CN109608399A - A kind of synthetic method of loop coil hexadiene pyrazoline - Google Patents
A kind of synthetic method of loop coil hexadiene pyrazoline Download PDFInfo
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- CN109608399A CN109608399A CN201910025044.2A CN201910025044A CN109608399A CN 109608399 A CN109608399 A CN 109608399A CN 201910025044 A CN201910025044 A CN 201910025044A CN 109608399 A CN109608399 A CN 109608399A
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- pyrazoline
- hexadiene
- loop coil
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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Abstract
The present invention provides a kind of synthetic methods of loop coil hexadiene pyrazoline, 1 ︰, 1.5 ︰ 1.5 in molar ratio takes 2,6- di-t-butyl contraposition methylene quinone, chlorobenzoyl chloride phenylhydrazone and alkali respectively, it is dissolved in organic solvent, 15~45 DEG C at a temperature of, 4~13h is stirred to react, after being extracted with ethyl acetate, organic phase is dry with anhydrous magnesium sulfate, solvent is removed, crude product carries out column chromatography, and loop coil hexadiene pyrazoline is made.The present invention uses one kettle way high yield, high diastereoselective synthesis loop coil hexadiene pyrazoline.Method raw material disclosed by the invention is simple and easy to get, and reaction condition is mild, and post-processing is simple and convenient, and substrate applicability is wide, high income, environmentally protective, is suitable for industrialized production.
Description
Technical field
The invention belongs to organic compound technical fields, are related to a kind of preparation process of organic compound, specially loop coil
The synthetic method of hexadiene pyrazoline.
Background technique
Pyrazoline compounds are a kind of very important heterocycle compounds, are had extensively in fields such as medicine, materials
Application, the compound containing spirane structure is also widely used in bioactive molecule and pharmaceutical activity molecule simultaneously.
Loop coil pyrazoline compounds are substantially better than isoxazoles compound to MCF-7 cytotoxic activity, but normally thin to the mankind
Born of the same parents HEK293T is without cytotoxic activity.Therefore, develop simple, efficient method and construct loop coil pyrazoline compounds, and apply it to
By the extensive concern of scientist in anti-tumor drug.In addition, cyclohexadienones compound is widely present in many activity point
In son and natural products, the natural products of many complexity can also be synthesized as organic synthesis building block.However, using simple
Method combines pyrazoline structure and cyclohexadienone structure, constructs a kind of novel loop coil hexadiene pyrazolines chemical combination
Object but never has document report.
Summary of the invention
The object of the present invention is to provide a kind of simple processes, easy to operate, at low cost, environmentally protective loop coil hexadiene pyrrole
The synthetic method of oxazoline.
To achieve the above object, the technical scheme adopted by the invention is that: a kind of synthesis side of loop coil hexadiene pyrazoline
Method, specifically: 1 ︰, 1.5 ︰ 1.5 in molar ratio takes 2,6- di-t-butyl contraposition methylene quinone, chlorobenzoyl chloride phenylhydrazone and alkali respectively,
Be dissolved in organic solvent, 15~45 DEG C at a temperature of, be stirred to react 4~13h, after being extracted with ethyl acetate, organic phase nothing
Water magnesium sulfate is dry, removing solvent, crude product progress column chromatography (V(petroleum ether):V(ethyl acetate)=200:1), spiral shell is made
Cyclohexadiene pyrazoline, reaction equation are as follows:
The structural formula of the loop coil hexadiene pyrazoline of synthesis is as follows:
The alkali uses potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine or 1,8- diazabicylo
11 carbon -7- alkene (DBU).It is cheap since potassium carbonate property is stablized, make alkali reactant using potassium carbonate in above-mentioned reaction
System is simple, target product yield is high.It is therefore highly preferred that potassium carbonate.
The organic solvent is acetonitrile, methylene chloride, tetrahydrofuran, toluene, ethyl alcohol, methanol or mixed solvent；The mixing
Solvent is formulated by the tetrahydrofuran that volume ratio is 200 ︰ 1 and water.The preferred mixed solvent in synthetic method of the present invention.
The mechanism of synthesizing spiro hexadiene pyrazoline:
Synthetic method of the present invention has the advantage that compared with the existing technology
1, using one kettle way in high yield, high diastereoselective synthesis loop coil hexadiene pyrazoline, it is simple process, easy to operate；
2, reaction reagent source is easy to get, cheap, and performance is stablized, safe to use；
3, reaction is not necessarily to inert gas shielding, and reaction dissolvent does not need specially treated, and no coupling product generates, post-reaction treatment letter
Single, environmental pollution is small, environmentally protective, is suitable for industrialized production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic spectrogram of 1 synthetic product of embodiment.
Specific embodiment
Invention synthetic method is described further below by specific embodiment.
