CN103601690B - 3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application - Google Patents
3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application Download PDFInfo
- Publication number
- CN103601690B CN103601690B CN201310501134.7A CN201310501134A CN103601690B CN 103601690 B CN103601690 B CN 103601690B CN 201310501134 A CN201310501134 A CN 201310501134A CN 103601690 B CN103601690 B CN 103601690B
- Authority
- CN
- China
- Prior art keywords
- compound
- phenyl
- ketone
- preparation
- dibenzodiazepine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application, has following formula:
wherein: R is 2-Cl, 4-Cl, 4-N, 3-N, 2-N, α-C
6h
5, 3,4-(OCH
3)
2, 4-OCH
3, any one in-H.The reaction conditions of this compound is gentle, operational path is short, reaction cost is low, catalyzer is cheap, and the compound prepared possesses bacteriostatic activity, thus for providing the proof of configuration aspects in the application of pharmacy and field of biology.
Description
Technical field
The invention belongs to pharmaceutical intermediate organic synthesis field, relate to the preparation of a kind of synthesis 3-phenyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone series derivates and synthetic method and its monocrystalline.
Background technology
1,5-Benzodiazepine derivative is the important organic nitrogen-containing heterogeneous ring compound of a class, it can be used as the inhibitor of a variety of proteolytic enzyme, it is also simultaneously the important pharmaceutical intermediate of a class, there is much good biological activity, there is strong physiologically active and pharmaceutical use, as characteristics such as anti-nerve, sleeping, calm, anti-inflammatory.Such as: leoponex, W-130 and olanzapine are all medicines of antipsychotic disease, and loxapine and amoxapine are antidepressant medicines etc.Therefore, for the relation between the research synthesis of this compounds, structure and biological activity, be the hot fields of this compounds research always.
In recent years, in the Study of synthesis method of this compounds, mainly concentrate on two aspects: be the diversity increasing side chain in framework on the one hand; Another aspect is on original framework basis and closes other ring system.Since two thousand six, (J.Mol.Catal.Chem.2006,259,201. such as Heravi; 2007,261,156) important contribution has been made to the study on the synthesis of preparation 1,5-benzodiazepine.And Song Huacan seminar also once reported two kinds of synthetic methods of 1,5-benzodiazepine compound in 2008 (organic chemistry .2008,317).
Summary of the invention
The technical problem solved: a kind of 3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application is provided, the reaction conditions of this compound is gentle, operational path is short, reaction cost is low, catalyzer is cheap, further clearly about the space structure of molecule, and determine its bacteriostatic activity, thus for providing the proof of configuration aspects in the application of pharmacy and field of biology.
Technical scheme: 3-phenyl dibenzodiazepine-1-ketone series derivates, has following formula:
Wherein: R is any one in 2-Cl, 4-Cl, 4-N, 3-N, 2-N, α-C6H5,3,4-(OCH3) 2,4-OCH3 ,-H.
The preparation method of 3-phenyl dibenzodiazepine-1-ketone series derivates, preparation process is: with 5-phenyl-1, hydroresorcinol and O-Phenylene Diamine are raw material according to mol ratio 1:1 ~ 1:1.5, heating reflux reaction in organic solvent, and with the water produced in water trap separating reaction process, after reaction, products therefrom is cooled to filtered at room temperature, gained solid volumetric concentration be 50% ~ 95% ethyl alcohol recrystallization can obtain orange-yellow intermediate enamine compound, described organic solvent is the one of dry toluene or benzene, and synthetic route is as follows:
Gained intermediate enamine compound is dissolved in solvent, under catalyst action, carries out ring closure reaction with aromatic aldehyde according to mol ratio 1:1 ~ 1:1.5, obtain 3-phenyl dibenzodiazepine-1-ketone series derivates through column chromatography; Described solvent is ethanol, methyl alcohol, the one in ethyl acetate; Described catalyzer is acetic acid, sulfuric acid, the one in hydrochloric acid; After reaction, the separation condition of column chromatography is: petrol ether/ethyl acetate=1:2 ~ 2:1(V/V), described aromatic aldehyde is 2-chlorobenzaldehyde, 4-chlorobenzaldehyde, 4-pyridylaldehyde, 3-pyridine phenyl aldehyde, 2-pyridylaldehyde, 1-naphthaldehyde, Veratraldehyde, 4-methoxybenzaldehyde or phenyl aldehyde; Synthetic route is as follows:
The preparation method of 3-furyl dibenzodiazepine-1-ketone series derivates monocrystalline, preparation process is: get in 3-furyl dibenzodiazepine-1-ketone series derivates any one, dissolved by ethanol or ethyl acetate, under being placed in room temperature, carried out volatilization 1 ~ 3 week.
