CN107501178A - Naphthalimide analog derivative and its preparation method and application - Google Patents
Naphthalimide analog derivative and its preparation method and application Download PDFInfo
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- CN107501178A CN107501178A CN201710737344.4A CN201710737344A CN107501178A CN 107501178 A CN107501178 A CN 107501178A CN 201710737344 A CN201710737344 A CN 201710737344A CN 107501178 A CN107501178 A CN 107501178A
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- 0 *C1(CC1)N(C(c(c1c2cc3)cccc1c3N1CCNCC1)=O)C2=O Chemical compound *C1(CC1)N(C(c(c1c2cc3)cccc1c3N1CCNCC1)=O)C2=O 0.000 description 3
- TTYCGDJBGRGSRO-UHFFFAOYSA-N C=CCN(C(c(c1c2cccc11)ccc2N2CCNCC2)=N)C1=O Chemical compound C=CCN(C(c(c1c2cccc11)ccc2N2CCNCC2)=N)C1=O TTYCGDJBGRGSRO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a kind of naphthalimide analog derivative and its officinal salt with formula I~IV structures, these compounds have certain inhibitory activity to gram positive bacteria, gram-negative bacteria and fungi, available for preparation antibacterium and/or antifungal drug.Its preparing raw material degree of commercialization is high, cheap and easily-available, and syntheti c route is short, method is easy.
Description
Technical field
The invention belongs to chemical field, be related to a kind of new organic compound, further relate to the compound preparation method and
Its purposes.
Background technology
The important nitrogenous aromatic heterocycle that naphthoyl imide compounds are made up of ring-type double imide and naphthalene nucleus skeleton, it is this
Special big conjugated structure passes through different non-binding effect power such as hydrogen bond, coordinate bond, ion dipole, π-π and stacks, be hydrophobic
Effect and Van der Waals force etc. interact with the avtive spot in organism, so as to show extensive bioactivity.Especially
It is that naphthalimide compound is widely used in medicine with DNA (DNA) or the interaction of topoisomerase (TOP) II
Design and exploitation.Up to the present, the derivative such as Amonafide of some naphthalimides and mitonafide are used as and resist
Cancer drug enters clinical test.Importantly, some nearest researchs find that naphthalimide also has in antimicrobial field
Larger application.Therefore, research naphthalimide compound class medicine has preferable development prospect.
The content of the invention
In view of this, an object of the present invention is to provide a kind of naphthalimide derivative and its officinal salt；Purpose
Two be preparation method that the naphthalimide derivative and its officinal salt are provided；The third purpose is to provide the naphthoyl
The purposes of imine derivative and its officinal salt.
For achieving the above object, following technical scheme is provided through research, the present invention：
1. naphthalimide derivative and its officinal salt shown in formula I~IV：
In formula, R1For hydrogen, methyl, hydroxyl, vinyl, acetenyl, ketone group, aldehyde radical, phenyl, substituted-phenyl, carbazyl, take
For carbazyl, cumarin base or substituted cumarin base；
N is 0~20 integer；
R2For methyl, methoxyl group, halogen.
The technical scheme further preferred as the present invention,
R1For methyl, hydroxyl, vinyl, acetenyl, ketone group, aldehyde radical；
N is 1~9 integer；
R2For methoxyl group, fluorine.
Most preferably, the naphthalimide analog derivative is any of following compounds：
2. the preparation method of naphthalimide derivative, comprises the following steps：
A. intermediate V~VII preparation：It is solvent in dichloromethane using m-difluorobenzene as raw material, the catalysis of alchlor
Under, react to obtain intermediate V with chloracetyl chloride return stirring, the latter under the conditions of acetonitrile as solvents, potassium alkaline with triazole
Reaction obtains intermediate VI, further makees solvent in dichloromethane, and potassium hydroxide cooks alkaline reagent, Iodotrimethylsilane catalysis
Under, epoxidation obtains intermediate VII；
B. the preparation of naphthalimide derivative shown in formula I：With bromo- 1, the 8- naphthalenes dicarboxylic anhydrides of 4- for raw material, reacted with ammoniacal liquor
Intermediate VIII is obtained, is further solvent in DMF, potassium alkaline condition reacts to obtain shown in formula IX with halogenated compound
Compound, further using glycol monoethyl ether as solvent, by the compound shown in formula IX with piperazine return stirring react
Obtain the naphthalimide derivative shown in formula I；
In above-mentioned formula VIII, IX, R1Definition with n and R in formula I1It is identical with n definition；
C. the preparation of the naphthalimide derivative shown in formula II：With bromo- 1, the 8- naphthalenes dicarboxylic anhydrides of 4- for raw material, ethanol solution
For solvent, compound shown in general formula X is obtained from different 60 DEG C of stirring reactions of substituted aniline temperature control, further with ethylene glycol list
Methyl ether is solvent, and compound shown in general formula X and piperazine return stirring are reacted to obtain the naphthalimide derivative shown in formula II；
In above-mentioned general formula X, R2Definition and formula II in R2Definition it is identical；
D. the preparation of the naphthalimide derivative shown in general formula III：Naphthalimide shown in intermediate VII, formula I is spread out
Return stirring reacts in ethanol for biology and triethylamine, and the naphthalimide derivative shown in general formula III is made；
E. the preparation of the naphthalimide derivative shown in formula IV：Naphthalimide shown in intermediate VII, formula II is spread out
Return stirring reacts in ethanol for biology and triethylamine, and the naphthalimide derivative shown in formula IV is made.
3. the application of naphthalimide derivative and its officinal salt in antibacterium and/or antifungal drug is prepared.
Further, the bacterium is staphylococcus aureus, enterococcus faecalis, Escherichia coli, klepsiella pneumoniae, copper
Green pseudomonad and Acinetobacter bauamnnii it is any one or more；The fungi is Candida albicans, aspergillus fumigatus, the false silk in the torrid zone
Any of saccharomycete and Candida parapsilosis are a variety of.
The beneficial effects of the present invention are：The present invention utilizes drug design principle of hybridization, and design has synthesized a series of structures
Novel naphthalimide derivative is compound shown in formula I~IV.Synthetic route is short, and preparation method is simple, and raw material is easy to get, into
This is low.In vitro anti-microbial activity testing result shows, the naphthalimide analog derivative that the present invention synthesizes to gram-positive bacteria,
Gram-negative bacteria and fungi show certain inhibitory action.Therefore, the naphthalimide derivative that synthesizes of the present invention and its
The folk prescription of various formulations can be made in officinal salt or compound antibacterium and/or antifungal drug supply Clinical practice, so as to face
Bed antimicrobial therapy provide it is more efficiently, the drug candidates of safety, the drug resistance for helping to solve to be on the rise, obstinate cause
The clinical treatment problem such as characteristic of disease microorganism and emerging harmful microorganism.
