CN101092420B - (1Z, 4Z, 5Z) - 6 N isopropyl - 6 - aza -2 - oxo - 3 - oxa - 4 - methoxy - dicyclo [3, 1, 0] hexane and preparation method - Google Patents
(1Z, 4Z, 5Z) - 6 N isopropyl - 6 - aza -2 - oxo - 3 - oxa - 4 - methoxy - dicyclo [3, 1, 0] hexane and preparation method Download PDFInfo
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- CN101092420B CN101092420B CN2006100901342A CN200610090134A CN101092420B CN 101092420 B CN101092420 B CN 101092420B CN 2006100901342 A CN2006100901342 A CN 2006100901342A CN 200610090134 A CN200610090134 A CN 200610090134A CN 101092420 B CN101092420 B CN 101092420B
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Abstract
This invention relates to an aziridine derivative, i.e., (1Z,4E,5Z)-6-N-n-isopropyl-6-aza-2-oxo-3-oxa-4-methoxy-bicyclo[3.1.0]hexane, as shown in chemical formula I. This invention also provides a method for preparing the aziridine derivative. The preparation method comprises: synthesizing 5-methoxy-3-bromo-2(5H)-furanone, reacting with isopropylamine, and Et3N in DMSO to obtain (1Z,4E,5Z)-6-N-n-isopropyl-6-aza-2-oxo-3-oxa-4-methoxy-bicyclo[3.1.0]hexane. The aziridine derivative has good inhibitive effect on human ovarian cancer cells (IC50 = 4.69X10 to the power-6 g/mL), and can be used in drugs for treating ovarian cancer. The preparation method avoids traditional phase transfer catalysis and water/oxygen-free operation, and adopts room temperature homogeneous catalytic condition, thus has such advantages as simple operation, low cost and high target compound yield. Besides, another diasteromer can be obtained.
Description
Pei Qiang, He Lan, stone is made contributions, Zhou Dongxin
Technical field
The present invention relates to a kind of aziridine derivative, specifically relate to a kind of (1Z, 4E, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane, and its production and use.
Background technology
Aziridine derivative is the important compound of a class.Much have in the natural product of physiologically active,, all contain the component of ethylenimine structure as mitomycin (mitomycin), porphyromycin (porgiromycin), nitrogen silk amino acid etc.For structure and the pharmacology relation of studying these natural products, people have synthesized a series of model compound that contains the various aziridine derivatives of quinoid and azacyclopropane.
In addition, aziridine derivative still is the important organic synthesis intermediate of a class, often is used to synthetic alkaloid, amino acid, beta-alkamine, beta-lactam, tetramethyleneimine polymkeric substance and chiral auxiliary reagent or chiral ligand.
Therefore, the research synthetic and textural property to aziridine derivative gets more and more people's extensive concerning always.
The synthetic method of now common aziridine derivative comprises: reaction is eliminated in the addition of inserting the two keys that insert methylene radical method, some group activation in nitrogen-atoms method, the carbon-to-nitrogen double bon in intramolecular cyclization method, the carbon-carbon double bond.As at document 1: Li Senlan, Guo Jinbo, Yu Zhaolian, Chen Qing Central China state chemistry 2004, disclose a kind of 5-of use methoxyl group-3-bromo-2 (5H)-furanone in 22 (4), 384 and be raw material, under phase transfer catalysis condition with primary amine reaction, the method of having synthesized racemic aziridine derivative, but this method productive rate is lower.
Summary of the invention
The object of the present invention is to provide a kind of aziridine derivative with antitumour activity.
Another object of the present invention is to provide a kind of method that can the described aziridine derivative of produced in high yields.
A further object of the present invention is to provide the purposes of described aziridine derivative.
The objective of the invention is to realize by the following technical solutions:
The invention provides a kind of aziridine derivative, it is that (5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane, the structural formula of this aziridine derivative is suc as formula shown in the I for 1Z, 4E.