3-phenyl-11-(3,4-Dimethoxyphenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone is preparing the application in antibacterial medicines.
Beneficial effect: the reaction conditions of this compound is gentle, operational path is short, reaction cost is low, catalyzer is cheap, and the compound prepared possesses bacteriostatic activity, thus for providing the proof of configuration aspects in the application of pharmacy and field of biology.
Accompanying drawing explanation
Fig. 1 is embodiment 2(3a) crystalline structure schematic diagram;
Fig. 2 is embodiment 4(3c) crystalline structure schematic diagram;
Fig. 3 is embodiment 6(3d) crystalline structure schematic diagram;
Fig. 4 is embodiment 8(3f) crystalline structure schematic diagram.
Embodiment
Describe technical scheme of the present invention in detail below in conjunction with embodiment, and do not mean that limitation of the present invention.
All reagent is all commercially available below, all solvents are all purchased from traditional Chinese medicines group, 2-chlorobenzaldehyde, 4-chlorobenzaldehyde, 4-pyridylaldehyde, 3-pyridylaldehyde, 2-pyridylaldehyde, α-naphthaldehyde, Veratraldehyde, 4-methoxybenzaldehyde and phenyl aldehyde are then purchased from Shanghai Aladdin reagent company limited.
The synthesis step of 5-phenyl-1,3 cyclohexanedione is with reference to following documents: Han Guangfan, Dong Junke, Wang Fangming, Xing Zheng, Zhao Yuyuan [J]. organic chemistry, 2008,28 (4): 750-754.
5-phenyl-1,3 cyclohexanedione and O-Phenylene Diamine are reacted, obtains intermediate compound enamine, then react from different aromatic aldehydes, prepare 3-phenyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone series derivates.Then solvent evaporation method is adopted to prepare its monocrystalline.
Synthetic route is as follows:
Method is led in the synthesis of intermediate compound enamine 2:
Method is led in the synthesis of 3-phenyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone series derivates 3:
The preparation method of monocrystalline is as follows:
By any one in 3-phenyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone series derivates, add in clean small beaker, get the suitable molten solid that makes and dissolve completely.Then with antistaling film, beaker mouth is sealed, and on film, prick several aperture, volatilize 1 ~ 3 week under being placed in room temperature.
Embodiment 1
The synthesis of enamine intermediates 2
In 50mL dry toluene, add 5mmol5-phenyl-hydroresorcinol, add the O-Phenylene Diamine of 5mmol, reflux 24h after it dissolves completely, the water water trap produced in reaction is separated.After reaction terminates, question response liquid is cooled to room temperature, and filter, the gained solid ethyl alcohol recrystallization of 95% can obtain intermediate compound 2.Yield: 92%.Fusing point: 208-210 DEG C.MS(ESI)m/z:279.2(M+H
+)。
1HNMR(DMSO-d6,500MHz)δ:2.26(m,1H,4a-H),2.53(m,1H,4b-H),2.66(m,1H,6a-H),2.85(m,1H,6b-H),4.72(s,1H,2-H),4.92(br,2H,14-NH),6.57(m,1H,5-H),6.76-7.35(m,4H,Ph-H),8.35(s,1H,7-NH),7.35(m,5H,Ph-H);IR(KBr)υ:3306(m),1638(s),1176(m),1108(m),738(m)。
Embodiment 2
The synthesis of compound 3-phenyl-11-(2-chloro-phenyl-)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3a)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol2-chlorobenzaldehyde and be dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, solvent is spin-dried for rear gained solid and obtains target compound 3a by column chromatography, eluent V
sherwood oil: V
ethyl acetate=1:2.Yield 65%.Fusing point: 136-138 DEG C.MS(ESI)m/z:401.2(M+H
+),423.2(M+Na
+),822.9(2M+Na
+)。
1HNMR（DMSO-d6,500MHz）δ:2.50(m,2H,2-H),2.95(m.1H,4a-H),3.13(m,1H,4b-H),3.45(m,1H,3-H),5.60(d,1H,J=6.0Hz,11-H),5.96(d,1H,J=6.0Hz,10-NH),6.48-6.64(m,4H,Ph-H),9.10(s,1H,5-NH);6.88-7.38(m,5H,Ph-H);R:7.05(m,1H,4'-H),7.26(t,1H,J
1=7.5Hz,J
2=14.5Hz,6'-H),7.38(m,2H,5'-H,3'-H)；IR(KBr)υ:3305(m),3058(m),1602(m),1529(s),1386(m),754(m),700(m)。
Embodiment 3
The synthesis of compound 3-phenyl-11-(4-chloro-phenyl-)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3b)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol4-chlorobenzaldehyde and be dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, light yellow solid is obtained after being spin-dried for by solvent, again by column chromatography, obtain two isomerss 3b (a) and 3b (b), the eluent V of target compound
sherwood oil: V
ethyl acetate=1:2.Wherein 3b (a) yield 40%.Fusing point: 222-224 DEG C.MS(ESI)m/z:401.2(M+H
+),423.3(M+Na
+),823.5(2M+Na
+).