Embodiment
In order that the purpose of the present invention, technical scheme and beneficial effect are clearer, below by the preferred reality of the present invention
Example is applied to be described in detail.
The preparation of embodiment 1, intermediate V~VII
Bibliography " Wang Y, Damu G.L.V., Lv J S, Geng R X, Yang D C, Zhou C H.Design,
synthesis and evaluation of clinafloxacin triazole hybrids as a new type of
antibacterial and antifungal agents.Bioorg.Med.Chem.Lett.,2012,22,5363–5366”
It is prepared by methods described.Obtain 10.08g intermediate V, yield 89.0%；Orange solids；Obtain 9.44g intermediate VI, yield
80.0%；White solid；Obtain 5.11g intermediate VII, yield 51.0%；White solid.
The preparation of embodiment 2, naphthalimide derivative VIII
Bibliography " Luo Y L, Kishore B, Kumar K V, Zhou C H, Cai G X.Novel
benzimidazole derived naphthalimide triazoles:synthesis,antimicrobial
activity and interactions with calf thymus DNA.Sci.China Chem.,2015,58,483–
It is prepared by 494 " methods describeds.Obtain 5.08g intermediate VIII, yield 92.0%；Brown solid.
The preparation of embodiment 3, naphthalimide derivative IX-1
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), bromoethane (2.18g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
1.99g compound IX-1, yield 65.3%；Yellow powder.
The preparation of embodiment 4, naphthalimide derivative IX-2
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), N-Propyl Bromide (2.46g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
1.94g compound IX-2, yield 61.2%；Yellow powder.
The preparation of embodiment 5, naphthalimide derivative IX-3
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), NBB (2.74g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
2.07g compound IX-3, yield 62.4%；Yellow powder.
The preparation of embodiment 6, naphthalimide derivative IX-4
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), bromo pentane silane (3.02g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
2.11g compound IX-4, yield 60.8%；Yellow powder.
The preparation of embodiment 7, naphthalimide derivative IX-5
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), bromohexane (3.30g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
2.22g compound IX-5, yield 61.7%；Yellow powder.
The preparation of embodiment 8, naphthalimide derivative IX-6
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), heptyl bromide (3.58g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
2.37g compound IX-6, yield 63.4%；Yellow powder.
The preparation of embodiment 9, naphthalimide derivative IX-7
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), bromooctane (3.86g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
2.53g compound IX-7, yield 65.1%；Yellow powder.
The preparation of embodiment 10, naphthalimide derivative IX-8
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), bromo-decane (4.42g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
2.69g compound IX-8, yield 64.6%；Yellow powder.
The preparation of embodiment 11, naphthalimide derivative IX-9
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), bromoethanol (2.50g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
1.97g compound IX-9, yield 61.5%；Yellow powder.
The preparation of embodiment 12, naphthalimide derivative IX-10
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), bromine ethene (2.42g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
1.90g compound IX-10, yield 60.1%；Yellow powder.
The preparation of embodiment 13, naphthalimide derivative IX-11
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), propargyl bromide (2.38g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
1.88g compound IX-11, yield 59.8%；Yellow powder.
The preparation of embodiment 14, naphthalimide derivative IX-12
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), chlroacetone (1.85g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
2.00g compound IX-12, yield 60.3%；Yellow powder.
The preparation of embodiment 15, naphthalimide derivative IX-13
In 100mL round-bottomed flasks, add intermediate VIII (2.76g, 10mmol), chloroacetaldehyde (1.57g, 20mmol) in
In 15mL organic solvent DMF, 70 DEG C of stirrings of temperature control, potassium carbonate (4.15g, 30mmol) is added after half an hour and continues to react.
Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25 DEG C), then concentrated, suction filtration, column chromatography for separation, is dried to obtain
1.88g compound IX-13, yield 59.2%；Yellow powder.
The preparation of embodiment 16, naphthalimide derivative I-1
In 100mL round-bottomed flasks, add intermediate compound I X-1 (3.04g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 1.89g compound I-1, yield 61.2%；Yellow powder.
The preparation of embodiment 17, naphthalimide derivative I-2
In 100mL round-bottomed flasks, add intermediate compound I X-2 (3.18g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 1.99g compound I-2, yield 61.5%；Yellow powder.
The preparation of embodiment 18, naphthalimide derivative I-3
In 100mL round-bottomed flasks, add intermediate compound I X-3 (3.32g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 2.08g compound I-3, yield 61.7%；Yellow powder.
The preparation of embodiment 19, naphthalimide derivative I-4
In 100mL round-bottomed flasks, add intermediate compound I X-4 (3.46g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 2.14g compound I-4, yield 60.9%；Yellow powder.
The preparation of embodiment 20, naphthalimide derivative I-5
In 100mL round-bottomed flasks, add intermediate compound I X-5 (3.60g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 2.20g compound I-5, yield 60.3%；Yellow powder.
The preparation of embodiment 21, naphthalimide derivative I-6
In 100mL round-bottomed flasks, add intermediate compound I X-6 (3.74g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 2.30g compound I-6, yield 60.5%；Yellow powder.
The preparation of embodiment 22, naphthalimide derivative I-7
In 100mL round-bottomed flasks, add intermediate compound I X-7 (3.88g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 2.43g compound I-7, yield 61.8%；Yellow powder.
The preparation of embodiment 23, naphthalimide derivative I-8
In 100mL round-bottomed flasks, add intermediate compound I X-8 (4.16g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 2.50g compound I-8, yield 59.2%；Yellow powder.
The preparation of embodiment 24, naphthalimide derivative I-9
In 100mL round-bottomed flasks, add intermediate compound I X-9 (3.20g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 1.90g compound I-9, yield 58.3%；Yellow powder.
The preparation of embodiment 25, naphthalimide derivative I-10
In 100mL round-bottomed flasks, add intermediate compound I X-10 (3.16g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 1.85g compound I-10, yield 57.6%；Yellow powder.
