CN102558184B - Synthesis method of phthalazine derivative - Google Patents
Synthesis method of phthalazine derivative Download PDFInfo
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- CN102558184B CN102558184B CN201110454799.8A CN201110454799A CN102558184B CN 102558184 B CN102558184 B CN 102558184B CN 201110454799 A CN201110454799 A CN 201110454799A CN 102558184 B CN102558184 B CN 102558184B
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- phthalocyclohydrazide
- alkanoic
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Abstract
The invention discloses a synthesis method of a phthalazine derivative. In the method, phthalylhydrazine and dimedone or 1,3-cyclohexanedione react with aromatic aldehyde or aliphatic aldehyde in the conditions that the ionic liquid [BSO3HMIm]HSO4 is used as a catalyst, PEG (polyethylene glycol) 600 is used as a solvent and the temperature is 100-160 DEG C; and the phthalazine derivative is synthesized from three components in one pot. The synthesis method has the advantages of low cost, good application prospect and the like, and is efficient, non-toxic and environment-friendly; and the catalyst and solvent are easily recycled and can be recycled.
Description
Technical field
The invention belongs to chemical field, relate to the synthetic method of a compounds.
Background technology
Compared with conventional linear building-up reactions, polycomponent building-up reactions has that cost is low, the time is short, atom economy, advantages of environment protection, can be one-step synthesis novelty and complicated molecular structure, cause in recent years increasing concern.
Heterogeneous ring compound is at occurring in nature ubiquity closely bound up with people's life.Phthalazine derivative belongs to heterogeneous ring compound, has that spasmolytic, cardiac stimulant, blood vessel relax, anticytotoxin, antibacterial, anti-inflammatory, a various biological activity such as anticancer, also has the potentiality as fluorescent material.The synthetic polyphosphoric acid of supporting mainly with tosic acid, sulfuric acid, silicotungstic acid, phospho-wolframic acid, silicon sulfonic acid, trimethylchlorosilane, silicon-dioxide of the phthalazine derivative of bibliographical information, the phospho-molybdic acid that silicon-dioxide is supported,
n, N, N ', N '-tetrabromo-benzene-1,3-disulfonic acid amide, poly-
n-bromo-
n-ethylbenzene-1,3-disulfonic acid amide etc. is catalyzer, also has recently the synthetic phthalazine derivative of one pot of four component of bibliographical information Catalyzed by Ceric Sulfate, but all there is the shortcoming that cannot avoid in these methods, as used toxic metal, noxious solvent or easy volatile solvent, catalyzer is expensive or catalyst loading is large, last handling process is loaded down with trivial details, catalyzer or solvent are difficult to reclaim etc.Therefore,, from the angle of Green Chemistry, still need to study new method and synthesize phthalazine derivative.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of green synthesis method of phthalazine derivative, efficient, nontoxic, environmental friendliness, catalyzer is easy to recovery, reusable, and cost is low.
For reaching this object, the invention provides following technical scheme:
The synthetic method of phthalazine derivative is at ionic liquid 1-butyl sulfonic acid-3-Methylimidazole hydrosulfate ([BSO by Phthalocyclohydrazide, methone or hydroresorcinol and aromatic aldehyde or alkanoic
3hMIm] HSO
4) for catalyzer, polyoxyethylene glycol (PEG) 600 is for solvent, temperature are to react under the condition of 100 ~ 160 DEG C, make phthalazine derivative.
Further, described aromatic aldehyde is phenyl aldehyde or substituted benzaldehyde.
Further again, the described substituted benzaldehyde phenyl aldehyde that to be phenyl ring replaced by 1 ~ 2 substituting group, described substituting group is independently selected from one or more in fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano group, hydroxyl, C1 ~ C6 alkoxyl group and C1 ~ C6 alkyl.
