CN102993115B - A kind of 3,5 – bis-substituted isoxazoles quinoline derivants and synthetic method thereof and application - Google Patents
A kind of 3,5 – bis-substituted isoxazoles quinoline derivants and synthetic method thereof and application Download PDFInfo
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- CN102993115B CN102993115B CN201210522822.7A CN201210522822A CN102993115B CN 102993115 B CN102993115 B CN 102993115B CN 201210522822 A CN201210522822 A CN 201210522822A CN 102993115 B CN102993115 B CN 102993115B
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- 0 CC*(C)c1cc(O)c*(*)c1O Chemical compound CC*(C)c1cc(O)c*(*)c1O 0.000 description 1
- ACYMGUSQXQEHGA-UHFFFAOYSA-N NC1C=CCCC1 Chemical compound NC1C=CCCC1 ACYMGUSQXQEHGA-UHFFFAOYSA-N 0.000 description 1
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Abstract
General formula is 3 of I, and 5 – bis-substituted isoxazolines compounds and synthetic method thereof and application, in formula, R represents hydrogen, 2 – methoxyl groups, 4 – methoxyl groups, 2 – bromines, 3 – chlorine, 4 – chlorine or 3,4 – dimethoxys.Compound of the present invention has significant restraining effect to intestinal bacteria, streptococcus aureus, Bacillus subtilus and Pseudomonas aeruginosa, and its minimal inhibitory concentration can reach 12.5 μ g/mL, can be used as fungistat.
Description
Technical field
The present invention relates to a kind of isoxazoline derivative medical compounds and its preparation method and application, be specifically related to a kind of 3,5 – bis-substituted isoxazoles quinoline derivant and synthetic methods thereof, and the application of this compound in antibacterial.
Background technology
Isoxazoline compounds is the important organic heterocyclic molecule of a class, has pharmaceutical activity widely.This important structural unit of isoxazoline ring is all contained in many medicines.This compounds of bibliographical information has good FXa inhibit activities.Nearly ten years, receive much concern about the synthesis of isoxazoline compounds and the research of pharmaceutical activity.Such as be developed as epoxy esterified enzyme (COX, cyclooxygenase) inhibitor Valdecoxib (Figure 1) and be isoxazoline compounds, have good anti-inflammatory curative effect.And find that this compounds more is as similar application thus further.The application of commodity in agricultural chemicals of this compounds is also very extensive, and commercial product has at present: clomazone (clomazone), topramezone, two benzene oxazole acid (isoxadifen-ethyl).While these commodity come into the market to obtain great economic benefit, we also find that the cost of this compounds and derivative exploitation thereof is higher, the construction cycle is longer, part of compounds is due to shortcomings such as life-time service develop immunity to drugs, and therefore exploitation is efficient, low cost isoxazoline compounds is extremely urgent.
It is main raw material that the present invention is intended to trihydroxy-acetophenone, designs, synthesizes novel 3, the 5 – bis-substituted isoxazolines compounds with bacteriostatic activity of a class.
Summary of the invention
The object of the invention is to explore the good compound of bacteriostatic activity, a kind of 3,5 – bis-substituted isoxazolines compounds with excellent bacteriostatic activity and preparation method thereof are provided.
Another object of the present invention is also to provide 3,5 described – bis-substituted isoxazolines compounds preparing the application in sterilant.
For achieving the above object, the present invention adopts following technical scheme: a kind of 3,5 – bis-substituted isoxazoles quinoline derivants, its general structure as shown in the formula shown in I,
I
R represents hydrogen, 2 – methoxyl groups, 4 – methoxyl groups, 2 – bromines, 3 – chlorine, 4 – chlorine or 3,4 – dimethoxys.