The preparation of embodiment 26, naphthalimide derivative I-11
In 100mL round-bottomed flasks, add intermediate compound I X-11 (3.14g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature (18~25
DEG C), then through suction filtration, column chromatography for separation, be dried to obtain 1.80g compound I-11, yield 56.5%；Yellow powder.
The preparation of embodiment 27, naphthalimide derivative I-12
In 100mL round-bottomed flasks, add intermediate compound I X-12 (3.32g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, then through filtering,
Column chromatography for separation, it is dried to obtain 1.93g compound I-12, yield 57.2%；Yellow powder.
The preparation of embodiment 28, naphthalimide derivative I-13
In 100mL round-bottomed flasks, add intermediate compound I X-13 (3.18g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, then through filtering,
Column chromatography for separation, it is dried to obtain 1.86g compound I-13, yield 57.4%；Yellow powder.
The preparation of embodiment 29, naphthalimide derivative X-1
In 100mL round-bottomed flasks, bromo- 1, the 8- naphthalenes dicarboxylic anhydrides (2.77g, 10mmol) of 4- are dissolved in ethanol solution, by
It is added dropwise to para-fluoroaniline (1.11g, 10mmol), 60 DEG C of stirring reactions of temperature control.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room
Temperature, then it is concentrated, filter, recrystallize, being dried to obtain 3.15g compound X-1, yield 85.2%；Gray solid.
The preparation of embodiment 30, naphthalimide derivative X-2
In 100mL round-bottomed flasks, bromo- 1, the 8- naphthalenes dicarboxylic anhydrides (2.77g, 10mmol) of 4- are dissolved in ethanol solution, by
It is added dropwise to P-nethoxyaniline (1.23g, 10mmol), 60 DEG C of stirring reactions of temperature control.Thin-layer chromatography, which tracks to reaction, to be terminated, cooling
To room temperature, then it is concentrated, filter, recrystallize, being dried to obtain 3.27g compound X-2, yield 85.6%；Gray solid.
The preparation of embodiment 31, naphthalimide derivative II-1
In 100mL round-bottomed flasks, add intermediate X -1 (3.70g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, then through filtering,
Column chromatography for separation, it is dried to obtain 2.76g compound II-1, yield 73.5%；Green solid.
The preparation of embodiment 32, naphthalimide derivative II-2
In 100mL round-bottomed flasks, add intermediate X -2 (3.82g, 10mmol), piperazine (3.45g, 40mmol) in
In 25mL glycol monoethyl ether, return stirring reaction.Thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, then through filtering,
Column chromatography for separation, it is dried to obtain 2.83g compound II-2, yield 73.1%；Green solid.
The preparation of embodiment 33, naphthalimide derivative III-1
In 100mL round-bottomed flasks, by compound I-1 (3.09g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
1.31g compound III-1, yield 48.0%.
Compound III-1：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.44 (d, J=
7.1Hz,1H,Nap-C9-H),8.38–8.32(m,2H,Nap-C7-H,Triazole-C3- H), 8.32 (d, J=2.9Hz, 1H,
Nap-C8-H),),7.78(s,1H,Triazole-C5- H), 7.76 (d, J=7.3Hz, 1H, Nap-C4- H), 7.46 (d, J=
16.0,8.7Hz,1H,Nap-C5- H), 7.26 (s, J=8.0Hz, 1H, difluorophenyl-C6- H), 7.18 (s, J=
10.4Hz,1H,difluorophenyl-C3- H), 6.99 (s, J=8.4Hz, 1H, difluorophenyl-C5-H),5.75(s,
1H,OH),4.63(s,2H,Triazole-CH2), 4.05 (d, J=7.0Hz, 2H ,-NCH2),3.11(s,4H,Piperazine-
H-2C2,Piperazine-H-2C6), 3.03 (d, J=13.8Hz, 1H, Piperazine-CH2), 2.82 (d, J=13.8Hz,
1H,Piperazine-CH2), 2.72 (d, J=10.9Hz, 4H, Piperazine-H-2C3,Piperazine-H-2C5),1.18
(d, J=5.8Hz, 3H ,-CH3)ppm。
The preparation of embodiment 34, naphthalimide derivative III-2
In 100mL round-bottomed flasks, by compound I-2 (3.23g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
1.16g compound III-2, yield 41.3%.
Compound III-2：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.45 (d, J=
7.0Hz,1H,Nap-C9- H), 8.38 (d, J=8.2Hz, 1H, Nap-C7-H),8.35(s,1H,Triazole-C3-H),8.32
(s,1H,Triazole-C5- H), 7.78 (d, J=8.0Hz, 2H, Nap-C4-H,difluorophenyl-C3-H),7.45(dd,
J=15.9,8.2Hz, 1H, Nap-C8- H), 7.27 (d, J=8.0Hz, 1H, Nap-C5- H), 7.19 (d, J=10.3Hz, 1H,
difluorophenyl-C6- H), 6.99 (d, J=8.3Hz, 1H, difluorophenyl-C5-H),5.76(s,1H,OH),
4.62(s,2H,Triazole-CH2), 3.98 (t, J=7.1Hz, 2H ,-NCH2CH2CH3),3.11(s,4H,Piperazine-
H-2C2,Piperazine-H-2C6), 3.03 (d, J=13.8Hz, 1H, Piperazine-CH2), 2.86 (d, J=42.6Hz,
1H,Piperazine-CH2),2.78–2.69(m,4H,Piperazine-H-2C3,Piperazine-H-2C5),1.63(dd,J
=14.5,7.2Hz, 2H ,-NCH2CH2CH3), 0.90 (t, J=7.3Hz, 3H ,-NCH2CH2CH3)ppm。
The preparation of embodiment 35, naphthalimide derivative III-3
In 100mL round-bottomed flasks, by compound I-3 (3.37g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
1.40g compound III-3, yield 48.6%.