1HNMR（DMSO-d6,500MHz）δ:2.46(m,1H,2a-H),2.60(m,1H,2b-H),2.91(m,1H,4a-H),3.09(m,1H,4b-H),3.46(m,1H,3-H),5.67(d,1H,J=6.0Hz,11-H),6.26(d,1H,J=6.0Hz,10-NH),7.04-7.39(m,4H,Ph-H),8.92(s,1H,5-NH);7.39(m,5H,Ph-H);R:7.27(m,2H,2'-H,6'-H),7.39(m,2H,3'-H,5'-H);IR(KBr)υ:1604(m),1511(s),1386(m),752(m),700(m)。
3b (b): yield 36%.Fusing point: 222-224 DEG C.
1HNMR（DMSO-d6,500MHz）δ:2.42(m,1H,2a-H),2.69(m,1H,2b-H),2.87(m,1H,4a-H),3.01(m,1H,4b-H),3.39(m,1H,3-H),5.77(d,1H,J=6.0Hz,11-H),6.31(d,1H,J=6.0Hz,10-NH),6.59-6.91((m,4H,Ph-H),8.87(s,1H,5-NH);6.59(m,5H,Ph-H);R:6.59(m,2H,2'-H,6'-H),7.12(m,2H,3'-H,5'-H);IR(KBr)υ:1604(m),1511(s),1386(m),752(m),700(m)。
Embodiment 4
The synthesis of compound 3-phenyl-11-(4-pyridyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3c)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol4-pyridylaldehyde and be dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, solvent is spin-dried for rear gained solid and obtains target compound 3c by column chromatography, eluent V
sherwood oil: V
ethyl acetate=1:2.Yield 61%.Fusing point: 246-248 DEG C.MS(ESI)m/z:368.2(M+H
+),390.1(M+Na
+),757.0(2M+Na
+).
1HNMR（DMSO-d6,500MHz）δ:2.45(m,1H,2a-H),2.70(m,1H,2b-H),2.91(m,1H,4a-H),3.01(m,1H,4b-H),3.42(m,1H,3-H),5.78(d,1H,J=6.0Hz,11-H),6.45(d,1H,J=6.0Hz,10-NH),6.62-6.91(m,4H,Ph-H),8.91(s,1H,5-NH);6.62-7.37(m,5H,Ph-H);R:7.44(m,2H,2'-H,6'-H),8.34(d,2H,J=5.5Hz,3'-H,5'-H);IR(KBr)υ:3290(m),1600(m),1537(s),1324(m),767(m),700(m)。
Embodiment 5
The synthesis of compound 3-phenyl-11-(3-pyridinylphenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3d)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol3-pyridine phenyl aldehyde and be dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, light yellow solid is obtained after being spin-dried for by solvent, target compound 3d is obtained again, eluent V by column chromatography
sherwood oil: V
ethyl acetate=1:2.Yield 71%, fusing point: 231-233 DEG C, MS (ESI) m/z:368.2 (M+H
+), 735.5 (2M+H
+).
1hNMR(DMSO-d6,500MHz) δ: 2.45 (m, 1H, 2a-H), 2.70 (m; 1H, 2b-H), 2.97 (m, 2H, 4-H); 3.40 (m, 1H, 3-H), 5.84 (d, 1H; J=6.0Hz, 11-H), 6.37 (d, 1H; J=6.0Hz, 10-NH), 6.94-7.35 (m, 4H; Ph-H), 8.95 (s, 1H, 5-NH); (7.17-7.35 m, 5H, Ph-H); R:7.35 (m, 2H, 5'-H, 6'-H), 8.24 (m, 1H, 2'-H), 8.36 (d, 1H, J=5.5Hz, 4'-H); IR (KBr) υ: 3301 (m), 1600 (m), 1544 (s), 1388 (m), 755 (m), 700 (m).