The invention still further relates to the preparation method of described compound, realized by following technical proposal:
A kind of preparation method of 3,5 – bis-substituted isoxazoles quinoline derivants, it is characterized in that, replacement cinnamophenone and the oxammonium hydrochloride addition reaction with formula II obtain 3,5 described – bis-substituted isoxazoles quinoline derivants;
II
In formula, R is hydrogen, 2 – methoxyl groups, 4 – methoxyl groups, 2 – bromines, 3 – chlorine, 4 – chlorine or 3,4 – dimethoxys.
Particularly, described method comprises the steps:
A. trihydroxy-acetophenone and methyl-sulfate are obtained by reacting 2 – Qiang Ji – 4,6 – bis-Jia Yang Ji – methyl phenyl ketones;
B. 2 – Qiang Ji – 4,6 – bis-Jia Yang Ji – methyl phenyl ketones and substituted benzaldehyde are obtained by reacting replacement cinnamophenone;
C. replace cinnamophenone in the NaOH aqueous solution, obtain 3,5 described – bis-substituted isoxazoles quinoline derivants with oxammonium hydrochloride addition reaction.
Its reaction process of preparation method of the present invention is as follows:
Described method, the trihydroxy-acetophenone wherein in step a and the mol ratio of methyl-sulfate are 1.0:2.0 ~ 3.0; The optimized proportion that the present invention recommends is 1.0:2.0.
Described method, the aromatic aldehyde wherein in step b adopts 4-chloro-benzaldehyde, aubepine, 2 – methoxybenzaldehydes, 2 – bromobenzaldehydes, 3 – chlorobenzaldehydes, 3,4 – dimethoxy benzaldehyde or phenyl aldehydes.
Described method, the cinnamophenone wherein in step c and the mol ratio of oxammonium hydrochloride are 1.0:1.0 ~ 4.0; The optimized proportion that the present invention recommends is 1.0:2.0 ~ 4.0.
Described addition reaction can adopt the 5% wt NaOH aqueous solution as solvent particularly, and temperature of reaction is 85 ~ 100 DEG C, and the reaction times is 6 ~ 8 hours.
The invention still further relates to the application of described derivative, 3,5 namely described – bis-substituted isoxazoles quinoline derivants are preparing the application in sterilant.
Beneficial effect: provided by the invention 3,5 – bis-substituted isoxazoles quinoline derivants are to intestinal bacteria, and streptococcus aureus, Bacillus subtilus, Pseudomonas aeruginosa has significant restraining effect, thus can be used as the effective constituent of fungistat.Compared with the minimal inhibitory concentration of standard drug amoxycilline Trihydrate bp, the fungistatic effect of isoxazoline derivative part of compounds of the present invention to streptococcus aureus, intestinal bacteria and Bacillus subtilus is better than amoxycilline Trihydrate bp, and therefore the pharmaceutical activity of described compound possesses using value.
Compound of the present invention and preparation method thereof is illustrated below by embodiment.
Embodiment
Embodiment 1
Step one, in 100 mL round-bottomed flasks, add 50 mL dry acetone, under stirring, add 3.36 g (20 mmol) trihydroxy-acetophenone, 9.0 gK
2cO
3, appropriate (Me)
2sO
4, stirring and refluxing 3 h, cooling, suction filtration and with washing with acetone for several times, concentrated, the thick silica gel adsorption of residue, chromatography (ethyl acetate: sherwood oil V/V=1:3), obtains white crystal, productive rate 60%.
Step 2, in 50 mL round-bottomed flasks, add ethanol 10.0 mL, 2 – Qiang Ji – 4 are added under stirring, 6 – bis-Jia Yang Ji – methyl phenyl ketone 1.96g(10 mmol), 4-chloro-benzaldehyde 10 mmol, the KOH aqueous solution 8.0 mL of 50% is dripped under ice bath, drip off in about 1 h, then room temperature reaction 24 h, by in reaction mixture impouring 20.0 mL water, and regulate its pH value to 2-3 with dilute hydrochloric acid, a large amount of yellow solid is had to separate out, suction filtration obtains cinnamophenone crude product, namely obtains sterling with ethyl alcohol recrystallization, productive rate 85%.