Compound III-3：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.40 (d, J=
7.2Hz,1H,Nap-C9- H), 8.38 (d, J=8.5Hz, 1H, Nap-C7-H),8.33(s,1H,Triazole-C3-H),8.31
(d, J=8.0Hz, 1H, Nap-C4-H),7.78(s,1H,Triazole-C5- H), 7.76 (s, J=7.7Hz, 1H,
difluorophenyl-C3-H),7.49-7.44(m,1H,Nap-C8- H), 7.26 (d, J=8.0Hz, 1H, Nap-C5-H),
7.21-7.15(d,1H,difluorophenyl-C6- H), 6.99 (d, J=7.2Hz, 1H, difluorophenyl-C5-H),
5.75(s,1H,OH),4.63(s,2H,Triazole-CH2),3.11(s,5H,Piperazine-H-2C2,Piperazine-H-
2C6,Piperazine-CH2), 3.03 (d, J=13.7Hz, 2H ,-NCH2(CH2)2CH3), 2.82 (d, J=13.8Hz, 2H ,-
NCH2CH2CH2CH3), 2.75 (d, J=21.4Hz, 5H, Piperazine-H-2C3,Piperazine-H-2C5,
Piperazine-CH2), 1.21 (d, J=17.0Hz, 3H ,-N (CH2)3CH3), 0.78 (d, J=15.9Hz, 2H ,-N (CH2)2CH2CH3)ppm。
The preparation of embodiment 36, naphthalimide derivative III-4
In 100mL round-bottomed flasks, by compound I-4 (3.51g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
1.29g compound III-4, yield 43.7%.
Compound III-4：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.45 (d, J=
7.1Hz,1H,Nap-C9- H), 8.38 (d, J=8.5Hz, 1H, Nap-C7- H), 8.36 (d, J=8.1Hz, 1H, Nap-C4-H),
8.32(s,1H,Triazole-C3-H),7.80–7.75(m,2H,Triazole-C5-H,Nap-C8- H), 7.45 (s, J=
16.0,8.5Hz,1H,difluorophenyl-C3- H), 7.27 (d, J=8.0Hz, 1H, Nap-C5- H), 7.18 (t, J=
10.5Hz,1H,difluorophenyl-C6- H), 6.98 (t, J=8.3Hz, 1H, difluorophenyl-C5-H),5.74(s,
1H,OH),4.62(s,2H,Triazole-CH2), 4.01 (t, J=7.3Hz, 2H ,-NCH2(CH2)3CH3),3.11(s,4H,
Piperazine-H-2C2,Piperazine-H-2C6), 3.03 (d, J=13.8Hz, 1H, Piperazine-CH2),2.81(d,
J=13.7Hz, 1H, Piperazine-CH2), 2.73 (dd, J=19.1,14.0Hz, 4H, Piperazine-H-2C3,
Piperazine-H-2C5),1.65–1.56(m,2H,-NCH2CH2(CH2)2CH3), 1.32 (d, J=11.5Hz, 4H ,-N (CH2)2
(CH2)2CH3), 0.87 (t, J=6.7Hz, 3H ,-N (CH2)4CH3)ppm。
The preparation of embodiment 37, naphthalimide derivative III-5
In 100mL round-bottomed flasks, by compound I-5 (3.65g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
1.14g compound III-5, yield 37.8%.
Compound III-5：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.44 (d, J=
7.2Hz,1H,Nap-C9- H), 8.37 (d, J=8.4Hz, 1H, Nap-C7- H), 8.34 (d, J=8.1Hz, 1H, Nap-C4-H),
8.32(s,1H,Triazole-C3-H),7.78(s,1H,Triazole-C5- H), 7.76 (s, J=8.1Hz, 1H,
difluorophenyl-C3- H), 7.45 (dd, J=15.9,8.6Hz, 1H, Nap-C8- H)), 7.26 (d, J=8.1Hz, 1H,
Nap-C5- H), 7.18 (d, J=9.6Hz, 1H, difluorophenyl-C6- H), 6.99 (d, J=7.5Hz, 1H,
difluorophenyl-C5-H),5.75(s,1H,OH),4.63(s,2H,Triazole-CH2), 4.00 (t, J=7.4Hz,
2H,-NCH2(CH2)4CH3),3.11(s,4H,Piperazine-H-2C2,Piperazine-H-2C6), 3.03 (d, J=
13.8Hz,1H,Piperazine-CH2), 2.81 (d, J=13.8Hz, 1H, Piperazine-CH2), 2.75 (d, J=
22.2Hz,4H,Piperazine-H-2C3,Piperazine-H-2C5),1.64–1.55(m,2H,-NCH2CH2(CH2)3CH3),
1.28(d,6H,-N(CH2)2(CH2)3CH3), 0.85 (t, J=6.3Hz, 3H ,-N (CH2)5CH3)ppm。
The preparation of embodiment 38, naphthalimide derivative III-6
In 100mL round-bottomed flasks, by compound I-6 (3.79g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
0.87g compound III-6, yield 28.2%.
Compound III-6：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.44 (d, J=
7.1Hz,1H,Nap-C9- H), 8.37 (d, J=8.4Hz, 1H, Nap-C7- H), 8.34 (d, J=8.1Hz, 1H, Nap-C4-H),
8.32(s,1H,Triazole-C3-H),7.80–7.73(m,2H,Triazole-C5-H,Nap-C8- H), 7.45 (s, J=
15.9,8.6Hz,1H,difluorophenyl-C3- H), 7.26 (d, J=8.1Hz, 1H, Nap-C5- H), 7.18 (t, J=
9.6Hz,1H,difluorophenyl-C6- H), 6.99 (t, J=7.6Hz, 1H, difluorophenyl-C5-H),5.76(s,
1H,OH),4.63(s,2H,Triazole-CH2), 4.00 (t, J=7.2Hz, 2H ,-NCH2(CH2)5CH3),3.11(s,4H,
Piperazine-H-2C2,Piperazine-H-2C6), 3.02 (d, J=13.8Hz, 1H, Piperazine-CH2),2.81(d,
J=13.8Hz, 1H, Piperazine-CH2), 2.74 (d, J=27.6Hz, 4H, Piperazine-H-2C3,Piperazine-
H-2C5),1.60(m,2H,-NCH2CH2(CH2)4CH3),1.30(m,4H,-N(CH2)2(CH2)2(CH2)2CH3),1.24(m,
4H,-N(CH2)4(CH2)2CH3), 0.84 (t, J=6.6Hz, 3H ,-N (CH2)6CH3)ppm。
The preparation of embodiment 39, naphthalimide derivative III-7
In 100mL round-bottomed flasks, by compound I-7 (3.93g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
1.03g compound III-7, yield 32.6%.