Embodiment 6
The synthesis of compound 3-phenyl-11-(2-pyridyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3e)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol2-pyridylaldehyde and be dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, solvent is spin-dried for rear gained solid and passes through column chromatography, obtain two isomerss 3e (a) and 3e (b), the eluent V of target compound
sherwood oil: V
ethyl acetate=1:2.Wherein 3e (a): yield 48%.Fusing point: 236-238 DEG C.MS(ESI)m/z:390.1(M+Na
+),757.0(2M+Na
+).
1HNMR（DMSO-d6,500MHz）δ:2.45(m,1H,2a-H),2.69(m,1H,2b-H),3.04(m,2H,4-H),3.38(m,1H,3-H),5.83(d,1H,J=5.5Hz,11-H),6.18(d,1H,J=6.0Hz,10-NH),7.05-7.39(m,4H,Ph-H),8.88(s,1H,5-NH);7.39(m,5H,Ph-H);R:7.39(m,2H,4'-H,6'-H),7.53(m,1H,5'-H),8.39(d,1H,J=4.0Hz,3'-H);IR(KBr)υ:3324(m),1592(m),1537(s),1388(m),752(m),700(m)。
3e (b): yield 25%.Fusing point: 236-238 DEG C.
1HNMR（DMSO-d6,500MHz)δ:2.41(m,1H,2a-H),2.57(m,1H,2b-H),2.93(m,2H,4-H),3.46(m,1H,3-H),5.72(d,1H,J=6.0Hz,11-H),6.11(d,1H,J=6.0Hz,10-NH),6.56(m,4H,Ph-H),8.92(s,1H,5-NH);6.56(m,5H,Ph-H);R:6.87(d,1H,J=8.0Hz,6'-H),6.92(s,1H,4'-H),7.01(m,1H,5'-H),8.37(d,1H,J=4.0Hz,3'-H);IR(KBr)υ:3324(m),1592(m),1537(s),1388(m),752(m),700(m)。
Embodiment 7
Compound 3-phenyl-11-(Alpha-Naphthyl) synthesis of-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3f)
The compound 2 5mmol embodiment 1 prepared and 5mmol1-naphthaldehyde are dissolved in the ethanol of 25mL under the condition of 2.5mL acetic acid, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, solvent is spin-dried for rear gained solid by column chromatography, obtains target compound 3f, eluent V
sherwood oil: V
ethyl acetate=1:2.Yield 80%.Fusing point: 166-168 DEG C.MS(ESI)m/z:417.1(M+H
+),439.2(M+Na
+),855.0(2M+Na
+).
1HNMR（DMSO-d6,500MHz）δ:2.50(m,2H,2-H),2.98(m,1H,4a-H),3.17(m,1H,4b-H),3.49(m,1H,3-H),5.90(d,1H,J=6.5Hz,11-H),6.06(d,1H,J=8.0Hz,10-NH),6.46-6.78(m,4H,Ph-H),9.01(s,1H,5-NH);7.04-7.52(m,5H,Ph-H);R:7.52-8.55(m,7H);IR(KBr)υ:32329(m),3025(m),1598(m),1390(s),1290(m),775(m),700(m)。
Embodiment 8
The synthesis of compound 3-phenyl-11-(3,4-Dimethoxyphenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3g)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol3,4-dimethoxy benzaldehyde and being dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, solvent is spin-dried for rear gained solid and obtains target compound 3g by column chromatography, eluent V
sherwood oil: V
ethyl acetate=1:2.Yield 61%.Fusing point: 134-136 DEG C.MS(ESI)m/z:427.1(M+H
+),449.2(M+Na
+),875.0(2M+Na
+).
1HNMR（DMSO-d6,500MHz）δ:2.66(m,2H,2-H),2.99(m,1H,4a-H),3.86(m,1H,4b-H),3.86(m,1H,3-H),5.73(d,1H,J=6.0Hz,11-H),6.23(d,1H,J=6.0Hz,10-NH),6.59-6.92(m,4H,Ph-H),8.77(s,1H,5-NH);6.59-7.35(m,5H,Ph-H);R:3.64(m,6H,3'-OCH3,4'-OCH3),6.59(m,1H,6'-H),6.92(m,1H,2'-H),7.35(m,1H,5'-H);IR(KBr)υ:3332(m),2935(m),1592(m),1533(s),1384(m),1267(m),757(m)。
Embodiment 9
The synthesis of compound 3-phenyl-11-(4-p-methoxy-phenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3h)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol4-methoxybenzaldehyde and be dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, light yellow solid is obtained after being spin-dried for by solvent, again by column chromatography, obtain two isomerss 3h (a) and 3h (b), the eluent V of target compound
sherwood oil: V
ethyl acetate=1:2.Wherein 3h (a) yield 35%, fusing point: 212-214 DEG C: MS (ESI) m/z:397.2 (M+H
+), 793.3 (2M+H
+).