Embodiment 1
2,6- di-t-butyl is aligned into methylene quinone (1 mmol), (4- aminomethyl phenyl) formyl chloride phenylhydrazone (1.5 mmol) and carbonic acid
Potassium (1.5 mmol) is dissolved in 10 mL tetrahydrofurans and 50 μ L water, after 8 h are stirred at room temperature, reaction system ethyl acetate
Extraction, organic phase is dry with anhydrous magnesium sulfate, removing solvent, crude product progress column chromatography (V(petroleum ether):V(ethyl acetate)=
200:1), it can be obtained target product (yellow solid), yield 88%, 184 ~ 185 DEG C of Mp.It is as follows that it synthesizes formula:
The nuclear magnetic data of compound is as follows:1H NMR (400 MHz, CDCl3) δ7.53 (d, J = 8.4 Hz, 2H),
7.25−7.14 (m, 7H), 7.11−7.09 (m, 2H), 7.05−7.03 (m, 2H), 6.90−6.86 (m, 1H),
6.79 (d, J = 2.8 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 4.64 (s, 1H), 2.32 (s,
3H), 1.20 (s, 9H), 0.90 (s, 9H); 13C NMR (150 MHz, CDCl3) δ185.7, 149.7,
147.7, 147.6, 144.9, 141.4, 141.3, 138.8, 134.9, 129.2, 128.9, 128.9, 128.8,
128.7, 127.9, 126.5, 121.0, 115.4, 70.9, 64.5, 35.0, 34.9, 29.3, 28.8, 21.4。
The nuclear magnetic spectrogram of 1 synthetic product of embodiment, as shown in Figure 1, hydrogen spectrum and carbon spectrum.Be shown to be the higher loop coil of purity oneself
Diene pyrazoline, purity are up to 95%, and product yield is up to 97%.
Embodiment 2
2,6- di-t-butyl is aligned into methylene quinone (1 mmol), (4- aminomethyl phenyl) formyl chloride phenylhydrazone (1.5 mmol) and carbonic acid
Potassium (1.5 mmol) is dissolved in 10 mL tetrahydrofurans and 50 μ L water, after 8 h are stirred at room temperature, reaction system ethyl acetate
Extraction, organic phase is dry with anhydrous magnesium sulfate, removes solvent, crude product carries out column chromatography, and ((eluant, eluent is petroleum ether: acetic acid second
Ester=200:1), it can be obtained target product (yellow solid), yield 84%, 213 ~ 216 DEG C of Mp.It is as follows that it synthesizes formula:
The nuclear magnetic data of compound is as follows:1H NMR (600 MHz, CDCl3) δ7.48 (d, J = 8.4 Hz, 2H),
7.40 (d, J = 8.4 Hz, 2H), 7.27−7.25 (m, 3H), 7.21−7.17 (m, 4H), 7.01−6.99 (m,
2H), 6.91−6.88 (m, 1H), 6.79 (d, J = 3.0 Hz, 1H), 6.16 (d, J = 3.0 Hz, 1H),
4.63 (s, 1H), 1.21 (s, 9H), 0.88 (s, 9H);
13C NMR (150 MHz, CDCl3) δ185.6, 148.2, 147.9, 147.8, 144.4, 141.0, 140.8,
134.5, 131.6, 130.6, 129.0, 128.8, 128.7, 128.2, 128.0, 122.7, 121.4, 115.4,
71.1, 64.2, 35.0, 34.9, 29.3, 28.8;
Embodiment 3
2,6- di-t-butyl is aligned into methylene quinone (1 mmol), (4- aminomethyl phenyl) formyl chloride phenylhydrazone (1.5 mmol) and carbonic acid
Potassium (1.5 mmol) is dissolved in 10 mL tetrahydrofurans and 50 μ L water, after 8 h are stirred at room temperature, reaction system ethyl acetate
Extraction, organic phase is dry with anhydrous magnesium sulfate, removing solvent, crude product progress column chromatography (V(petroleum ether):V(ethyl acetate)=
200:1), it can be obtained target product (yellow solid), yield 97%, 183 ~ 185 DEG C of Mp.It is as follows that it synthesizes formula:
The nuclear magnetic data of compound is as follows:1H NMR (600 MHz, CDCl3) δ7.64−7.62 (m, 2H), 7.31−
7.23 (m, 6H), 7.18−7.16 (m, 2H), 7.05−7.04 (m, 2H), 6.91−6.87 (m, 2H), 6.74
(d, J = 3.0 Hz, 1H), 6.16 (d, J = 3.0 Hz, 1H), 4.66 (s, 1H), 1.18 (s, 9H),
0.90 (s, 9H);
13C NMR (150 MHz, CDCl3) δ185.6, 158.2 (d, J = 238.5 Hz), 150.1, 147.9 (d,J = 4.5 Hz), 141.2 (d, J = 1.5 Hz), 140.7 (d, J = 18.0 Hz),134.6, 131.6,
128.9, 128.8, 128.5, 128.0, 126.6, 117.5, 117.4, 115.2, 115.1, 71.4, 64.3,
35.0, 34.9, 29.3, 28.8;
Embodiment 4
2,6- di-t-butyl is aligned into methylene quinone (1 mmol), (4- aminomethyl phenyl) formyl chloride phenylhydrazone (1.5 mmol) and carbonic acid