Compound III-7：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.44 (d, J=
7.1Hz,1H,Nap-C9- H), 8.37 (d, J=8.4Hz, 1H, Nap-C7- H), 8.34 (d, J=8.1Hz, 1H, Nap-C4-H),
8.32(s,1H,Triazole-C3-H),7.80–7.73(m,2H,Triazole-C5-H,Nap-C8- H), 7.45 (s, J=
15.9,8.6Hz,1H,difluorophenyl-C3- H), 7.26 (d, J=8.1Hz, 1H, Nap-C5- H), 7.18 (t, J=
9.6Hz,1H,difluorophenyl-C6- H), 6.99 (t, J=7.6Hz, 1H, difluorophenyl-C5-H),5.76(s,
1H,OH),4.63(s,2H,Triazole-CH2), 4.00 (t, J=7.2Hz, 2H ,-NCH2(CH2)6CH3),3.11(s,4H,
Piperazine-H-2C2,Piperazine-H-2C6), 3.02 (d, J=13.8Hz, 1H, Piperazine-CH2),2.81(d,
J=13.8Hz, 1H, Piperazine-CH2), 2.74 (d, J=27.6Hz, 4H, Piperazine-H-2C3,Piperazine-
H-2C5),1.60(m,2H,-NCH2CH2(CH2)5CH3),1.27(m,10H,-N(CH2)2(CH2)5CH3), 0.84 (t, J=
6.6Hz,3H,-N(CH2)7CH3)ppm。
The preparation of embodiment 40, naphthalimide derivative III-8
In 100mL round-bottomed flasks, by compound I-8 (4.22g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
0.81g compound III-8, yield 24.7%.
Compound III-8：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.43 (d, J=
7.2Hz,1H,Nap-C9-H),8.37–8.33(m,2H,Nap-C7-H,Nap-C4-H),8.33(s,1H,Triazole-C3-H),
7.78(s,1H,Triazole-C5- H), 7.75 (d, J=7.9Hz, 1H, difluorophenyl-C3- H), 7.46 (dd, J=
15.6,8.1Hz,1H,Nap-C8- H), 7.25 (d, J=8.0Hz, 1H, Nap-C5- H), 7.18 (d, J=9.9Hz, 1H,
difluorophenyl-C6- H), 6.99 (d, J=7.3Hz, 1H, difluorophenyl-C5-H),5.76(s,1H,OH),
4.63(s,2H,Triazole-CH2), 3.99 (t, J=7.2Hz, 2H ,-NCH2(CH2)8CH3),3.13–2.99(m,4H,
Piperazine-H-2C2,Piperazine-H-2C6), 2.82 (d, J=13.7Hz, 1H, Piperazine-CH2),2.75(d,
J=22.5Hz, 4H, Piperazine-H-2C3,Piperazine-H-2C5),2.09(s,1H,Piperazine-CH2),1.59
(s,2H,-NCH2CH2(CH2)7CH3), 1.25 (d, J=46.8Hz, 14H ,-N (CH2)2(CH2)7CH3), 0.83 (t, J=
6.8Hz,3H,-N(CH2)9CH3)ppm。
The preparation of embodiment 41, naphthalimide derivative III-9
In 100mL round-bottomed flasks, by compound I-9 (3.25g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and is cooled to room temperature, is added after concentration
Enter mixture of ice and water suction filtration, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, be dried to obtain
1.51g compound III-9, yield 53.7%.
Compound III-9：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.45 (d, J=
7.2Hz,1H,Nap-C9- H), 8.38 (d, J=8.4Hz, 1H, Nap-C7- H), 8.35 (d, J=8.1Hz, 1H, Nap-C8-H),
8.32(s,1H,Triazole-C3-H),7.80–7.75(m,2H,difluorophenyl-C3-H,Triazole-C5-H),
7.45 (dd, J=15.9,8.6Hz, 1H, Nap-C4- H), 7.27 (d, J=8.1Hz, 1H, Nap-C5- H), 7.18 (t, J=
9.8Hz,1H,Nap-C8- H), 6.99 (d, J=7.6Hz, 1H, difluorophenyl-C6-H),5.74(s,1H,OH),4.76
(s,1H,-CH2OH),4.62(s,2H,Triazole-CH2),4.12(s,2H,-NCH2CH2OH),3.62–3.57(m,2H,-
NCH2CH2OH),3.11(m,4H,Piperazine-H-2C2,Piperazine-H-2C6), 3.03 (d, J=13.8Hz, 1H,
Piperazine-CH2), 2.83 (d, J=13.8Hz, 1H, Piperazine-CH2),2.81–2.69(m,4H,Piperazine-
H-2C3,Piperazine-H-2C5)ppm。
The preparation of embodiment 42, naphthalimide derivative III-10
In 100mL round-bottomed flasks, by compound I-10 (3.21g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Middle return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and room temperature is cooled to, after concentration
Add mixture of ice and water to filter, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, dry
To 1.60g compound III-10, yield 57.4%.
Compound III-10：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.46(s,1H,
Triazole-C3- H), 8.40 (d, J=7.2Hz, 1H, Nap-C9- H), 8.37 (d, J=12.9,8.3Hz, 1H, Nap-C7-H),
8.32(s,1H,Triazole-C5- H), 7.79 (d, J=7.8Hz, 1H, Nap-C4-H),7.77(s,1H,
difluorophenyl-C3-H),7.46(d,1H,Nap-C8- H), 7.28 (d, J=8.2Hz, 1H, Nap-C5-H),7.18(d,J
=10.7Hz, 1H, difluorophenyl-C6- H), 6.98 (d, J=8.3Hz, 1H, difluorophenyl-C5-H),5.92
(dd,1H,-CH2CH=CH2),5.75(s,1H,OH),5.13-5.08(s,2H,-CH2CH=CH2),4.63(d,4H,
Triazole-CH2,-CH2CH=CH2),3.12(t,4H,Piperazine-H-2C2,Piperazine-H-2C6),3.03(d,J
=13.8Hz, 1H, Piperazine-CH2), 2.82 (d, J=13.8Hz, 1H, Piperazine-CH2), 2.75 (t, J=
21.9Hz,4H,Piperazine-H-2C3,Piperazine-H-2C5)ppm。
The preparation of embodiment 43, naphthalimide derivative III-11
In 100mL round-bottomed flasks, by compound I-11 (3.19g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Middle return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and room temperature is cooled to, after concentration
Add mixture of ice and water to filter, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, dry
To 1.48g compound III-11, yield 53.2%.