1hNMR(DMSO-d6,500MHz) δ: 2.53 (m, 2H, 2-H), 2.91 (m; 1H, 4a-H), 3.06 (m, 1H, 4b-H); 3.45 (m, 1H, 3-H), 5.64 (d, 1H; J=6.0Hz, 11-H), 6.16 (d, 1H; J=6.0Hz, 10-NH), 6.88-7.35 (m, 4H; Ph-H), 8.82 (s, 1H, 5-NH); (6.97-7.35 m, 5H, Ph-H); R:3.62 (s, 3H, 4'-OCH3), 7.35 (m, 4H, 2'-H, 3'-H, 5'-H, 6'-H);
3h (b): yield 28%, fusing point: 212-214 DEG C: MS (ESI) m/z:397.2 (M+H
+), 793.3 (2M+H
+);
1hNMR(DMSO-d6,500MHz) δ: 2.42 (m, 1H, 2a-H), 2.68 (m; 1H, 2b-H), 2.87 (m, 1H, 4a-H); 2.99 (m, 1H, 4b-H), 3.38 (m, 1H; 3-H), 5.74 (d, 1H, J=5.5Hz, 11-H); 6.22 (d, 1H, J=6.5Hz, 10-NH), 6.58-6.69 (m; 4H, Ph-H), 8.78 (s, 1H, 5-NH); 6.59 (m, 5H, Ph-H); R:3.64 (s, 3H, 4'-OCH3), 6.58 (m, 2H, 2'-H, 6'-H), 7.09 (d, 2H, J=8.5Hz, 3'-H, 5'-H).
Embodiment 10
The synthesis of compound 3-phenyl-11-phenyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone (3i)
Compound 2 prepared by 5mmol embodiment 1 and 5mmol phenyl aldehyde and be dissolved under the condition of 2.5mL acetic acid in the ethanol of 25mL, stirring and refluxing 3 ~ 4h, after reaction terminates, question response liquid is cooled to room temperature, light yellow solid is obtained after being spin-dried for by solvent, again by column chromatography, obtain two isomerss 3i (a) and 3i (b), the eluent V of target compound
sherwood oil: V
acetic acid second ester=1:2.Wherein 3i (a) yield 50%, fusing point: 206-208 DEG C: MS (ESI) m/z:367.2 (M+H
+), 733.3 (2M+H
+);
1hNMR(DMSO-d6,500MHz) δ: 2.46 (m, 1H, 2a-H), 2.60 (m; 1H, 2b-H), 2.89 (m, 1H, 4a-H); 3.09 (m, 1H, 4b-H), 3.46 (m, 1H; 3-H), 5.70 (d, 1H, J=6.0Hz, 11-H); 6.24 (d, 1H, J=6.0Hz, 10-NH), 6.89-7.05 ((m; 4H, Ph-H), 8.88 (s, 1H, 5-NH); (7.05-7.36 m, 5H, Ph-H); R:7.36 (m, 5H, Ph-H); IR (KBr) υ: 3295 (m), 1594 (m), 1529 (s), 1388 (m), 754 (m), 698 (m).
3i (b): yield 25%, fusing point: 206-208 DEG C: MS (ESI) m/z:367.2 (M+H
+), 733.3 (2M+H
+); 1HNMR(DMSO-d6,500MHz) δ: 2.43 (m, 1H, 2a-H), 2.69 (m; 1H, 2b-H), 2.96 (m, 2H, 4-H); 3.38 (m, 1H, 3-H), 5.80 (d, 1H; J=6.0Hz, 11-H), 6.29 (d, 1H; J=4.0Hz, 10-NH), 6.58 (m, 4H; Ph-H), 8.84 (s, 1H, 5-NH); (6.58-6.98 m, 5H, Ph-H); R:6.98-7.16 (m, 5H, Ph-H); IR (KBr) υ: 3295 (m), 1594 (m), 1529 (s), 1388 (m), 754 (m), 698 (m).