Step 3, in 50 mL three-necked round bottom flask, add 4 – Cl – 2 ’ – Qiang Ji – 4 ', 6 ’ – dimethoxy cinnamophenone 0.63 g (2.0 mmol), 0.32 g (4.0 mmol) NH
2the 5% wt NaOH aqueous solution of OHHCl and 10mL, adds 20 mL dehydrated alcohols when dissolution of solid, be warming up to 95 DEG C of back flow reaction 6-8 h, have after cooling and pour reaction solution in cold water adularescent solid precipitation, ethyl alcohol recrystallization obtains white crystals, fusing point: 222 – 224 DEG C, productive rate 92%.
Compound 1 is for having 3,5 – bis-substituted isoxazolines of formula I structure, and wherein R is 4-chlorine.
Nuclear-magnetism:
1h NMR (DMSO, 400 MHz) δ: 2.63 (dd, 1H, C4-H, Jg=16.76 Hz, Jv=11.52 Hz, trans-H), 3.71 (dd, 1H, C4-H, Jg=16.64 Hz, Jv=2.60 Hz, cis-H), 3.74 (s, 6H ,-OCH
3), 5.10 (dd, 1H, C5-H, J=3.12 Hz and 11.52 Hz); 6.20 (d, 2H, J=16.0 Hz, ArH), 7.45-7.51 (m; 4H, ArH), 11.18 (s, 1H ,-OH); Mass spectrum: MS:m/z (%): 333 (M+, 11), 314 (100), 258 (4), 206 (71), 179 (29), 77 (29); Ultimate analysis: theoretical value C 61.18%; H 4.83%; N 4.20%; Measured value: C 61.16%; H 4.52%; N 4.03%.
Embodiment 2
Step one, in 100 mL round-bottomed flasks, add 50 mL dry acetone, under stirring, add 3.36 g (20 mmol) trihydroxy-acetophenone, 9.0 gK
2cO
3, appropriate (Me)
2sO
4, stirring and refluxing 3 h, cooling, suction filtration and with washing with acetone for several times, concentrated, the thick silica gel adsorption of residue, chromatography (ethyl acetate: sherwood oil V/V=1:3), obtains white crystal, productive rate 60%.
Step 2, in 50 mL round-bottomed flasks, add ethanol 10.0 mL, 2 – Qiang Ji – 4 are added under stirring, 6 – bis-Jia Yang Ji – methyl phenyl ketone 1.96g(10 mmol), 2 – methoxybenzaldehyde 10 mmol, the KOH aqueous solution 8.0 mL of 50% is dripped under ice bath, drip off in about 1 h, then room temperature reaction 24 h, by in reaction mixture impouring 20.0 mL water, and regulate its pH value to 2-3 with dilute hydrochloric acid, a large amount of yellow solid is had to separate out, suction filtration obtains cinnamophenone crude product, namely obtains sterling with ethyl alcohol recrystallization, productive rate 83%.
Step 3, in 50 mL three-necked round bottom flask, add 2 – Jia Yang Ji – 2 ’ – Qiang Ji – 4 ', 6 ’ – dimethoxy cinnamophenone 0.62 g (2.0 mmol), 0.64 g (8.0 mmol) NH
2oHHCl and 10mL 5% the NaOH aqueous solution, add 20 mL dehydrated alcohols when dissolution of solid, be warming up to 95 DEG C of back flow reaction 6-8 h, have after cooling and pour reaction solution in cold water adularescent solid precipitation, ethyl alcohol recrystallization obtains white crystals, fusing point: 226-227 DEG C, productive rate 85%.
Compound 2 is for having 3,5 – bis-substituted isoxazolines of formula I structure, and wherein R is 2 – OCH
3.