Compound III-11：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.45 (d, J=
7.2Hz,1H,Nap-C9- H), 8.38 (d, J=8.4Hz, 1H, Nap-C7- H), 8.35 (d, J=8.1Hz, 1H, Nap-C8-H),
8.32(s,1H,Triazole-C3-H),7.80–7.75(m,2H,difluorophenyl-C3-H,Triazole-C5-H),
7.45 (dd, J=15.9,8.6Hz, 1H, Nap-C4- H), 7.27 (d, J=8.1Hz, 1H, Nap-C5- H), 7.18 (t, J=
9.8Hz,1H,Nap-C8- H), 6.99 (d, J=7.6Hz, 1H, difluorophenyl-C6-H),5.74(s,1H,OH),4.76
(s,1H,-CH2C≡CH),4.62(s,2H,Triazole-CH2-),4.12(s,2H,-N-CH2C≡CH),3.11(m,4H,
Piperazine-H-2C2,Piperazine-H-2C6), 3.03 (d, J=13.8Hz, 1H, Piperazine-CH2-),2.83
(d, J=13.8Hz, 1H, Piperazine-CH2-),2.81–2.69(m,4H,Piperazine-H-2C3,Piperazine-H-
2C5,Piperazine-CH2-)ppm。
The preparation of embodiment 44, naphthalimide derivative III-12
In 100mL round-bottomed flasks, by compound I-12 (3.37g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Middle return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and room temperature is cooled to, after concentration
Add mixture of ice and water to filter, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, dry
To 1.60g compound III-12, yield 55.7%.
Compound III-12：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.47(s,1H,
Triazole-C3- H), 8.46 (d, J=7.2Hz, 1H, Nap-C9- H), 8.44 (d, J=12.9,8.3Hz, 1H, Nap-C7-H),
8.43(s,1H,Triazole-C5- H), 7.80 (d, J=7.8Hz, 1H, Nap-C4-H),7.78(s,1H,
difluorophenyl-C3-H),7.47(d,1H,Nap-C8- H), 7.31 (d, J=8.2Hz, 1H, Nap-C5-H),7.21(d,J
=10.7Hz, 1H, difluorophenyl-C6- H), 7.18 (d, J=8.3Hz, 1H, difluorophenyl-C5-H),5.76
(s,1H,OH),4.93(s,2H,-N-CH2COCH3),4.63(s,4H,Triazole-CH2,-NCH2),3.15(s,4H,
Piperazine-H-2C2,Piperazine-H-2C6), 3.05 (d, J=13.8Hz, 1H, Piperazine-CH2),2.84(d,
J=13.8Hz, 1H, Piperazine-CH2), 2.81 (d, J=21.9Hz, 4H, Piperazine-H-2C3,Piperazine-
H-2C5),2.27(s,3H,-COCH3)ppm。
The preparation of embodiment 45, naphthalimide derivative III-13
In 100mL round-bottomed flasks, by compound I-13 (3.23g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Middle return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and room temperature is cooled to, after concentration
Add mixture of ice and water to filter, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, dry
To 1.17g compound III-13, yield 41.6%.
Compound III-13：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:11.52(s,1H,-
CHO),8.42–8.36(m,2H,Nap-C9-H,Nap-C7-H),8.47(s,1H,Triazole-C3-H,1H,Nap-C4-H),
7.77 (d, J=12.2Hz, 2H, Triazole-C5-H,Nap-C8- H), 7.46 (s, J=7.3Hz, 1H, difluorophenyl-
C3- H), 7.26 (d, J=7.2Hz, 1H, Nap-C5- H), 7.18 (d, J=10.1Hz, 1H, difluorophenyl-C6-H),
6.99 (d, J=7.6Hz, 1H, difluorophenyl-C5-H),5.74(s,1H,OH),4.63(s,4H,Triazole-CH2,-
NCH2CHO),3.11(m,4H,Piperazine-H-2C2,Piperazine-H-2C6),3.03(m,2H,Piperazine-
CH2), 2.09 (m, J=21.9Hz, 4H, Piperazine-H-2C3,Piperazine-H-2C5)ppm。
The preparation of embodiment 46, naphthalimide derivative IV-1
In 100mL round-bottomed flasks, by compound II-1 (3.75g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Middle return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and room temperature is cooled to, after concentration
Add mixture of ice and water to filter, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, dry
To 1.58g compound IV-1, yield 51.6%.
Compound IV-1：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.47-8.43(m,
2H,Nap-C9-H,Nap-C7- H), 8.36 (d, J=8.0Hz, 1H, Nap-C4-H),8.32(s,1H,Triazole-C3-H),
7.81 (d, J=7.7Hz, 1H, Nap-C5-H),7.78(s,1H,Triazole-C5- H), 7.46 (d, J=7.4Hz, 1H,
difluorophenyl-C6-H),7.42–7.39(m,2H,flurophenyl-C2-H,flurophenyl-C6-H),7.33
(dd, J=18.9,8.6Hz, 3H, flurophenyl-C3-H,flurophenyl-C5-H,difluorophenyl-C6-H),
7.21–7.16(s,1H,difluorophenyl-C3- H), 6.99 (t, J=8.3Hz, 1H, Nap-C8-H),5.77(s,1H,
OH),4.63(s,2H,Triazole-CH2),3.13(s,4H,Piperazine-H-2C2,Piperazine-H-2C6),3.04
(d, J=13.7Hz, 1H, Piperazine-CH2), 2.79 (dd, J=32.9,19.8Hz, 5H, Piperazine-H-2C3,
Piperazine-H-2C5,Piperazine-CH2)ppm。
The preparation of embodiment 47, naphthalimide derivative IV-2
In 100mL round-bottomed flasks, by compound II-2 (3.87g, 10mmol) and VII (1.19g, 5mmol) in ethanol
Middle return stirring, and catalytic amount triethylamine about 0.2mL is added, thin-layer chromatography, which tracks to reaction, to be terminated, and room temperature is cooled to, after concentration
Add mixture of ice and water to filter, filtrate concentrates after being extracted with ethyl acetate.By obtained crude product through column chromatography for separation, dry
To 1.75g compound IV-2, yield 55.9%.
Compound IV-2：Yellow solid；250 DEG C of fusing point ＞；1H NMR(600MHz,DMSO-d6)δ:8.46–8.43(m,
1H,Nap-C9-H),8.42(s,1H,Triazole-C3- H), 8.36 (d, J=8.1Hz, 1H, Nap-C7-H),8.32(s,1H,
Triazole-C5- H), 7.80 (t, J=7.9Hz, 1H, Nap-C8-H),7.78(s,1H,difluorophenyl-C3-H),
7.46 (dd, J=15.9,8.7Hz, 1H, Nap-C4- H), 7.30 (d, J=8.2Hz, 1H, Nap-C5- H), 7.24 (d, J=
8.7Hz,2H,methoxyphenyl-C2-H,methoxyphenyl-C6-H),7.21-7.16(m,1H,difluorophenyl-
C6- H), 7.04 (d, J=8.8Hz, 2H, methoxyphenyl-C3-H,methoxyphenyl-C5- H), 6.99 (d, J=
8.2Hz,1H,difluorophenyl-C5-H),5.75(s,1H,OH),4.63(s,2H,Triazole-CH2),3.83(s,3H,
OCH3- Ph), 3.11 (d, J=27.0Hz, 4H, Piperazine-H-2C2,Piperazine-H-2C6), 3.04 (d, J=
13.8Hz,1H,Piperazine-CH2), 2.84 (d, J=13.8Hz, 1H, Piperazine-CH2),2.82-2.71(m,4H,
Piperazine-H-2C3,Piperazine-H-2C5)ppm。
Embodiment 48, the experiment of the in vitro anti-microbial activity of naphthalimide derivative
Clinical trial standard (the National Committee for formulated using United States National Committee in 1993 is met
Clinical Laboratory Standards, NCCLS) 96 hole micro-dilution methods, detection naphthalimide derivative I~IV
To staphylococcus aureus, enterococcus faecalis, Escherichia coli, klepsiella pneumoniae, pseudomonas aeruginosa, Bao Man not lever,
Candida albicans, aspergillus fumigatus, the minimum inhibitory concentration (MIC) of Candida tropicalis and Candida parapsilosis.By to be measuredization
After compound is dissolved with a small amount of dimethyl sulfoxide, it is diluted with water and solution of the concentration for 1.28mg/mL is made, then diluted with inoculum
To 1024 μ g/mL, 37 DEG C are cultivated 24~72 hours, culture plate are put after fully being stirred evenly on oscillator, are determined at wavelength 490nm
MIC.It the results are shown in Table 1.
The ill vitro antibacterial activity (MIC, μm ol/mL) of the compound of table 1
As it can be seen from table 1-5~I-8 of naphthalimide derivative I, III-5, III-9 that the present invention synthesizes are blue to leather
Family name's positive bacteria, Gram-negative bacteria show certain inhibitory action, it is even more important that part of compounds is to gram sun
Property bacterium, the antibacterial activity of Gram-negative bacteria can compare favourably with clinical medicine Norfloxacin, or even stronger.
The extracorporeal antifungal activity (MIC, μm ol/mL) of the compound of table 2
From table 2 it can be seen that some compounds all show certain inhibitory activity to surveyed fungi.Part of compounds pair
The inhibitory activity of aspergillus fumigatus, Candida tropicalis and Candida parapsilosis is suitable with reference drug Fluconazole or better than fluorine health
Azoles.
The pharmaceutical applications of embodiment 49, naphthalimide derivative
According to above-mentioned antimicrobial acivity testing result, the naphthalimide derivative that the present invention synthesizes has preferably anti-thin
Bacterium and antifungal activity, can be made antibacterium and/or antifungal drug supplies Clinical practice.The antibacterium and/or antimycotic
Medicine both can be single preparations of ephedrine, such as naphthalimide derivative or its pharmaceutically acceptable salt and pharmacy by a kind of structure
Upper acceptable auxiliary material is made；Can also be compound preparation, for example, by a kind of naphthalimide derivative of structure or its pharmaceutically
Acceptable salt and existing antibacterium, Active antifungal compound (such as Norfloxacin, Ciprofloxacin, Sulfamethoxazole, Fluconazole,
Phosphorus Fluconazole, Itraconazole etc.) and pharmaceutically acceptable auxiliary material be made, or spread out by several naphthalimides of different structure
Biology or its pharmaceutically acceptable salt are made with pharmaceutically acceptable auxiliary material.The preparation type includes but is not limited to piece
It is agent, capsule, powder, granule, pill, injection, powder-injection, solution, supensoid agent, emulsion, suppository, ointment, solidifying
The formulations such as jelly, film, aerosol, percutaneous absorption patch, and various slow-release controlled-release preparations and nanometer formulation.
1st, tablet I preparation
Prescription：Compound I-6 10g, lactose 187g, cornstarch 50g, magnesium stearate 3.0g, concentration expressed in percentage by volume are
70% ethanol solution is appropriate, and 1000 are made altogether.
Preparation method：By cornstarch in 105 DEG C dry 5 hours it is standby；Compound I-3 is mixed with lactose, cornstarch
It is even, with 70% ethanol solution softwood, sieve series wet granular is crossed, is dried, whole grain of sieving, magnesium stearate is added, tabletting, produces；
Every weight 250mg, active component content 10mg.
2nd, tablet II preparation
Prescription：Compound I-7 10g, lactose 80g, microcrystalline cellulose 5.0g, magnesium stearate 5.0g, are made 200 altogether.
Preparation method：Compound I-7 is well mixed with lactose, microcrystalline cellulose and magnesium stearate, tabletting, produced；Every weight
0.5g, active component content 50mg.
3rd, the preparation of capsule
Prescription：Compound I-8 10g, lactose 188g, magnesium stearate 2.0g, concentration expressed in percentage by volume are 70% ethanol solution
In right amount, 1000 are made altogether.
Preparation method：Compound I-8, lactose and magnesium stearate are well mixed, is sieved, is fitted into capsulae vacuus, produces；Every glue
Intracapsular tolerant heavy 200mg, active ingredient content are 10mg.
4th, the preparation of granule
Prescription：Compound I-5 126g, dextrin 120g, sucrose 280g.
Preparation method：Compound I-5, dextrin and sucrose are well mixed, wet granulation, 60 DEG C of dryings, dispense, produce.
5th, the preparation of injection
Prescription：Compound III-5 10g, propane diols 500mL, water for injection 500mL, are made 1000mL altogether.
Preparation method：Weigh Compound III-5, propane diols and water for injection, stirring and dissolving are added, 1g activated carbons is added, fills
Stands 15 minutes after point stirring, it is smart with the miillpore filter that aperture is 0.45 μm and 0.22 μm with 5 μm of stud filtering decarbonizations, then successively
Filter, last embedding 100 DEG C of circulation steam sterilizations 45 minutes, produce in 10mL ampoules.
6th, the preparation of powder-injection
Preparation method：Compound III-5 aseptic powdery is aseptically dispensed, produced.
7th, the preparation of eye drops
Prescription：Compound I-6 3.78g, sodium chloride 0.9g, benzyl carbinol 3g, appropriate borate buffer solution, distilled water add to
1000mL。
Preparation method：Compound I-6 and sodium chloride are added in 600mL distilled water, adjusted after dissolving completely with borate buffer solution
PH to 6.5 is saved, adds benzyl carbinol, then adds distilled water to be stirred, filtering with microporous membrane is filling, sealing, 100 DEG C to 1000mL
Circulation steam sterilization 1 hour, is produced.
8th, the preparation of liniment
Prescription：Compound I-7 4g, SOFT SOAP 7.5g, camphor 5g, distilled water add to 100mL.
Preparation method：The ethanol solution that camphor concentration expressed in percentage by volume is 95% is dissolved, it is standby；SOFT SOAP is heats liquefied,
It is standby；Weigh Compound I-7, lower addition potash fertilizer soap lye and camphor ethanol solution are being stirred continuously, then are being gradually added into distilled water, breast
Distilled water is added to full dose after changing completely, is produced.
9th, the preparation of suppository
Prescription：Compound I-8 4g, gelatin 14g, glycerine 70g, distilled water add to 100mL, 100 pieces are made altogether.
Preparation method：Weigh gelatin and glycerine, add distilled water to 100mL, 60 DEG C of heating fusings of water-bath, in the pasty state when add chemical combination
Thing I-8, stirs, and pours into vaginal plug mould, cooled and solidified, produces when closely solidifying.
10th, the preparation of ointment
Prescription：Compound 0.5~2g of I-5,6~8g of hexadecanol, 8~10g of albolene, 8~19g of atoleine are single sweet
2~5g of ester, polyoxyethylene (40) 2~5g of stearate, 5~10g of glycerine, ethylparaben 0.1g, distilled water add to 100g.
Preparation method：The heating of hexadecanol, albolene, atoleine, monoglyceride and polyoxyethylene (40) stearate is complete
Mixed after thawing, 80 DEG C of insulation is standby as oil phase；Ethylparaben is added in glycerine and distilled water, be heated to 85 DEG C it is molten
Solution, then lower addition oil phase is being stirred continuously, compound I-5 is added after emulsification, stirring cooling, is produced.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment the present invention is described in detail, it is to be understood by those skilled in the art that can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (9)
1. naphthalimide analog derivative and its officinal salt shown in formula I~IV：
In formula,
R1For hydrogen, methyl, hydroxyl, vinyl, acetenyl, ketone group, aldehyde radical, phenyl, substituted-phenyl, carbazyl, substituted carbazole base,
Cumarin base or substituted cumarin base；
N is 0~20 integer；
R2For methyl, methoxyl group, halogen.
2. naphthalimide derivative as claimed in claim 1 and its officinal salt, it is characterised in that
R1For methyl, hydroxyl, vinyl, acetenyl, ketone group, aldehyde radical；
N is 1~9 integer；
R2For methoxyl group, fluorine.
3. naphthalimide derivative as claimed in claim 2 and its officinal salt, it is characterised in that the naphthalimide derives
Thing is any of following compounds：
4. naphthalimide derivative according to claim 3 and its officinal salt, it is characterised in that the officinal salt is
Hydrochloride, nitrate or acetate.
5. the preparation method of the naphthalimide derivative and its officinal salt described in any one of Claims 1-4, its feature exist
In comprising the following steps：
A. intermediate V~VII preparation：It is solvent in dichloromethane using m-difluorobenzene as raw material, under the catalysis of alchlor,
React to obtain intermediate V with chloracetyl chloride return stirring, the latter reacts under the conditions of acetonitrile as solvents, potassium alkaline with triazole
Intermediate VI is obtained, further makees solvent in dichloromethane, potassium hydroxide cooks alkaline reagent, under Iodotrimethylsilane catalysis, ring
Oxidation obtains intermediate VII；
B. the preparation of naphthalimide derivative shown in formula I：With bromo- 1, the 8- naphthalenes dicarboxylic anhydrides of 4- for raw material, react to obtain with ammoniacal liquor
Intermediate VIII, it is further solvent in DMF, potassium alkaline condition reacts to obtain the change shown in formula IX with halogenated compound
Compound, further using glycol monoethyl ether as solvent, the compound shown in formula IX is reacted with piperazine return stirring and led to
Naphthalimide derivative shown in Formulas I；
In above-mentioned formula VIII, IX, R1Definition with n and R in formula I1It is identical with n definition；
C. the preparation of the naphthalimide derivative shown in formula II：With bromo- 1, the 8- naphthalenes dicarboxylic anhydrides of 4- for raw material, ethanol solution is molten
Agent, compound shown in general formula X is obtained from different 60 DEG C of stirring reactions of substituted aniline temperature control, further with glycol monoethyl ether
For solvent, compound shown in general formula X and piperazine return stirring are reacted to obtain the naphthalimide derivative shown in formula II；
In above-mentioned general formula X, R2Definition and formula II in R2Definition it is identical；
D. the preparation of the naphthalimide derivative shown in general formula III：By the naphthalimide derivative shown in intermediate VII, formula I
Return stirring reacts in ethanol with triethylamine, and the naphthalimide derivative shown in general formula III is made；
E. the preparation of the naphthalimide derivative shown in formula IV：By the naphthalimide derivative shown in intermediate VII, formula II
Return stirring reacts in ethanol with triethylamine, and the naphthalimide derivative shown in formula IV is made.
6. the naphthalimide derivative and its officinal salt described in claim 1 are in antibacterium and/or antifungal drug is prepared
Application.
7. application according to claim 6, it is characterised in that the bacterium be the bacterium be staphylococcus aureus,
Enterococcus faecalis, Escherichia coli, klepsiella pneumoniae, pseudomonas aeruginosa and Acinetobacter bauamnnii it is any one or more；
The fungi is any of Candida albicans, aspergillus fumigatus, Candida tropicalis and Candida parapsilosis or a variety of.
8. the preparation of the naphthalimide derivative and its officinal salt described in 1 to 4 any one containing claim.
9. preparation according to claim 8：It is characterized in that：The preparation is tablet, capsule, powder, granule, drop
Pill, injection, powder-injection, solution, supensoid agent, emulsion, ointment, gel, film, aerosol and Transdermal absorption patch
Agent.
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