Embodiment 11
3-phenyl-the 11-(2-chloro-phenyl-)-2 will obtained through pillar layer separation under room temperature, 3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] phenodiazine Zhuo-1-ketone (3a) is dissolve under the condition of solvent in ethyl acetate, is placed in the monocrystalline of solvent flashing 1 ~ 3 week obtained compound under room temperature.
Embodiment 12
3-phenyl-the 11-(4-pyridyl)-2 will obtained through pillar layer separation under room temperature, 3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] phenodiazine Zhuo-1-ketone (3c) is dissolve under the condition of solvent at ethanol, is placed in the monocrystalline of solvent flashing 1 ~ 3 week obtained compound under room temperature.
Embodiment 13
3-phenyl-the 11-(3-pyridyl)-2 will obtained through pillar layer separation under room temperature, 3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] phenodiazine Zhuo-1-ketone (3d) is dissolve under the condition of solvent in ethyl acetate, is placed in the monocrystalline of solvent flashing 1 ~ 3 week obtained compound under room temperature.
Embodiment 14
3-phenyl-11-(the Alpha-Naphthyl will obtained through pillar layer separation under room temperature)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] phenodiazine Zhuo-1-ketone (3f) is dissolve under the condition of solvent in ethyl acetate, is placed in the monocrystalline of solvent flashing 1 ~ 3 week obtained compound under room temperature.
Crystal structure determination to embodiment 2 (3a), embodiment 4 (3c), embodiment 5 (3d) and embodiment 7 (3f):
Choose the monocrystalline of suitable size under the microscope, point diffraction data collected by Bruker SMART APEX CCD detection instrument.At 291 (2) K temperature, with epoxy resin glue by single crystal sticky on glass yarn, use graphite monochromatised Mo K α radiation (λ=0.071073nm) ray to collect.Diffracted intensity data correct through Lp Summing Factor empirical absorption.Crystal structure analysis and the calculating SHELXL program of compound complete, and have made absorption or extinction correction with SADABS.Non-hydrogen atom coordinate difference Fourier synthesizes acquisition, and carried out complete matrix least-squares refinement to whole non-hydrogen atom coordinate and anisotropy thermal parameter, hydrogen atom obtains with theoretical method of hydrotreating, and the participation structure factor calculates.Relevant crystallographic data is in Table 1(3a), table 2(3c), table 3(3d) and show 4(3f).And their minimum asymmetric cell structure iron is shown in Fig. 1 (3a), Fig. 2 (3c), Fig. 3 (3d) and Fig. 4 (3f).
Table 1 is the crystallographic data of compound 3a
| Molecular formula | C 25H 21ClN 2O |
| Molecular weight | 400.13 |
| Crystallographic system | Monocline |
| Spacer | P21/c |
| a/nm | 14.3192(17) |
| b/nm | 7.9273(9) |
| c/nm | 18.744(2) |
| α/(°) | 90.00 |
| β/(°) | 97.831(2) |
| γ/(°) | 90.00 |
| Volume/nm 3 | 2107.8(4) |
| Z | 42 |
| Density | 1.535 |
| Absorption factor | 0.257 |
| F(000) | 992 |
| Final R indices[I>2sigma(I)] | R1=0.0741,wR2=0.1927 |
| R indices(all data) | R1=0.0579,wR2=0.1735 |
Table 2 is the crystallographic data of compound 3c
| Molecular formula | C 24H 24N 3O 3 |
| Molecular weight | 402.08 |
| Crystallographic system | Three is oblique |
| Spacer | P-1 |
| a/nm | 28.39(4) |
| b/nm | 9.275(12) |
| c/nm | 16.84(2) |
| α/(°) | 90.00 |
| β/(°) | 104.98(3) |
| γ/(°) | 90.00 |
| Volume/nm 3 | 4284(10) |
| Z | 8 |
| Density | 1.247 |
| Absorption factor | 0.083 |
| F(000) | 1701 |
| Final R indices[I>2sigma(I)] | R1=0.2125,wR2=0.2977 |
| R indices(all data) | R1=0.1049,wR2=0.2490 |
Table 3 is the crystallographic data of compound 3d
| Molecular formula | C 24H 21N 3O |
| Molecular weight | 367.44 |
| Crystallographic system | Monocline |
| Spacer | P2(1)/c |
| a/nm | 11.625(5) |
| b/nm | 19.055(9) |
| c/nm | 8.741(4) |
| α/(°) | 90.00 |
| β/(°) | 95.547(6) |
| γ/(°) | 90.00 |
| Volume/nm 3 | 1927.1(15) |
| Z | 4 |
| Density | 1.266 |
| Absorption factor | 0.079 |
| F(000) | 776 |