Further, described aromatic aldehyde is phenyl aldehyde, 4-nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-nitrobenzaldehyde, 4-fluorobenzaldehyde, 3-fluorobenzaldehyde, 2-fluorobenzaldehyde, 2, 3-difluorobenzaldehyde, 2, 4-difluorobenzaldehyde, 2, 5-difluorobenzaldehyde, 2, 6-difluorobenzaldehyde, 4-chlorobenzaldehyde, 3-chlorobenzaldehyde, 2-chlorobenzaldehyde, 2, 3-dichlorobenzaldehyde, 2, 4-dichlorobenzaldehyde, 2, 5-dichlorobenzaldehyde, 2, 6-dichlorobenzaldehyde, 4-bromobenzaldehyde, 3-bromobenzaldehyde, 2-bromobenzaldehyde, 2, 3-dibromo benzaldehyde, 2, 4-dibromo benzaldehyde, 2, 5-dibromo benzaldehyde, 2, 6-dibromo benzaldehyde, 4-tolyl aldehyde, 3-tolyl aldehyde or 2-tolyl aldehyde, described alkanoic is propionic aldehyde or butyraldehyde.
Further, described alkanoic is C1 ~ C6 alkanal.
Further, described alkanoic is propionic aldehyde or butyraldehyde.
The molar ratio of described Phthalocyclohydrazide, methone or 1,3-cyclopentanedione and aromatic aldehyde or alkanoic is preferably 1:1 ~ 1.5:1 ~ 1.7, and more preferably 1:1.3 ~ 1.5:1.5 ~ 1.7, most preferably are 1:1.4:1.6.
Described ionic liquid [BSO
3hMIm] HSO
4mole dosage be preferably 10% ~ 25% of Phthalocyclohydrazide mole dosage, more preferably 15% ~ 25% of Phthalocyclohydrazide mole dosage, most preferably be 15% of Phthalocyclohydrazide mole dosage.
More preferably 120 ~ 160 DEG C of described temperature of reaction, most preferably are 120 DEG C.
Catalyzer [BSO in the inventive method
3hMIm] HSO
4can reclaim and recycle with solvent PEG 600, technical scheme has following two kinds:
The first: after completion of the reaction, reaction solution is cooled to room temperature, stirring adds water, suction filtration, filter cake makes phthalazine derivative by washing with alcohol, after washing lotion and filtrate merge, in 100 ~ 160 DEG C of dephlegmates and ethanol, then adds wherein Phthalocyclohydrazide, methone or 1, hydroresorcinol and aromatic aldehyde or alkanoic carry out circulating reaction, and circulating reaction number of times can be 1 ~ 5 time.
The second: after completion of the reaction, reaction solution is cooled to room temperature, stirring adds water, with organic solvent extraction, the underpressure distillation of organic solvent extraction liquid, except desolventizing, is purified and made phthalazine derivative by column chromatography, surplus solution after extraction is in 100 ~ 160 DEG C of dephlegmates, add wherein Phthalocyclohydrazide, methone or hydroresorcinol and aromatic aldehyde or alkanoic to carry out circulating reaction, circulating reaction number of times can be 1 ~ 5 time again.
Beneficial effect of the present invention is: the invention provides a kind of simple, efficient, green phthalazine derivative synthetic method, is with ionic liquid [BSO
3hMIm] HSO
4for catalyzer, PEG 600 are solvent, one pot of three synthetic phthalazine derivative of component, has efficiently, nontoxic, environmental friendliness, and catalysts and solvents is easy to recovery, reusable, low cost and other advantages, application prospect is good.
Brief description of the drawings
Fig. 1 shows the recovery and recycling result of catalysts and solvents system, wherein
aexperiment condition is: Phthalocyclohydrazide (1.0 mmol), methone (1.4 mmol), paranitrobenzaldehyde (1.6 mmol), [BSO
3hMIm] HSO
4(0.15 mmol), PEG 600(1.0 ml), 120 DEG C of reactions of temperature;
bexperiment condition is: Phthalocyclohydrazide (1.0 mmol), methone (1.0 mmol), paranitrobenzaldehyde (1.0 mmol), the last catalysts and solvents system reclaiming, 120 DEG C of reactions of temperature.
Embodiment
In order to make the object, technical solutions and advantages of the present invention clearer, below in conjunction with accompanying drawing, the present invention is described in detail.