The invention provides a kind of preparation method of above-mentioned aziridine derivative, its synthetic route as shown in Figure 1, concrete steps comprise:
1) hydroxyl butylene lactone (compound 2) is synthetic
To newly steam furfural (compound 1) 236g (2.46mol) is dissolved in 2300mL 95% ethanol, add 2g rose-red (Rose Bengal) as photosensitizers, aerating oxygen, shine with the 1000W tungsten-iodine lamp, temperature remains on 23～27 ℃, magnetic stirs, and TLC (thin layer chromatography) follows the tracks of reaction, and reaction needs 40h approximately; Behind the stopped reaction, on Rotary Evaporators, revolve and steam ethanol, the burgundy magma, separate out yellow solid after freezing, quick suction filtration, the dry light yellow solid that gets, the sherwood oil recrystallization obtains hydroxyl butylene lactone (compound 2), white needle-like crystals 158g, productive rate 64%, m.p.54～55 ℃;
2) 5-methoxyl group-2 (5H)-furanone (compound 3) is synthetic
20g (200mmol) hydroxyl butylene lactone (compound 2) is dissolved in the 80mL methyl alcohol, oil bath reflux (about 72h), TLC follows the tracks of reaction; After reaction finished, decompression steamed methyl alcohol on Rotary Evaporators, obtains thick product; Underpressure distillation or rapid column chromatography (sherwood oil/acetone=20: 1) obtain 5-methoxyl group-2 (5H)-furanone (compound 3), colourless liquid, 16g, productive rate 70%;
3) 5-methoxyl group-3-bromo-2 (5H)-furanone (compound 4) is synthetic
5-methoxyl group-2 (5H)-furanone (compound 3) 16g (140.4mmol) is dissolved in the 140mL benzene, slowly drips Br again
2, stirring under the room temperature, ice-water bath is cooled to 0 ℃, slowly drips pyridine, after adding, removes ice-water bath, and stirring at normal temperature is reacted about 1.5h; After reaction finishes, add 50mL water, bromizate the dissolving of pyridinium hydroxide salt, tell organic layer, use the saturated common salt water washing, add anhydrous magnesium sulfate drying again; Filter, decompression steams solvent, obtains thick product underpressure distillation or rapid column chromatography (sherwood oil/acetone=20: 1), obtains 5-methoxyl group-3-bromo-2 (5H)-furanone (compound 4), faint yellow look liquid, 20g, productive rate 73.8%;
4) (1Z, 4E, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane synthetic
Isopropylamine 5.5mmol is added 10mL DMSO, add 0.8mL Et under the stirring at room
3N reacted after ten minutes, added 5-methoxyl group-3-bromo-2 (5H)-furanone (compound 4) 5.0mmol, and TLC detects, until reacting completely; Add the dilution of 30mL ethyl acetate then, water 2 * 20mL and saturated aqueous common salt 20mL wash successively, the anhydrous MgSO of organic layer
4Dry; Decompression steams solvent, thick product is through rapid column chromatography (sherwood oil/acetone=20: 1), obtain (1Z, 4E, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane (compound 5A) and its diastereomer (1Z, 4Z, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane (compound 5B).
Aziridine derivative provided by the invention (compound 5A) has good inhibitory effect to Proliferation of Human Ovarian Cell (A2780), its IC
50=4.69 * 10
-6G/mL can be applicable to prepare the medicine of ovarian cancer resistance tumour.
Compared with prior art, the present invention found first (1Z, 4E, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane has antitumour activity.The present invention is by improving test method, abandoned the operation of traditional phase-transfer catalysis and anhydrous and oxygen-free, adopt homogeneous catalysis condition under the room temperature, not only simplify test operation, reduced cost, and improved the productive rate of target compound (5A) greatly, obtain another diastereomer (5B) simultaneously.
Description of drawings
Fig. 1 is the synthetic route synoptic diagram of aziridine derivative of the present invention.
Embodiment
Furfural among the following embodiment, Isopropylamine, triethylamine, rose-red all purchasing in Beijing reagent company, solvent is all purchased in the Beijing Chemical Plant.
Synthesizing of embodiment 1, hydroxyl butylene lactone (compound 2)
To newly steam furfural (compound 1) 236g (2.46mol) is dissolved in 2300mL 95% ethanol, add 2g rose-red (Rose Bengal) as photosensitizers, aerating oxygen, shine with the 1000W tungsten-iodine lamp, temperature remains on 23～27 ℃, magnetic stirs, and TLC (thin layer chromatography) follows the tracks of reaction, and reaction needs 40h approximately; Behind the stopped reaction, pressure reducing and steaming ethanol on Rotary Evaporators, the burgundy magma, separate out yellow solid after freezing, suction filtration fast, dry light yellow solid; The sherwood oil recrystallization obtains hydroxyl butylene lactone (compound 2), white needle-like crystals 158g, productive rate 64%, m.p.54～55 ℃.
Synthesizing of embodiment 2,5-methoxyl group-2 (5H)-furanone (compound 3)
20g (200mmol) hydroxyl butylene lactone (compound 2) is dissolved in the 80mL methyl alcohol, oil bath reflux (about 72h), TLC follows the tracks of reaction; After reaction finished, decompression steamed methyl alcohol on Rotary Evaporators, obtains thick product; Underpressure distillation or rapid column chromatography (sherwood oil/acetone=20: 1) obtain 5-methoxyl group-2 (5H)-furanone (compound 3), colourless liquid, 16g, productive rate 70%.