Nuclear-magnetism:
1h NMR (DMSO, 400 MHz) δ: 2.52 (dd, 1H, C4-H, Jg=16.96 Hz, Jv=11.88 Hz, trans-H), 3.39 (dd, 1H, C4-H, Jg=16.80 Hz, Jv=3.24 Hz, cis-H), 3.75 (s, 3H ,-OCH
3), 3.76 (s, 3H ,-OCH
3), 3.81 (s, 3H ,-OCH
3), 5.24 (dd, 1H, C5-H, J=3.16 Hz and 11.88 Hz); 6.17 (d, 1H, J=2.44 Hz, ArH), 6.23 (d; 1H, J=2.4 Hz, ArH), 6.99 (t, 1H; J=7.08 Hz, ArH), 7.04 (d, 1H, J=7.80 Hz; ArH), 7.31 (m, 1H, ArH), 7.04 (m; 1H, ArH), 10.9 (s, 1H ,-OH); Mass spectrum: MS:m/z (%): 329 (M+, 20), 312 (64), 280 (65), 206 (100), 192 (12), 77 (13); Ultimate analysis: theoretical value C 65.64%; H 5.81%; N 4.25%; Measured value: C 65.30%; H 5.81%; N 4.18%.
Embodiment 3
Step one, in 100 mL round-bottomed flasks, add 50 mL dry acetone, under stirring, add 3.36 g (20 mmol) trihydroxy-acetophenone, 9.0 gK
2cO
3, appropriate (Me)
2sO
4, stirring and refluxing 3 h, cooling, suction filtration and with washing with acetone for several times, concentrated, the thick silica gel adsorption of residue, chromatography (ethyl acetate: sherwood oil V/V=1:3), obtains white crystal 3-1, productive rate 60%.
Step 2, in 50 mL round-bottomed flasks, add ethanol 10.0 mL, 2 – Qiang Ji – 4 are added under stirring, 6 – bis-Jia Yang Ji – methyl phenyl ketone 1.96g(10 mmol), 4 – methoxybenzaldehyde 10 mmol, the KOH aqueous solution 8.0 mL of 50% is dripped under ice bath, drip off in about 1 h, then room temperature reaction 24 h, by in reaction mixture impouring 20.0 mL water, and regulate its pH value to 2-3 with dilute hydrochloric acid, a large amount of yellow solid is had to separate out, suction filtration obtains cinnamophenone crude product, namely obtains sterling with ethyl alcohol recrystallization, productive rate 70%.
Step 3, in 50 mL three-necked round bottom flask, add 4 – Jia Yang Ji – 2 ’ – Qiang Ji – 4 ', 6 ’ – dimethoxy cinnamophenone 0.62 g (2.0 mmol), 0.48 g (6.0 mmol) NH
2oHHCl and 10mL 5% the NaOH aqueous solution, add 20 mL dehydrated alcohols when dissolution of solid, be warming up to 95 DEG C of back flow reaction 6-8 h, have after cooling and pour reaction solution in cold water adularescent solid precipitation, ethyl alcohol recrystallization obtains white crystals, fusing point: 212-214 DEG C, productive rate 87%.
Compound 3 is for having 3,5 – bis-substituted isoxazolines of formula I structure, and wherein R is 4 – OCH
3.
Nuclear-magnetism:
1h NMR (DMSO, 400 MHz) δ: 2.66 (dd, 1H, C4-H, Jg=16.84 Hz, Jv=11.56 Hz, trans-H), 3.35 (dd, 1H, C4-H, Jg=16.84 Hz, Jv=3.28 Hz, cis-H), 3.74 (s, 3H ,-OCH
3), 3.77 (s, 3H ,-OCH
3), 3.79 (s, 3H ,-OCH
3), 5.20 (dd, 1H, C5-H; J=3.12 Hz and 11.52 Hz), 6.17 (d, 1H, J=2.36 Hz; ArH), 6.23 (d, 1H, J=2.32 Hz; ArH), 6.94 (d, 2H, J=8.68 Hz; ArH), 7.39 (d, 2H, J=8.64 Hz; ArH), 11.01 (s, 1H ,-OH); Mass spectrum: MS:m/z (%): 329 (M+, 9), 312 (100), 310 (88), 206 (34), 134 (38), 77 (10); Ultimate analysis: theoretical value C 65.64%; H 5.81%; N 4.25%; Measured value: C 65.46%; H 5.53%; N 4.10%.