| Final R indices[I>2sigma(I)] | R1=0.1042,wR2=0.2200 |
| R indices(all data) | R1=0.0688,wR2=0.1934 |
Table 4 is the crystallographic data of compound 3f
| Molecular formula | C 29H 26N 2O 2 |
| Molecular weight | 434.52 |
| Crystallographic system | Monocline |
| Spacer | P2(1)/c |
| a/nm | 15.959(3) |
| b/nm | 7.9008(14) |
| c/nm | 18.583(4) |
| α/(°) | 90.00 |
| β/(°) | 106.247(5) |
| γ/(°) | 90.00 |
| Volume/nm 3 | 2249.5(8) |
| Z | 4 |
| Density | 1.283 |
| Absorption factor | 0.081 |
| F(000) | 920 |
| Final R indices[I>2sigma(I)] | R1=0.0898,wR2=0.1693 |
| R indices(all data) | R1=0.0606,wR2=0.1533 |
Embodiment 12
By 3-(2-furyl)-2,3,4,5,10, any one in 11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone series derivates 3a ~ 3g, different concns is made into respectively with DMSO or ethanol, be added on filter paper with micro sample adding appliance, make its quality containing compound be respectively 200,100,50,25,12.5 μ g, for subsequent use after solvent evaporates.
The bacterial classification MH liquid nutrient medium of logarithmic phase is diluted to 10
-6/ mlCFU, gets 0.2ml and is added on MH agar plate, even with the coating of L rod, is then attached on substratum by the pastille scraps of paper, cultivates 24 hours observationss in 37 DEG C.
Experiment repeats for several times, antibacterial results averaged.Test result reference standard, antibacterial circle diameter size is less than 6mm scope, and compound does not have bacteriostatic activity; Antibacterial circle diameter size is in 6 ~ 10mm scope, and the bacteriostatic activity of compound is resistance; Antibacterial circle diameter size is in 11 ~ 15mm scope, and the bacteriostatic activity of compound is slight sensitive; Antibacterial circle diameter size is in 16 ~ 20mm scope, and the bacteriostatic activity of compound is extremely sensitive.Fungistatic effect is in table 5 and table 6.
Table 5 compound 3a ~ 3g is to the inhibition zone data of streptococcus aureus
Table 6 compound 3a ~ 3g is to colibacillary inhibition zone data
Experimental result shows: the part of compounds of this series derivates has certain bacteriostatic action to streptococcus aureus and intestinal bacteria, wherein the bacteriostatic activity of compound 3g is best, next is compound 3h and 3a, the fungistatic effect of compound 3b is general, and compound 3c, 3d, 3e, 3f, 3i then do not have fungistatic effect.
Claims (1)
1.3-phenyl-11-(3,4-Dimethoxyphenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [Isosorbide-5-Nitrae] phenodiazine Zhuo-1-ketone suppresses the application in streptococcus aureus or intestinal bacteria medicine in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310501134.7A CN103601690B (en) | 2013-10-23 | 2013-10-23 | 3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310501134.7A CN103601690B (en) | 2013-10-23 | 2013-10-23 | 3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103601690A CN103601690A (en) | 2014-02-26 |
| CN103601690B true CN103601690B (en) | 2015-09-02 |
Family
ID=50119973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310501134.7A Expired - Fee Related CN103601690B (en) | 2013-10-23 | 2013-10-23 | 3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103601690B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080293699A1 (en) * | 2007-05-25 | 2008-11-27 | Burnham Institute For Medical Research | Inhibitors of thapsigargin-induced cell death |
| CN101321534A (en) * | 2005-09-02 | 2008-12-10 | 泰博特克药品有限公司 | Benzodiazepines as HCV inhibitors |
| WO2013068592A1 (en) * | 2011-11-10 | 2013-05-16 | Fondation Jerome Lejeune | Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7186713B2 (en) * | 2003-01-21 | 2007-03-06 | Ecopia Biosciences, Inc. | Farnesyl dibenzodiazepinones and methods of treating cancer using same |
| WO2007118320A1 (en) * | 2006-04-14 | 2007-10-25 | Thallion Pharmaceuticals Inc. | Process for producing farnesylated dibenzodiazepinone by fermentation |
-
2013
- 2013-10-23 CN CN201310501134.7A patent/CN103601690B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101321534A (en) * | 2005-09-02 | 2008-12-10 | 泰博特克药品有限公司 | Benzodiazepines as HCV inhibitors |