The reagent using in embodiment is all from commercial channel and do not pass through further purifying.Reaction process is all used tlc (TLC) monitoring, and used silica gel plate is GF254.Portion of product adopts flash column chromatography purifying, and chromatographic column used is 200-300 order silica gel pressured column.Proton nmr spectra (
1h NMR) and carbon spectrum (
13c NMR) adopt Bruker AV-300 nuclear magnetic resonance analyser record, chemical shift δ measures with ppm, uses TMS to make interior mark, coupling constant
jcalculate with Hz.
the impact of embodiment 1, catalyst type and carrying capacity
Ionic liquid (IL) has returnability and good solubility, not only can be used as solvent, but also is good catalyzer.The present embodiment is taking the reaction of Phthalocyclohydrazide, methone and paranitrobenzaldehyde as template reaction, and catalytic activity and carrying capacity to ionic liquid are investigated.Experimental technique is: in reaction flask, add Phthalocyclohydrazide (1.0mmol), methone (1.0mmol) and paranitrobenzaldehyde (1.2mmol), do not add catalyzer or add respectively following several ionic liquid as catalyzer: 1-butyl-3-methyl imidazolium tetrafluoroborate ([BMIm] BF
4), 1-butyl-3-Methylimidazole hexafluorophosphate ([BMIm] PF
6), 1-butyl-3-Methylimidazole acetate [BMIm] Ac, 1-butyl-3-Methylimidazole hydrosulfate ([BMIm] HSO
4), 1-butyl sulfonic acid-3-Methylimidazole hydrosulfate ([BSO
3hMIm] HSO
4), then add 1ml PEG 600,120 DEG C of reactions of temperature control.After completion of the reaction, be cooled to room temperature, the 5ml that adds water, stirs 5 minutes, has insolubles to occur, suction filtration, and filter cake absolute ethanol washing, obtains target product.Result is as shown in table 1.
The impact of table 1 catalyst type and carrying capacity
As shown in Table 1, when (1) catalyst-free, react and within 240 minutes, have not yet to see product and generate, and during taking ionic liquid as catalyzer, [BSO
3hMIm] HSO
4demonstrate best catalytic activity, react and within 30 minutes, provide 81% productive rate, [BMIm] HSO
4catalytic activity take second place, all the other several ionic liquids do not have catalytic activity substantially, therefore, preferably [BSO of catalyzer of the present invention
3hMIm] HSO
4.(2) as [BSO
3hMIm] HSO
4carrying capacity is the i.e. [BSO of 10%(
3hMIm] HSO
4mole dosage be Phthalocyclohydrazide mole dosage 10%) time, the productive rate reacting 30 minutes is 73%; In the time that carrying capacity is increased to 15%, gain in yield to 81%; Continuing afterwards increases carrying capacity, and productive rate does not almost change, and therefore, catalyst loading of the present invention is preferably 15% ~ 25%, and more preferably 15%.
the impact of embodiment 2, reaction solvent and temperature of reaction
The present embodiment is taking the reaction of Phthalocyclohydrazide, methone and paranitrobenzaldehyde as template reaction, with [BSO
3hMIm] HSO
4for catalyzer, reaction solvent and temperature of reaction are investigated.Experimental technique is: in reaction flask, add Phthalocyclohydrazide (1.0mmol), methone (1.0mmol), paranitrobenzaldehyde (1.2mmol) and [BSO
3hMIm] HSO
4(0.15mmol), then add solvent, temperature control reaction 30 minutes, post-treating method is with embodiment 1.Result is as shown in table 2.
The impact of table 2 reaction solvent and temperature
As shown in Table 2, (1), taking water or ethanol as solvent, the back flow reaction productive rate of 30 minutes is very low, and taking PEG 600 as solvent, 120 DEG C of reactions of temperature control productive rates of 30 minutes reach 81%, and therefore, reaction solvent of the present invention is preferably PEG 600.(2) when PEG 600 add volume to be 1ml time, productive rate the highest (81%); In the time adding volume to be reduced to 0.5ml, productive rate slightly declines (79%), and possible cause is that solvent volume is little, causes the solubleness of Phthalocyclohydrazide and product little; When adding volume to be increased to 2 ~ 3ml, along with the increase of volume, productive rate declines obviously (being low to moderate 45%), and possible cause is that solvent volume is large, causes the concentration of substrate and catalyzer low, is unfavorable for effectively carrying out of reaction; Therefore, solvent volume of the present invention is preferably 0.5 ~ 1ml, more preferably 1ml.(3) under the same conditions, the reaction yield that temperature control is 100 DEG C is 70%, and the reaction yield that temperature control is 120 DEG C is increased to 81%, but continue rising reaction temperature to 160 DEG C, therefore productive rate is without considerable change,, temperature of reaction of the present invention is preferably 120 ~ 160 DEG C, more preferably 120 DEG C.
the impact of embodiment 3, substrate molar ratio
The present embodiment is taking the reaction of Phthalocyclohydrazide, methone and paranitrobenzaldehyde as template reaction, with [BSO
3hMIm] HSO
4for catalyzer, substrate molar ratio is investigated.Experimental technique is: in reaction flask, add Phthalocyclohydrazide (1.0mmol), methone (1.0 ~ 1.5mmol), paranitrobenzaldehyde (1.2 ~ 1.7mmol) and [BSO
3hMIm] HSO
4(0.15mmol), then add 1ml PEG 600,120 DEG C of reactions of temperature control 30 minutes, post-treating method is with embodiment 1.Result is as shown in table 3.
The impact of table 3 substrate molar ratio
As shown in Table 3, along with the increase of Phthalocyclohydrazide, methone and paranitrobenzaldehyde molar ratio, productive rate increases gradually, while reaching 1:1.4:1.6 to three's mol ratio, productive rate is up to 95%, continues afterwards to increase substrate mol ratio, productive rate does not almost change, therefore, in the present invention, the molar ratio of Phthalocyclohydrazide, methone and paranitrobenzaldehyde is preferably 1:1.3 ~ 1.5:1.5 ~ 1.7, more preferably 1:1.4:1.6.
the recovery of embodiment 4, catalysts and solvents system and recycling
In embodiment 1 ~ 3, after completion of the reaction, in reaction mixture, add water, product, excessive substrate (intermediate that methone, paranitrobenzaldehyde, methone and paranitrobenzaldehyde reaction generate) are separated out because of water insoluble, and catalyzer [BSO
3hMIm] HSO
4exist in solution because of soluble in water with solvent PEG 600, can be easily product and excessive substrate and catalysts and solvents be separated by solid-liquid separation, isolated solid can be removed excessive substrate with absolute ethanol washing, washing lotion and isolated liquid merge, in 120 DEG C of dephlegmates and ethanol, resistates is the mixed solution of catalyzer, solvent and excessive substrate, adds wherein appropriate substrate, can carry out secondary response again.The present embodiment is to ionic liquid [BSO
3hMIm] HSO
4investigate with recycling effect with the recovery of solvent PEG 600.Experimental technique is: in reaction flask, add Phthalocyclohydrazide (1.0mmol), methone (1.4mmol), paranitrobenzaldehyde (1.6mmol) and [BSO
3hMIm] HSO
4(0.15mmol), then add 1ml PEG 600,120 DEG C of reactions of temperature control 30 minutes, after completion of the reaction, are cooled to room temperature, and the 5ml that adds water, stirs 5 minutes, has insolubles to occur, suction filtration, and filter cake washing with alcohol, obtains target product; Filtrate is in 120 DEG C of dephlegmates and ethanol, then adds wherein Phthalocyclohydrazide (1.0mmol), methone (1.0mmol) and paranitrobenzaldehyde (1.0mmol) to carry out lower secondary response, altogether circulating reaction 5 times.Result as shown in Figure 1, catalyzer [BSO
3hMIm] HSO
4after 4 circulations, productive rate only slightly declines (being down to 92% by 95%) with solvent PEG 600, after 5 circulations, still can obtain good productive rate (87%).
embodiment 5, [BSO
3
hMIm] HSO
4
one pot of three component of catalysis synthesized phthalazine derivative
On the optimal conditions basis filtering out at embodiment 1 ~ 3, the present embodiment is to [BSO
3hMIm] HSO
4the versatility of the synthetic phthalazine derivative of one pot of three component of catalysis is investigated.Experimental technique is: in reaction flask, add Phthalocyclohydrazide (1.0mmol), methone or hydroresorcinol (1.4mmol), aldehyde (1.6mmol) and [BSO
3hMIm] HSO
4(0.15mmol), then add 1ml PEG 600,120 DEG C of reactions of temperature control 30 minutes.Product
4a10with
4a11post-treating method be: after completion of the reaction, be cooled to room temperature, the 10ml that adds water, stirs 5 minutes, with dichloromethane extraction 2 times, each 10ml, combined dichloromethane extraction liquid, underpressure distillation, except desolventizing, is purified with flash column chromatography, obtains object product; Product
4a1 ~ 4a9with
4b1 ~ 4b8post-treating method with embodiment 1.Result is as shown in table 4.
Table 4 [BSO
3hMIm] HSO
4one pot of three component of catalysis synthesized phthalazine derivative
As shown in Table 4, (1) in the time that aldehyde is aromatic aldehyde, no matter be connected with electron-withdrawing substituent or electron donating group on aromatic ring, no matter ortho position, position or the contraposition of this substituting group in aromatic ring, it can and obtain good productive rate (being not less than 70%) with Phthalocyclohydrazide and methone or the synthetic phthalazine derivative of one pot of three component of hydroresorcinol; Wherein, the aromatic aldehyde that is connected with electron-withdrawing substituent on aromatic ring is compared the aromatic aldehyde productive rate better (being not less than 80%) that is connected with electron donating group on aromatic ring.(2) in the time that aldehyde is saturated aliphatic aldehyde, compare the reaction times that aromatic aldehyde need to be longer, productive rate is relatively low.(3), compared with hydroresorcinol, methone has better productive rate conventionally with reacting of Phthalocyclohydrazide and aldehyde.
Above-mentioned product
4a1~
4a11,
4b1~
4b8structure warp
1h NMR and
13c NMR confirmation, concrete data are as follows:
4a1: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.37-8.19 (4H, m, Ph), 7.89,7.62-7.59 (4H, m, Ph), 6.51 (1H, s, CHN), 3.44-3.22 (2H, AB system,
j18.99 Hz, CH
ah
bcO), 2.34 (2H, s, CH
2c), 1.22,1.19 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:191.98,155.87,154.50,151.66,147.80,143.43,134.73,133.89,128.89,128.66,128.54,128.15,128.03,127.66,123.94,123.80,117.20,64.09,50.74,37.96,34.65,28.61,28.29.
4a2: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.39-8.18 (4H, m, Ph), 7.89 (3H, m, Ph), 7.59-7.53 (1H, m, Ph), 6.52 (1H, s, CHN), 3.47-3.24 (2H, AB system
j19.22 Hz, CH
ah
bcO), 2.35 (2H, s, CH
2c), 1.22 (6H, s, 2Me).
4a3: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.34-8.27 (2H, m, Ph), 7.85 (2H, m, Ph), 7.40 (2H, m, Ph), 7.02 (2H, m, Ph), 6.43 (1H, s, CHN), 3.38-3.27 (2H, AB system), 2.34 (2H, s, CH
2c), 1.21 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:192.10,155.96,154.33,150.97,134.53,133.57,132.21,132.17,128.99,128.93,128.88,127.97,127.65,118.15,115.80,115.51,64.23,50.86,37.98,34.60,28.62,28.40.
4a4: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.34-8.25 (2H, m, Ph), 7.85 (2H, m, Ph), 7.37-7.28 (4H, m, Ph), 6.40 (1H, s, CHN), 3.43-3.20 (2H, AB system
j19.10 Hz, CH
ah
bcO), 2.33 (2H, s, CH
2c), 1.20 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:192.06,155.96,154.34,150.95,134.52,133.56,132.22,132.17,128.99,128.95,128.91,128.87,127.97,127.65,118.16,115.80,115.50,64.23,50.88,37.99,34.59,28.62,28.40.
4a5: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm: δ 8.37-8.24 (2H, m, Ph), 7.85-7.84 (2H, m, Ph), 7.49-7.47 (1H, m, Ph), 7.33-7.29 (2H, m, Ph), (7.23-7.21 1H, m, Ph), (6.68 1H, s, CHN), 3.44-3.20 (2H, AB system
j19.09 Hz, CH
ah
bcO), 2.32 (2H, s, CH
2c) 1.21 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:192.05,156.11,154.17,151.80,134.47,133.53,132.96,132.51,130.47,129.82,128.98,128.65,127.97,127.61,127.16,125.65,116.60,64.01,50.80,37.96,34.54,28.74,28.34.
4a6: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.35-8.27,7.86 (4H, m, Ph), 7.47-7.28 (4H, m, Ph), 6.40 (1H, s, CHN), 3.43-3.20 (2H, AB system,
j19.09 Hz, CH
ah
bcO), 2.33 (2H, s, CH
2c), 1.20 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:192.04,155.93,154.33,151.09,135.44,134.57,133.63,131.84,128.88,128.84,128.77,128.00,127.66,122.69,117.92,64.33,50.83,37.97,34.61,28.64,28.36.
4a7: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.37-7.26 (7H, m, Ph), 6.70 (1H, s, CHN), 3.43-3.21 (2H, AB system,
j17.98 Hz, CH
ah
bcO), 2.33 (2H, s, CH
2c), 1.21 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:192.05,156.07,154.24,152.13,135.30,134.58,134.10,133.67,130.85,130.68,130.18,128.94,128.49,128.05,127.62,127.50,116.11,64.43,50.77,37.95,34.56,28.70,28.40.
4a8: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.35-8.27 (2H, m, Ph), 7.85 (2H, m, Ph), 7.40-7.27 (5H, m, Ph), 6.45 (1H, s, CHN), 3.45-3.21 (2H, AB system
j19.06 Hz, CH
ah
bcO), 2.33 (2H, s, CH
2c), 1.21 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:192.02,155.98,154.23,150.79,136.36,134.43,133.45,129.05,128.94,128.64,128.61,127.90,127.67,127.07,118.55,64.91,50.91,38.00,34.58,28.63,28.40.
4a9: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.35-8.27 (2H, m, Ph), (7.84 2H, m, Ph), (7.31-7.29 2H, m, Ph), (7.15-7.12 2H, m, Ph), (6.42 1H, s, CHN), 3.45-3.20 (2H, AB system
j19.02 Hz, CH
ah
bcO), 2.33 (2H, s, CH
2c), 2.29 (3H, s, Me), 1.21 (6H, s, 2Me);
13c NMR (75 MHz, CDCl
3) δ ppm:192.08,155.99,154.19,150.68,138.42,134.38,133.39,129.39,129.12,128.94,127.86,127.66,127.01,118.64,64.79,50.92,38.01,34.58,28.64,28.40,21.15.
4a10: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.38-8.33 (2H, m, Ph), 7.93-7.84 (2H, m, Ph), 5.72 (1H, s, CHN), 3.38-3.11 (2H, AB system,
j19.15 Hz, CH
ah
bcO), 2.59-2.50 (1H, m, CH), 2.39 (2H, s, CH
2c), 2.19-2.10 (1H, m, CH), 1.23-1.20 (6H, s, 2Me), 0.77-0.72 (3H, t, Me);
13c NMR (75 MHz, CDCl
3) δ ppm:193.01,156.02,154.66,151.84,134.41,133.37,128.94,128.83,127.83,127.45,116.64,63.43,50.93,38.02,34.43,28.79,28.32,22.05,7.21.
4a11: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.38-8.32 (2H, m, Ph), 7.92-7.83 (2H, m, Ph), 5.70 (1H, s, CHN), 3.36-3.10 (2H, AB system,
j19.25 Hz, CH
ah
bcO), 2.44-2.38 (3H, m), 2.12-2.03 (1H, m), 1.22-1.10 (8H, m), 0.89-0.84 (3H, t, Me);
13c NMR (75 MHz, CDCl
3) δ ppm:193.00,156.02,154.66,151.56,134.39,133.34,128.95,128.82,127.80,127.45,117.22,62.77,50.93,37.98,34.40,31.46,28.69,28.39,16.69,13.67.
4b1: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.39-8.19 (4H, m, Ph), 7.90-7.89 (2H, m, Ph), 7.63-7.60 (2H, m, Ph), 6.51 (1H, s, CHN), 3.60-3.32 (2H, AB system
j19.23 Hz, CH
ah
bcO), 2.48-2.36 (2H, m), 2.33-2.27 (2H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.28,155.91,154.48,153.00,147.85,143.28,134.77,134.76,133.88,128.87,128.59,128.56,128.19,128.06,127.74,123.94,118.34,64.15,36.72,24.47,22.16.
4b2: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.39-8.25 (2H, m, Ph), 8.17 (2H, m, Ph), 7.89 (3H, m, Ph), 7.56 (1H, Ph), 6.52 (1H, s, CHN), 3.63-3.33 (2H, AB system
j18.76 Hz, CH
ah
bcO), 2.48 (2H, m), 2.28 (2H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.42,155.91,154.57,153.17,138.54,135.78,134.70,134.18,133.86,129.54,128.90,128.58,128.19,127.66,123.60,121.55,118.17,64.17,36.71,24.46,22.16.
4b3: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.35-8.27 (2H, m, Ph), (7.85 2H, m, Ph), (7.41-7.39 2H, m, Ph), (7.04-6.99 2H, m, Ph), (6.44 1H, s, CHN), 3.60-3.29 2H, AB system
j19.24 Hz, CH
ah
bcO), 2.47-2.45 (2H, m), 2.28-2.24 (2H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.43,155.98,154.29,152.37,134.53,133.56,132.13,132.09,129.04,128.95,128.92,128.87,127.98,127.66,119.25,115.75,115.46,64.24,36.84,24.43,22.23.
4b4: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.36-8.27 (2H, m, Ph), 7.86 (2H, m, Ph), 7.36-7.31 (4H, m, Ph), 6.42 (1H, s, CHN), 3.59-3.29 (2H, AB system
j18.30 Hz, CH
ah
bcO), 2.47 (2H, m), 2.25 (2H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.39,155.95,154.29,152.47,134.82,134.57,134.51,134.45,133.61,128.86,128.52,128.00,127.67,119.08,64.29,36.81,24.43,22.21.
4b5: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.35-8.25 (2H, m, Ph), (7.85 2H, m, Ph), (7.46-7.44 2H, m, Ph), (7.32-7.29 2H, m, Ph), (6.39 1H, s, CHN), 3.58-3.28 (2H, AB system
j19.29 Hz, CH
ah
bcO), 2.46-2.44 (2H, m), 2.26-2.24 (2H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.40,155.94,154.29,152.51,135.35,135.15,134.58,133.63,131.80,128.85,128.82,128.01,127.67,122.70,119.02,64.35,36.81,24.44,22.22.
4b6: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.37-8.25 (2H, m, Ph); (7.87 2H, m, Ph); (7.42-7.27 3H, m, Ph); (6.62 1H, s, CHN); 3.54-3.25 (2H, AB system); 2.46-2.26 (4H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.34,156.05,154.25,153.43,135.06,134.57,133.65,133.33,131.63,130.28,128.92,128.54,128.06,127.62,127.54,117.18,111.41,63.62,36.74,24.42,22.20.
4b7: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.35-8.25 (2H, m, Ph), 7.84 (2H, m, Ph), 7.43-7.31 (5H, m, Ph), 6.45 (1H, s, CHN), 3.60-3.29 (2H, AB system
j19.27 Hz, CH
ah
bcO), 2.47-2.45 (2H, m), 2.27-2.23 (2H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.47,155.97,154.18,152.27,136.29,134.47,133.48,129.00,128.88,128.60,127.90,127.65,127.11,119.60,111.41,64.90,36.85,24.43,22.22.
4b8: yellow solid;
1h NMR (300 MHz, CDCl
3) δ ppm:8.35-8.26 (2H, m, Ph), (7.84 2H, m, Ph), (7.32-7.26 2H, m, Ph), (7.15-7.12 2H, m, Ph), (6.42 1H, s, CHN), 3.60-3.29 (2H, AB system
j19.09 Hz, CH
ah
bcO), 2.46 (2H, m), 2.29 (3H, s, Me), 2.25 (2H, m);
13c NMR (75 MHz, CDCl
3) δ ppm:192.50,155.91,154.08,152.18,138.37,134.41,133.42,133.34,129.33,129.03,128.86,127.82,127.59,127.07,119.64,64.77,36.87,24.43,22.24,21.19.
Finally explanation is, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by with reference to the preferred embodiments of the present invention, invention has been described, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
Claims (5)
1. the synthetic method of phthalazine derivative, is characterized in that, by Phthalocyclohydrazide, methone or hydroresorcinol and aromatic aldehyde or alkanoic at ionic liquid [BSO
3hMIm] HSO
4for catalyzer, PEG 600 for solvent, temperature be to react under the condition of 100 ~ 160 DEG C, after completion of the reaction, reaction solution is cooled to room temperature, the stirring that adds water, suction filtration, filter cake makes phthalazine derivative by washing with alcohol, after washing lotion and filtrate merge in 100 ~ 160 DEG C of dephlegmates and ethanol, add wherein Phthalocyclohydrazide, methone or hydroresorcinol and aromatic aldehyde or alkanoic to carry out circulating reaction, circulating reaction number of times is 1 ~ 5 time again; Or, after completion of the reaction, reaction solution is cooled to room temperature, and the stirring that adds water, with organic solvent extraction, the underpressure distillation of organic solvent extraction liquid is removed to desolventizing, purify and make phthalazine derivative by column chromatography, the surplus solution after extraction is in 100 ~ 160 DEG C of dephlegmates, then adds wherein Phthalocyclohydrazide, methone or 1, hydroresorcinol and aromatic aldehyde or alkanoic carry out circulating reaction, and circulating reaction number of times is 1 ~ 5 time; Described aromatic aldehyde is phenyl aldehyde or substituted benzaldehyde, the described substituted benzaldehyde phenyl aldehyde that to be phenyl ring replaced by 1 ~ 2 substituting group, described substituting group is independently selected from one or more in fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano group, hydroxyl, C1 ~ C6 alkoxyl group and C1 ~ C6 alkyl; Described alkanoic is C1 ~ C6 alkanal; The molar ratio of described Phthalocyclohydrazide, methone or hydroresorcinol and aromatic aldehyde or alkanoic is 1:1 ~ 1.5:1 ~ 1.7; Described ionic liquid [BSO
3hMIm] HSO
4mole dosage be 10% ~ 25% of Phthalocyclohydrazide mole dosage.
2. the synthetic method of phthalazine derivative according to claim 1, it is characterized in that, described aromatic aldehyde is phenyl aldehyde, 4-nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-nitrobenzaldehyde, 4-fluorobenzaldehyde, 3-fluorobenzaldehyde, 2-fluorobenzaldehyde, 2, 3-difluorobenzaldehyde, 2, 4-difluorobenzaldehyde, 2, 5-difluorobenzaldehyde, 2, 6-difluorobenzaldehyde, 4-chlorobenzaldehyde, 3-chlorobenzaldehyde, 2-chlorobenzaldehyde, 2, 3-dichlorobenzaldehyde, 2, 4-dichlorobenzaldehyde, 2, 5-dichlorobenzaldehyde, 2, 6-dichlorobenzaldehyde, 4-bromobenzaldehyde, 3-bromobenzaldehyde, 2-bromobenzaldehyde, 2, 3-dibromo benzaldehyde, 2, 4-dibromo benzaldehyde, 2, 5-dibromo benzaldehyde, 2, 6-dibromo benzaldehyde, 4-tolyl aldehyde, 3-tolyl aldehyde or 2-tolyl aldehyde, described alkanoic is propionic aldehyde or butyraldehyde.
3. the synthetic method of phthalazine derivative according to claim 1 and 2, is characterized in that, the molar ratio of described Phthalocyclohydrazide, methone or 1,3-cyclopentanedione and aromatic aldehyde or alkanoic is 1:1.4:1.6.
4. the synthetic method of phthalazine derivative according to claim 1 and 2, is characterized in that, described ionic liquid [BSO
3hMIm] HSO
4mole dosage be 15% of Phthalocyclohydrazide mole dosage.
5. the synthetic method of phthalazine derivative according to claim 1 and 2, is characterized in that, described temperature of reaction is 120 DEG C.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3882119A (en) * | 1970-01-27 | 1975-05-06 | Lepetit Spa | Tetracyclic substituted phthalazine compounds |
| CN1047499A (en) * | 1989-05-11 | 1990-12-05 | 美国辉瑞有限公司 | The method and the intermediate that prepare oxo phthalazinyl acetate and homologue |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3882119A (en) * | 1970-01-27 | 1975-05-06 | Lepetit Spa | Tetracyclic substituted phthalazine compounds |
| CN1047499A (en) * | 1989-05-11 | 1990-12-05 | 美国辉瑞有限公司 | The method and the intermediate that prepare oxo phthalazinyl acetate and homologue |
Non-Patent Citations (2)
| Title |
|---|
| Abolghasem Davoodnia，等.Bronsted-acidic ionic liquid [HO3S(CH2)4MIM][HSO4] as efficient and reusable catalyst for one-pot synthesis of β-acetamido ketones.《Monatsh Chem》.2009,第140卷(第12期),第1499-1502页. * |
| Lingaiah Nagarapu,等.TMSCl-Mediated One-Pot, Three-Component Synthesis of 2H-Indazolo[2,1-b]phthalazine-triones.《J. Heterocyclic Chem.》.2009,第46卷(第4期),第728-731页. * |
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