Embodiment 4
Step one, in 100 mL round-bottomed flasks, add 50 mL dry acetone, under stirring, add 3.36 g (20 mmol) trihydroxy-acetophenone, 9.0 gK
2cO
3, appropriate (Me)
2sO
4, stirring and refluxing 3 h, cooling, suction filtration and with washing with acetone for several times, concentrated, the thick silica gel adsorption of residue, chromatography (ethyl acetate: sherwood oil V/V=1:3), obtains white crystal, productive rate 60%.
Step 2, in 50 mL round-bottomed flasks, add ethanol 10.0 mL, 2 – Qiang Ji – 4 are added under stirring, 6 – bis-Jia Yang Ji – methyl phenyl ketone 1.96g(10 mmol), 2 – bromobenzaldehyde 10 mmol, the KOH aqueous solution 8.0 mL of 50% is dripped under ice bath, drip off in about 1 h, then room temperature reaction 24 h, by in reaction mixture impouring 20.0 mL water, and regulate its pH value to 2-3 with dilute hydrochloric acid, a large amount of yellow solid is had to separate out, suction filtration obtains cinnamophenone crude product, namely obtains sterling with ethyl alcohol recrystallization, productive rate 80%.
Step 3, in 50 mL three-necked round bottom flask, add 2 – Xiu – 2 ’ – Qiang Ji – 4 ', 6 ’ – dimethoxy cinnamophenone 0.73 g (2.0 mmol), 0.48 g (6.0 mmol) NH
2oHHCl and 10mL 5% the NaOH aqueous solution, add 20 mL dehydrated alcohols when dissolution of solid, be warming up to 95 DEG C of back flow reaction 6-8 h, have after cooling and pour reaction solution in cold water adularescent solid precipitation, ethyl alcohol recrystallization obtains white crystals, fusing point: 216-217 DEG C, productive rate 88%.
Compound 4 is for having 3,5 – bis-substituted isoxazolines of formula I structure, and wherein R is 2 – Br.
Nuclear-magnetism:
1h NMR (DMSO, 400 MHz) δ: 2.52 (dd, 1H, C4-H, Jg=16.88 Hz, Jv=12.08 Hz, trans-H), 3.52 (dd, 1H, C4-H, Jg=16.84 Hz, Jv=3.16 Hz, cis-H), 3.76 (s, 3H ,-OCH
3), 3.77 (s, 3H ,-OCH
3), 5.21 (dd, 1H, C5-H, J=2.96 Hz and 12.0 Hz); 6.22 (d, 1H, J=2.40 Hz, ArH); 6.25 (d, 1H, J=2.40 Hz, ArH); 7.31-7.35 (m, 1H, ArH), 7.47-7.51 (m; 1H, ArH), 7.64-7.69 (m, 2H; ArH), 11.14 (s, 1H ,-OH); Mass spectrum: MS:m/z (%): 377 (M+, 9), 360 (44), 280 (36), 206 (100), 179 (22), 89 (10); Ultimate analysis: theoretical value C, 53.99%; H, 4.26%; N, 3.70%; Measured value: C, 53.85%; H, 4.21%; N, 3.65%.
Embodiment 5
Step one, in 100 mL round-bottomed flasks, add 50 mL dry acetone, under stirring, add 3.36 g (20 mmol) trihydroxy-acetophenone, 9.0 gK
2cO
3, appropriate (Me)
2sO
4, stirring and refluxing 3 h, cooling, suction filtration and with washing with acetone for several times, concentrated, the thick silica gel adsorption of residue, chromatography (ethyl acetate: sherwood oil V/V=1:3), obtains white crystal, productive rate 60%.
Step 2, in 50 mL round-bottomed flasks, add ethanol 10.0 mL, 2 – Qiang Ji – 4 are added under stirring, 6 – bis-Jia Yang Ji – methyl phenyl ketone 1.96g(10 mmol), 3 – chlorobenzaldehyde 10 mmol, the KOH aqueous solution 8.0 mL of 50% is dripped under ice bath, drip off in about 1 h, then room temperature reaction 24 h, by in reaction mixture impouring 20.0 mL water, and regulate its pH value to 2-3 with dilute hydrochloric acid, a large amount of yellow solid is had to separate out, suction filtration obtains cinnamophenone crude product, namely obtains sterling with ethyl alcohol recrystallization, productive rate 81%.
Step 3, in 50 mL three-necked round bottom flask, add 3 – Lv – 2 ’ – Qiang Ji – 4 ', 6 ’ – dimethoxy cinnamophenone 0.63 g (2.0 mmol), 0.48 g (6.0 mmol) NH
2oHHCl and 10mL 5% the NaOH aqueous solution, add 20 mL dehydrated alcohols when dissolution of solid, be warming up to 85 DEG C of back flow reaction 6-8 h, have after cooling and pour reaction solution in cold water adularescent solid precipitation, ethyl alcohol recrystallization obtains white crystals, fusing point: 217-218 DEG C, productive rate 90%.
Compound 5 is for having 3,5 – bis-substituted isoxazolines of formula I structure, and wherein R is 3 – Cl.
Nuclear-magnetism:
1h NMR (DMSO, 400 MHz) δ: 2.64 (dd, 1H, C4-H, Jg=16.80 Hz, Jv=11.52 Hz, trans-H), 3.35 (dd, 1H, C4-H, Jg=16.76 Hz, Jv=3.36 Hz, cis-H), 3.74 (s, 6H ,-OCH
3), 5.12 (dd, 1H, C5-H; J=3.24 Hz and 11.44 Hz), 6.22 (d, 1H, J=2.32 Hz; ArH), 6.25 (d, 1H, J=2.32 Hz; ArH), 7.41-7.45 (m, 3H, ArH); 7.55 (s, 1H, ArH); 11.18 (s, 1H ,-OH); Mass spectrum: MS:m/z (%): 333 (M+, 6), 332 (1), 316 (64), 206 (100), 179 (7), 89 (2); Ultimate analysis: theoretical value C, 61.18%; H, 4.83%; N, 4.20%; Measured value: 61.08%; H, 4.63%; N, 4.05%.
Embodiment 6
Step one, in 100 mL round-bottomed flasks, add 50 mL dry acetone, under stirring, add 3.36 g (20 mmol) trihydroxy-acetophenone, 9.0 gK
2cO
3, appropriate (Me)
2sO
4, stirring and refluxing 3 h, cooling, suction filtration and with washing with acetone for several times, concentrated, the thick silica gel adsorption of residue, chromatography (ethyl acetate: sherwood oil V/V=1:3), obtains white crystal, productive rate 60%.
Step 2, in 50 mL round-bottomed flasks, add ethanol 10.0 mL, add 2 – Qiang Ji – 4,6 – bis-Jia Yang Ji – methyl phenyl ketone 1.96g(10 mmol under stirring), phenyl aldehyde 10 mmol, under ice bath drip 50% the KOH aqueous solution 8.0 mL, drip off in about 1 h, then room temperature reaction 24 h, by reaction mixture impouring 20.0 mL water, and regulates its pH value to 2-3 with dilute hydrochloric acid, a large amount of yellow solid is had to separate out, suction filtration obtains cinnamophenone crude product, namely obtains sterling with ethyl alcohol recrystallization, productive rate 92%.