| US20080293699A1 (en) * | 2007-05-25 | 2008-11-27 | Burnham Institute For Medical Research | Inhibitors of thapsigargin-induced cell death |
| WO2013068592A1 (en) * | 2011-11-10 | 2013-05-16 | Fondation Jerome Lejeune | Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide |
Non-Patent Citations (2)
| Title |
|---|
| 1,5-苯并二氮杂卓的合成及其生物活性研究;刘进兵等;《有机化学》;20081231;第28卷(第2期);317-320 * |
| Jir#780;í Schimer,et al..Structure-Aided Design of Novel Inhibitors of HIV Protease Based on a Benzodiazepine Scaffold.《Journal of Medicinal Chemistry》.2012,第55卷(第22期),10130-10135. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103601690A (en) | 2014-02-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Sabitha et al. | Cerium (III) chloride–catalyzed one-pot synthesis of tetrahydrobenzo [b] pyrans | |
| Jin et al. | A clean one-pot synthesis of tetrahydrobenzo [b] pyran derivatives catalyzed by hexadecyltrimethyl ammonium bromide in aqueous media | |
| Li et al. | One‐pot synthesis of 2‐amino‐4‐aryl‐3‐carbalkoxy‐7, 7‐dimethyl‐5, 6, 7, 8‐tetrahydrobenzo [b] pyran derivatives catalyzed by KF/basic Al2O3 under ultrasound irradiation | |
| Yan et al. | Microwave-assisted four-component, one-pot condensation reaction: an efficient synthesis of annulated pyridines | |
| Ghashang et al. | Pentafluorophenylammonium triflate (PFPAT) catalyzed facile construction of substituted chromeno [2, 3-d] pyrimidinone derivatives and their antimicrobial activity | |
| Prasad et al. | Synthesis and Antimicrobial Activity of Some Novel Chalcones of 2‐Hydroxy‐1‐Acetonapthone and 3‐Acetyl Coumarin | |
| JPH02258738A (en) | Benzocycloalkenyldihydroxyalkanoic acid compound, preparation thereof, and drug composition containing same | |
| CN103601690B (en) | 3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application | |
| CN103755659B (en) | 6-cinnamon acyl-2H-benzo [b] [1, 4] oxazine-3 (4H)-ketone compound and application thereof | |
| Dabholkar et al. | Synthesis and antibacterial activity of isochromene and isoquinoline derivative | |
| CN109651333A (en) | A kind of 2- indol-3-yl-quinolines with anti-tumor activity and its preparation method and application | |
| Horton et al. | 2-Substituted 1, 3-Indandiones | |
| CN111303190A (en) | Propenone derivative for removing N-methylrufloxacin and preparation method and application thereof | |
| CN104016898B (en) | 3,4-disubstituted pyrroles compounds and its preparation method and application | |
| CN103601721B (en) | 3-furyl dibenzodiazepine-1-ketone series derivates and its preparation method and application | |
| CN112824391A (en) | Propylene ketone derivative of gatifloxacin and preparation method and application thereof | |
| CN111647004B (en) | Propenone derivative for removing N-methylofloxacin and preparation method and application thereof | |
| Khoza et al. | Synthesis and photophysical properties of 2-aryl-6, 8-bis (arylethenyl)-4-methoxyquinolines | |
| CN101137609B (en) | Desmosdumotin, its production method and application against tumour and AIDS | |
| Abdi et al. | A One-Pot Diastereoselective Synthesis of 2-[Aryl (hydroxy) methyl]-6-methyl-2H-furo [3, 2-c] pyran-3, 4-diones: Crystallographic Evidence for the Furanone Ring Closure | |
| Xie et al. | Molecular modeling, design, synthesis, and biological evaluation of novel 3′, 4′-dicamphanoyl-(+)-cis-khellactone (DCK) analogs as potent anti-HIV agents | |
| Thorat et al. | Wittig reaction approach for the synthesis of 7-methoxy-2-[4-alkyl/aryl]-l-benzofuran-5-carboxaldehyde | |
| Bolos et al. | A new efficient synthesis of 3‐(hydroxymethyl)‐4H‐chromen‐4‐ones | |
| Tang et al. | A new process for the total synthesis of Sparstolonin B | |
| Majumdar et al. | An Atom-Economical Approach to the Synthesis of Potentially Bioactive 2H-Chromenes via CuI-Catalyzed Reactions of Alkyl/Aryl-(E)-(o-Propargyloxy) styryl Ketones |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150902 Termination date: 20181023 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |