200071
1H?NMR(500MHz，CDCl 3)δ＝3.48(dd，J＝7.2Hz，17.4Hz，1H)，3.70(dd，J＝4.4Hz，17.4Hz，1H)，3.76(s，3H)，4.82(dd，J＝4.4Hz，7.2Hz，1H)，6.88(t，1H)，7.13(d，J＝8.0Hz，2H)，7.3-7.5(m，5H)，7.72(d，J＝7.2Hz，2H)。
Embodiment 2
Reactions steps is with embodiment 1, and different is in the step 1 employedly is the 3.0ml methacrylic chloride; The product that obtains is 1-phenyl-3-phenyl-5-methyl-5-methyl-formiate pyrazoline.Purity 100%, productive rate 91%.
1H-NMR(500MHZ，CDCl 3)δ＝1.64(s，3H)，3.31(d，J＝16.6Hz，1H)，3.71(d，J＝16.6Hz，1H)，3.77(s，3H)，6.88(t，1H)，7.11(d，J＝8.3Hz，2H)，7.25(d，J＝7.3Hz，2H)，7.40(m，3H)，7.70(d，J＝7.3Hz，2H).
Embodiment 3
Reactions steps is with embodiment 1, and different is in the step 1 employedly is the 3.0ml methacrylic chloride; The used solvent of crystallization is the 50ml Virahol in the step 2; Added aromatic aldehyde is aubepine 164mg in the step 2.The product that obtains is 1-phenyl-3-p-methoxyphenyl-5-methyl-5-methyl-formiate pyrazoline.Purity 98%, productive rate 90%.
Figure C0312968200073
1H-NMR(500MHZ，CDCl 3)δ＝1.62(s，3H)，3.27(d，J＝16.5Hz，1H)，3.69(d，J＝16.5Hz，1H)，3.76(s，3H)，3.84(s，3H)，6.86(t，1H)，6.91(d，J＝8.7Hz，2H)，7.10(d，J＝7.0Hz，2H)，7.23(m，2H)，7.65(d，J＝7.0Hz，2H).
Embodiment 4
Reactions steps is with embodiment 1, different is in the step 1 employedly is the 3.0ml methacrylic chloride, employed molecular weight polyethylene glycol is 3000, and added aromatic aldehyde is aubepine 164mg in the step 2, and aryl hydrazine is to tolylhydrazine hydrochloride 200mg.The product that obtains is 1-p-methylphenyl-3-p-methoxyphenyl-5-methyl-5-methyl-formiate pyrazoline.Purity 97%, productive rate 85%.
Figure C0312968200081
1H-NMR(500MHZ，CDCl 3)δ＝1.59(s，3H)，2.28(s，3H)，3.26(d，J＝17Hz，1H)，3.64(d，J＝17Hz，1H)，3.76(s，3H)，3.84(s，3H)，6.92(d，J＝8.8Hz，2H)，7.00(d，J＝8.5Hz，2H)，7.06(d，J＝8.5Hz，2H)，7.64(d，J＝8.8Hz，2H).
Embodiment 5
Reactions steps is with embodiment 1, different is in the step 1 employedly is the 3.0ml methacrylic chloride, and employed molecular weight polyethylene glycol is 5000, and added aromatic aldehyde is aubepine 163mg in the step 2, aryl hydrazine is to fluorophenyl hydrazine hydrochloride 204mg, and the cyclisation temperature is 70 ℃.The product that obtains is that 1-is to fluorophenyl-3-p-methoxyphenyl-5-methyl-5-methyl-formiate pyrazoline.Purity 98%, productive rate 81%.
1H-NMR(500MHZ，CDCl 3)δ＝1.57(s，3H)，3.28(d，J＝16Hz，1)，3.65(d，J＝16Hz，1H)，3.76(s，3H)，3.85(s，3H)，6.92(d，J＝8.8Hz，2H)，6.95(d，J＝8.4Hz，2H)，7.08(m，2H)，7.64(d，J＝8.8Hz，2H).
Embodiment 6
Reactions steps is with embodiment 1, and different is in the step 1 employedly is the 3.0ml methacrylic chloride, and employed molecular weight polyethylene glycol is 5000, and added aryl hydrazine is to tolylhydrazine hydrochloride 200mg in the step 2; The employed solvent of crystallization is the Virahol of 50ml in the step 2.The product that obtains is 1-p-methylphenyl-3-phenyl-5-methyl-5-methyl-formiate pyrazoline.Purity 99%, productive rate 87%.
1H-NMR(500MHZ，CDCl 3)δ＝1.60(s，3H)，2.28(s，3H)，3.29(d，J＝16.5Hz，1H)，3.67(d，J＝16.5Hz，1H)，3.76(s，3H)，7.00(d，J＝8.5Hz，2H)，7.05(d，J＝8.5Hz，2H)，7.40(m，3H)，7.70(d，J＝8.5Hz，2H)。
Embodiment 7
Reactions steps is with embodiment 1; different is in the step 1 employedly is the 3.0ml methacrylic chloride; the soluble polymer that uses be the polyoxyethylene glycol (MeOPEG) of 5000 mono methoxy protection as molecular-weight average, added aryl hydrazine is to fluorophenyl hydrazine hydrochloride 200mg in the step 2.The product that obtains is that 1-phenyl-3-is to fluorophenyl-5-methyl-5-methyl-formiate pyrazoline.Purity 100%, productive rate 88%.
1H-NMR(500MHZ，CDCl 3)δ＝1.61(s，3H)，3.34(d，
Figure C0312968200091
J＝16Hz，1H)，3.75(d，J＝16Hz，1H)，3.79(s，3H)，7.06(t，2H)，7.05(m，2H)，7.40(m，3H)，7.72(d，J＝7.5Hz，2H).

Claims (7)

1. one kind 5 contain 1 of ester group, the liquid-phase synthesis process of the pyrazoline that the 3-aryl replaces, it is characterized in that in room temperature, in organic solvent, under the organic bases effect, mix the aromatic aldehyde of equivalent and the corresponding hydrazone that fragrant hydrazonium salt obtains, add acrylate and oxygenant that soluble resin props up the replacement of carrying then, promptly obtain resin-carried 5 at a certain temperature and contain 1 of ester group, the pyrazoline that the 3-aryl replaces with the annulation of one kettle way; Through simple crystallization, washing and drying, the pyrazoline of these polymer-supporteds is in alcoholic solvent, and under corresponding sodium alkoxide catalysis, the pyrazoline of these polymer-supporteds disintegrates down from soluble resin, obtain 5 and contain 1 of ester group, the pyrazoline that the 3-aryl replaces; Reaction formula is:
R wherein 1, R 2=H, alkyl, cyano group, halogen, nitro, methoxyl group, oxyethyl group, wherein alkyl is C nH 2n+1, n=1-5; R 3=methyl, ethyl; R 4=H, alkyl, wherein alkyl is C nH 2n+1, n=1-5.
2. a kind of 5 according to claim 1 contain 1 of ester group; the pyrazoline liquid-phase synthesis process that the 3-aryl replaces is characterized in that said soluble resin is that molecular-weight average is the polyoxyethylene glycol of the polyoxyethylene glycol of 3000-5000 or the mono methoxy protection that molecular-weight average is 3000-5000.
3. a kind of 5 according to claim 1 contain 1 of ester group, and the pyrazoline liquid-phase synthesis process that the 3-aryl replaces is characterized in that said cyclization temperature is 25-80 ℃.
4. a kind of 5 according to claim 1 contain 1 of ester group, and the pyrazoline liquid-phase synthesis process that the 3-aryl replaces is characterized in that said organic bases is a diisopropyl ethyl amine, triethylamine, tripropyl amine, trioctylamine; Aldehyde and hydrazonium salt are the 3-5 equivalent; Alkali wherein: aldehyde: hydrazonium salt: oxygenant=1: 1: 1: 1.
5. a kind of 5 according to claim 1 contain 1 of ester group, and the pyrazoline liquid-phase synthesis process that the 3-aryl replaces is characterized in that said organic solvent is methyl alcohol, ethanol.
6. a kind of 5 according to claim 1 contain 1 of ester group, and the pyrazoline liquid-phase synthesis process that the 3-aryl replaces is characterized in that said sodium alkoxide is sodium methylate, sodium ethylate, and its consumption is the 0.5-3.0 equivalent, and alcoholic solvent is methyl alcohol, ethanol.
7. a kind of 5 according to claim 1 contain 1 of ester group, and the pyrazoline liquid-phase synthesis process that the 3-aryl replaces is characterized in that said oxygenant is p-methyl benzene sulfonic chloride amine sodium salt, Chloramine B salt.
CN 03129682 2003-06-30 2003-06-30 1,3-aryl group substituted pyrazoline whose 5 position contains ester gruop and its liquid phase synthesis method Expired - Fee Related CN1219772C (en)

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WO2016184429A1 (en) * 2015-05-21 2016-11-24 常州强力先端电子材料有限公司 Pyrazoline sensitizer and preparation method and use thereof
CN113527207B (en) 2020-04-22 2023-06-06 常州强力电子新材料股份有限公司 Ethoxy/propoxy modified pyrazoline organic matter, application thereof, photo-curing composition and photoresist
CN112574184B (en) * 2020-12-25 2022-12-20 同济大学 Epoxide-substituted pyrazoline derivative, photocuring composition and preparation method
CN115572263B (en) * 2022-10-17 2023-12-12 郑州中科新兴产业技术研究院 Method for synthesizing pyrazoline by catalyzing ketazine cyclization with hydrazine salt

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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