Step 3, in 50 mL three-necked round bottom flask, add 2 ’ – Qiang Ji – 4 ', 6 ’ – dimethoxy cinnamophenone 0.57 g (2.0 mmol), 0.64 g (8.0 mmol) NH
2oHHCl and 10mL 5% the NaOH aqueous solution, add 20 mL dehydrated alcohols when dissolution of solid, be warming up to 85 DEG C of back flow reaction 6-8 h, have after cooling and pour reaction solution in cold water adularescent solid precipitation, ethyl alcohol recrystallization obtains white crystals, fusing point: 220-222 DEG C, productive rate 82%.
Compound 6 is for having 3,5 – bis-substituted isoxazolines of formula I structure, and wherein R is H.
Nuclear-magnetism:
1h NMR (DMSO, 400 MHz) δ: 2.66 (dd, 1H, C4-H, Jg=16.80 Hz, Jv=11.44 Hz, trans-H), 3.22 (dd, 1H, C4-H, Jg=16.80 Hz, Jv=3.44 Hz, cis-H), 3.75 (s, 3H ,-OCH
3), 3.76 (s, 3H ,-OCH
3), 5.00 (dd, 1H, C5-H; J=3.36 Hz and 11.40 Hz), 6.19 (d, 1H, J=2.40 Hz; ArH), 6.24 (d, 1H, J=2.40 Hz; ArH), 7.30-7.42 (m, 3H, ArH); (7.46-7.48 m, 2H, ArH); 10.96 (s, 1H ,-OH); Mass spectrum: MS:m/z (%): 299 (M+, 25), 298 (3), 280 (37), 206 (100), 178 (9), 77 (15); Ultimate analysis: theoretical value C, 68.22%; H, 5.72%; N, 4.68%; Measured value: C, 68.02%; H, 5.64%; N, 4.61%.
Embodiment 7
Step one, in 100 mL round-bottomed flasks, add 50 mL dry acetone, under stirring, add 3.36 g (20 mmol) trihydroxy-acetophenone, 9.0 gK
2cO
3, appropriate (Me)
2sO
4, stirring and refluxing 3 h, cooling, suction filtration and with washing with acetone for several times, concentrated, the thick silica gel adsorption of residue, chromatography (ethyl acetate: sherwood oil V/V=1:3), obtains white crystal, productive rate 60%.
Step 2, in 50 mL round-bottomed flasks, add ethanol 10.0 mL, 2 – Qiang Ji – 4 are added under stirring, 6 – bis-Jia Yang Ji – methyl phenyl ketone 1.96g(10 mmol), 3,4 – dimethoxy benzaldehyde 10 mmol, the KOH aqueous solution 8.0 mL of 50% is dripped under ice bath, drip off in about 1 h, then room temperature reaction 24 h, by in reaction mixture impouring 20.0 mL water, and regulate its pH value to 2-3 with dilute hydrochloric acid, have a large amount of yellow solid to separate out, suction filtration obtains cinnamophenone crude product, namely sterling is obtained, productive rate 85% with ethyl alcohol recrystallization.
Step 3, in 50 mL three-necked flasks, add 3,4 – bis-Jia Yang Ji – 2 ’ – Qiang Ji – 4 ', 6 ’ – dimethoxy cinnamophenone 0.66 g (2.0 mmol), 0.32 g (4.0 mmol) NH
2oHHCl and 10mL 5% the NaOH aqueous solution, add 20 mL dehydrated alcohols when dissolution of solid, be warming up to 100 DEG C of back flow reaction 6-8 h, have after cooling and pour reaction solution in cold water adularescent solid precipitation, ethyl alcohol recrystallization obtains white crystals, fusing point: 226-227 DEG C, productive rate 82%.
Compound 7 is for having 3,5 – bis-substituted isoxazolines of formula I structure, and wherein R is 3,4 – dimethoxys.