Synthesizing of embodiment 3,5-methoxyl group-3-bromo-2 (5H)-furanone (compound 4)
5-methoxyl group-2 (5H)-furanone (compound 3) 16g (140.4mmol) is dissolved in the 140mL benzene, slowly drips Br again
2, stirring under the room temperature, ice-water bath is cooled to 0 ℃, slowly drips pyridine, after adding, removes ice-water bath, and stirring at normal temperature is reacted about 1.5h; After reaction finishes, add 50mL water, bromizate the dissolving of pyridinium hydroxide salt, tell organic layer, use the saturated common salt water washing, add anhydrous magnesium sulfate drying again; Filter, decompression steams solvent, obtains thick product underpressure distillation or rapid column chromatography (sherwood oil/acetone=20: 1), obtains 5-methoxyl group-3-bromo-2 (5H)-furanone (compound 4), faint yellow look liquid, 20g, productive rate 73.8%.
Embodiment 4, (1Z, 4E, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane synthetic
Isopropylamine 5.5mmol is added 10mL DMSO, add 0.8mL Et under the stirring at room
3N reacted after ten minutes, added 5-methoxyl group-3-bromo-2 (5H)-furanone (compound 4) 5.0mmol, and TLC detects, until reacting completely; Add the dilution of 30mL ethyl acetate then, water 2 * 20mL and saturated aqueous common salt 20mL wash successively, the anhydrous MgSO of organic layer
4Dry; Decompression steams solvent, thick product is through rapid column chromatography (sherwood oil/acetone=20: 1), obtain (1Z, 4E, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane (compound 5A) 610mg, productive rate 71.3%, white solid, with and diastereomer (1Z, 4Z, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane (compound 5B).
IR(KBr)
/cm
-1：2966，1798，1767(C＝O)，1639，1463，1384，1348，1221，1175。
1H?NMR(500MHz，CDCl
3)δ：5.22(s，1H，O-CH-O)，3.55(s，3H，OCH
3)，2.83(d，J＝4.1Hz，1H，N-CH)，2.62(d，J＝4.1Hz，1H，N-CH)，1.75(m，1H，-CH-)，1.20(t，J＝5.9Hz，6H，2×CH
3)。
13C?NMR(125MHz，CDCl
3)δ：171.6(C＝O)，103.5(O-C-O)，58.2(O-C)，56.7(N-C)，44.5(N-C)，37.9(N-C)，21.9，21.7。
EIMS?m/z(％)：172(M
++1，59)，140(C
7H
10NO
2 +，20)，112(C
6H
10NO
+，53)，96(C
4H
2NO
2 +，22)，84(100)。
Ultimate analysis C
8H
13NO
3: C 56.13, and H 7.65, and N 8.22; Found C 56.16, H 7.75, and N 8.32.
The antitumour activity screening experiment of embodiment 5, compound 5A
The experiment cancer cells
Colon cancer cell (HCT-8), liver cancer cell (BEL-7402), gastric carcinoma cells (BGC-823), lung adenocarcinoma cell (A549) and Proliferation of Human Ovarian Cell (A2780), the institute of materia medica provides by Beijing.
The experiment medicine
Sample to be measured (compound 5A) with the DMSO dissolving, is mixed with the solution that concentration is respectively 3mg/mL and 30mg/mL (containing DMSO≤3%), preserves for experiment in 4 ℃ of refrigerators and use.
Substratum
The PDA substratum: potato 50g, glucose 5g, agar 5g adds water to 250mL; Preparation according to a conventional method, activated spawn is used.
Sha Shi liquid base (SDB): glucose 2g, protein 1g adds water to 100mL; Preparation according to a conventional method, test tube medicine base dilution experiment method is used.
Experimental technique
(1) preparation of drug dilution liquid: the soup of each concentration is with 10 times of Sha Shi liquid base dilutions, and then is initial concentration with this concentration, and doubling dilution, the final concentration of experimental drug substrate concentration are 3000-46.9ug/mL and 300-4.69ug/mL.
(2) preparation of bacteria suspension: strain subject (experiment cancer cells) through the activation of PDA substratum, is got bacterium colony and make bacteria suspension in 2ml distilled water, shakes 15 seconds, with blood cell counting plate its concentration is transferred to 1 * 10
1-2 * 10
1CFU/mL.
(3) get the drug dilution liquid for preparing, to the every test tube of lower concentration, add 1mL solution by high density successively, with the Sha Shi liquid base that contains 3%DMSO as solvent control, not adding medicine with Sha Shi liquid base is blank, respectively each bacteria suspension 10uL is inoculated in the test tube with transfering loop, puts in the 27-30 ℃ of thermostat container and cultivate.
(4) result's judgement: through constant temperature culture respectively at 24h, 48h, 72h, 96h, 124h and 148h observations, naked eyes are judged under the situation of not stirring, the Clear ﹠ Transparent cancer cells that is considered as of solution is not grown fully, and getting fully not, the growth tube lowest concentration of drug is minimum inhibitory concentration (MIC).
Experimental result
Table 1, antitumour activity test-results IC
50(g/mL)
By experimental result as can be seen, compound 5A has good inhibitory effect to Proliferation of Human Ovarian Cell (A2780), its worker C
50=4.69 * 10
-6G/mL can be applicable to prepare the medicine of ovarian cancer resistance tumour.
Claims (4)
1. aziridine derivative, it is that (5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane, the structural formula of this aziridine derivative is suc as formula shown in the I for 1Z, 4E.
2. the preparation method of the described aziridine derivative of claim 1 comprises following step:
Isopropylamine 5.5mmol is added 10mL DMSO, add 0.8mL Et under the stirring at room
3N reacted after ten minutes, added 5-methoxyl group-3-bromo-2 (5H)-furanone 5.0mmol, and TLC detects, until reacting completely; Add the dilution of 30mL ethyl acetate then, water 2 * 20mL and saturated aqueous common salt 20mL wash successively, the anhydrous MgSO of organic layer
4Dry; The organic phase decompression is steamed solvent, thick product is through rapid column chromatography, obtain (1Z, 4E, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane, with its diastereomer (1Z, 4Z, 5Z)-6-N-sec.-propyl-6-azepine-2-oxo-3-oxa--4-methoxyl group-dicyclo [3.1.0] hexane.
3. the preparation method of aziridine derivative as claimed in claim 2, it is characterized in that: described 5-methoxyl group-3-bromo-2 (5H)-furanone obtains with the following method:
1) hydroxyl butylene lactone is synthetic
To newly steam furfural 236g and be dissolved in 2300mL 95% ethanol, 2g is rose-red as photosensitizers in adding, aerating oxygen, and with the irradiation of 1000W tungsten-iodine lamp, temperature remains on 23～27 ℃, and magnetic stirs, and TLC follows the tracks of reaction, and reaction needs 40h approximately; Behind the stopped reaction, on Rotary Evaporators, revolve and boil off ethanol, the burgundy magma, separate out yellow solid after freezing, quick suction filtration, the dry light yellow solid that gets, the sherwood oil recrystallization obtains hydroxyl butylene lactone, white needle-like crystals 158g, productive rate 64%, m.p.54～55 ℃;
2) 5-methoxyl group-2 (5H)-furanone is synthetic
20g hydroxyl butylene lactone is dissolved in the 80mL methyl alcohol, the oil bath reflux, TLC follows the tracks of reaction; After reaction finishes, on Rotary Evaporators, revolve to steam and remove methyl alcohol, obtain thick product; Underpressure distillation or rapid column chromatography obtain 5-methoxyl group-2 (5H)-furanone, colourless liquid, 16g, productive rate 70%;
3) 5-methoxyl group-3-bromo-2 (5H)-furanone is synthetic
5-methoxyl group-2 (5H)-furanone 16g is dissolved in the 140mL benzene, slowly drips Br again
2, stirring under the room temperature, ice-water bath is cooled to 0 ℃, slowly drips pyridine, after adding, removes ice-water bath, stirring at normal temperature, reaction 1.5h; After reaction finishes, add 50mL water, bromizate the dissolving of pyridinium hydroxide salt, tell organic layer, use the saturated common salt water washing, add anhydrous magnesium sulfate drying again; Filter, the pressure reducing and steaming solvent obtains thick product underpressure distillation or rapid column chromatography, obtains 5-methoxyl group-3-bromo-2 (5H)-furanone, faint yellow look liquid, 20g, productive rate 73.8%.
4. the described aziridine derivative of claim 1 purposes in the medicine of preparation ovarian cancer resistance tumour.
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|---|---|---|---|---|
| CN1302804A (en) * | 1999-11-24 | 2001-07-11 | 阿迪尔公司 | Dihydrofuro [3,4-b] quinoline-1-ketone type compound, its preparation method and medicinal composition containing these compounds |
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| CN1302804A (en) * | 1999-11-24 | 2001-07-11 | 阿迪尔公司 | Dihydrofuro [3,4-b] quinoline-1-ketone type compound, its preparation method and medicinal composition containing these compounds |
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