Potassium (1.5 mmol) is dissolved in 10 mL tetrahydrofurans and 50 μ L water, after 8 h are stirred at room temperature, reaction system ethyl acetate
Extraction, organic phase is dry with anhydrous magnesium sulfate, removing solvent, crude product progress column chromatography (V(petroleum ether):V(ethyl acetate)=
200:1), target product (yellow liquid), yield 96% can be obtained.It is as follows that it synthesizes formula:
The nuclear magnetic data of compound is as follows:1H NMR (600 MHz, CDCl3) δ 7.64 (dd, J = 7.8, 1.8 Hz,
2H), 7.31−7.27 (m, 3H), 7.23−7.17 (m, 4H), 6.96 (d, J = 9.0 Hz, 2H), 6.90−
6.87 (m, 1H), 6.80−6.78 (m, 3H), 6.22 (d, J = 3.0 Hz, 1H), 4.63 (s, 1H), 3.75
(s, 3H), 1.21 (s, 9H), 0.94 (s, 9H);
13C NMR (150 MHz, CDCl3) δ185.7, 159.3, 149.7, 147.7, 147.6, 144.8, 141.4,
141.4, 131.7, 129.9, 128.7, 128.6, 128.4, 126.8, 126.5, 121.1, 115.4, 114.3,
71.0, 63.8, 55.3, 35.0, 34.9, 29.3, 28.8。
Claims (4)
1. a kind of synthetic method of loop coil hexadiene pyrazoline, which is characterized in that the synthetic method specifically: 1 ︰ in molar ratio
1.5 ︰ 1.5 take 2,6- di-t-butyl contraposition methylene quinone, chlorobenzoyl chloride phenylhydrazone and alkali respectively, are dissolved in organic solvent, 15~
At a temperature of 45 DEG C, it is stirred to react 4~13h, after being extracted with ethyl acetate, organic phase is dry with anhydrous magnesium sulfate, solvent is removed,
Crude product carries out column chromatography, and loop coil hexadiene pyrazoline is made.
2. the synthetic method of loop coil hexadiene pyrazoline as described in claim 1, it is characterised in that: the alkali uses carbonic acid
Potassium, cesium carbonate, sodium carbonate, sodium bicarbonate, 11 carbon -7- alkene of sodium hydroxide, organic bases triethylamine or 1,8- diazabicylo.
3. the synthetic method of loop coil hexadiene pyrazoline as described in claim 1, it is characterised in that: the organic solvent is adopted
With acetonitrile, methylene chloride, tetrahydrofuran, toluene, ethyl alcohol, methanol or mixed solvent.
4. the synthetic method of loop coil hexadiene pyrazoline as claimed in claim 3, it is characterised in that: the mixed solvent by
Volume ratio is that the tetrahydrofuran of 200 ︰ 1 and water are formulated.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850274A (en) * | 2012-09-29 | 2013-01-02 | 苏州大学 | Method for synthesizing chiral spiro-pyrazolone |
| CN108117507A (en) * | 2018-03-14 | 2018-06-05 | 吉首大学 | A kind of preparation method and use of azaspiro cyclohexadienone |
| CN108484509A (en) * | 2018-05-18 | 2018-09-04 | 河南大学 | One kind carries Boc amino barbiturates-cyclohexadiene spiro-compound and its synthetic method |
| CN110452109A (en) * | 2018-05-08 | 2019-11-15 | 五邑大学 | A kind of method that phenol ether goes aromatization to prepare loop coil hexadiene ketone compounds |
-
2019
- 2019-01-11 CN CN201910025044.2A patent/CN109608399A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850274A (en) * | 2012-09-29 | 2013-01-02 | 苏州大学 | Method for synthesizing chiral spiro-pyrazolone |
| CN108117507A (en) * | 2018-03-14 | 2018-06-05 | 吉首大学 | A kind of preparation method and use of azaspiro cyclohexadienone |
| CN110452109A (en) * | 2018-05-08 | 2019-11-15 | 五邑大学 | A kind of method that phenol ether goes aromatization to prepare loop coil hexadiene ketone compounds |
| CN108484509A (en) * | 2018-05-18 | 2018-09-04 | 河南大学 | One kind carries Boc amino barbiturates-cyclohexadiene spiro-compound and its synthetic method |
Non-Patent Citations (1)
| Title |
|---|
| YINGPENG SU,ET AL.: "[3 + 2] Cycloaddition of para-Quinone Methides with Nitrile Imines:", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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