Nuclear-magnetism:
1h NMR (DMSO, 400 MHz) δ: 2.65 (dd, 1H, C4-H, Jg=16.72Hz, Jv=11.52 Hz, trans-H), 3.29 (dd, 1H, C4-H, Jg=16.80 Hz, Jv=3.20 Hz, cis-H), 3.74 (s, 3H ,-OCH
3), 3.73 (s, 3H ,-OCH
3), 4.98 (dd, 1H, C5-H, J=3.06 Hzand 11.52 Hz), 6.00 (s, 2H ,-OCH
2o-), 6.16 (d, 2H, J=2.28 Hz, ArH), 6.23 (d; 2H, J=2.20 Hz, ArH), 6.89-6.95 (m, 2H, ArH); 7.00 (s, 1H, ArH), 10.94 (s, 1H ,-OH); Mass spectrum: MS:m/z (%): 343 (M+, 7), 342 (9); 324 (100), 280 (14), 206 (24); 148 (59), 89 (31); Ultimate analysis: theoretical value C, 62.97%; H, 4.99%; N, 4.08%; Measured value: C, 62.91%; H, 4.94%; N, 4.05%.
Embodiment 8 bacteriostatic experiment
Respectively the derivative that embodiment 1-7 synthesizes is made into the DMSO solution of 200 μ g/mL, 100 μ g/mL, 50 μ g/mL, 25 μ g/mL, 12.5 μ g/mL, 6.25 μ g/mL.It is 5x10 that the sample pipetting 10 μ L joins containing 100 μ L bacterial concentrations
5in 96 orifice plates of cfu/mL, under 37 DEG C of conditions, cultivate 24 h, use microplate reader reading numerical values, test parallel three times and average.Obtain data as follows:
The minimal inhibitory concentration (MIC in μ g/mL) of table 1 compound 1-7.
Experimental result shows, of the present invention above-mentioned 3, and 5-two substituted isoxazoles quinoline derivants have good bacteriostatic activity, as follows respectively to the minimal inhibitory concentration scope of different bacterium:
To intestinal bacteria, its minimal inhibitory concentration scope is 25-200 μ g/mL.
To golden yellow grape bacillus, its minimal inhibitory concentration scope is 12.5-200 μ g/mL.
To Bacillus subtilus, its minimal inhibitory concentration scope is 12.5-200 μ g/mL.
To Pseudomonas aeruginosa, its minimal inhibitory concentration scope is 25-200 μ g/mL.
Claims (1)
1. 3,5 – bis-substituted isoxazoles quinoline derivants of formula I structure are preparing the application in sterilant,
I
R represents hydrogen, 2 – methoxyl groups, 4 – methoxyl groups, 2 – bromines, 3 – chlorine, 4 – chlorine or 3,4 – dimethoxys.
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| US20060160773A1 (en) * | 2003-07-18 | 2006-07-20 | Giuseppe Giannini | Combretastatin derivatives with cytotoxic action |
| WO2010058417A1 (en) * | 2008-11-19 | 2010-05-27 | Council Of Scientific & Industrial Research | Isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids as potential anticancer agents and process for the preparation thereof |
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| US20060160773A1 (en) * | 2003-07-18 | 2006-07-20 | Giuseppe Giannini | Combretastatin derivatives with cytotoxic action |
| WO2010058417A1 (en) * | 2008-11-19 | 2010-05-27 | Council Of Scientific & Industrial Research | Isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids as potential anticancer agents and process for the preparation thereof |
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| 4-苯基-3-异恶唑羧酸乙酯的合成;贾日红等;《科学技术与工程》;20111031;第11卷(第29期);第7210-7212页 * |
| 吡唑啉等含氮杂环化合物的合成;徐助雄;《中国优秀博硕学位论文全文数据库(硕士)》;20061215(第12期);第22页scheme 2-4，第四章第65页第1段，第四章第67页scheme 4-4，第68页Table4-1，第4.3.2节合成实验1> * |
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