CN104829534A - Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs - Google Patents

Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs Download PDF

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CN104829534A
CN104829534A CN201510268943.7A CN201510268943A CN104829534A CN 104829534 A CN104829534 A CN 104829534A CN 201510268943 A CN201510268943 A CN 201510268943A CN 104829534 A CN104829534 A CN 104829534A
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朱海亮
严晓强
王庆泽
王忠长
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Nanjing University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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Abstract

The invention discloses dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks, a preparation method of the dihydro-pyrazole morpholine derivatives and application of the dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs. The preparation method is characterized in that the dihydro-pyrazole morpholine derivatives are prepared according to a general formula shown in the specification. The dihydro-pyrazole morpholine derivatives have obvious inhibiting effects on human breast cancer cells (MCF-7), cervical cancer cells (HeLa), lung cancer cells (A549) and liver cancer cells (HepG2), the effects of the dihydro-pyrazole morpholine derivatives are approximate to those of a positive control drug Celecoxib, some of the dihydro-pyrazole morpholine derivatives are superior to the positive control drug, and meanwhile the dihydro-pyrazole morpholine derivatives are the same as or superior to the positive control drug Celecoxib in cytoxicity on human kidney epithelial cells. Therefore, the dihydro-pyrazole morpholine derivatives containing the naphthalene nucleus frameworks, disclosed by the invention, have better biological activity, higher selectivity and lower toxicity.

Description

One class is containing the preparation method of pyrazoline morpholine derivative of naphthalene nucleus skeleton and the application in cancer therapy drug
Technical field
The present invention relates to field of pharmaceutical chemistry technology, is that a class is containing the preparation method of pyrazoline morpholine derivative of naphthalene nucleus skeleton and the application in cancer therapy drug.
Background technology
The report of naphthalene nucleus skeleton on all kinds of International Periodicals is many, can be described as the large focus that compound structure modifies field.Except having outstanding anti-microbial activity, and there is outstanding anti-tumor activity.Along with the mechanism of tumor development is furtherd investigate gradually, naphthalene cycle compound is broadly applied in the exploitation of antitumor lead compound gradually.
Pyrazoles is the important heterogeneous ring compound of a class, is extensively distributed in occurring in nature.Since being found to have easing pain and diminishing inflammation and antipyretic effect containing the antipyrine of pyrazole ring, this compounds because of its have efficiently, low toxicity, and the character of the multi-faceted conversion of its ring substituents and being used widely in pharmaceutical field.Research finds that pyrazole compound has the pharmacologically actives such as anti-inflammatory, pain relieving, antibacterial, sterilization, hyperglycemia, anticancer, anti-coagulant.In recent years, the commercialization in succession of many novel pyrazoles medicine, has become one of focus of current medicinal design study on the synthesis to the further investigation of pyrazole compound.
Pyrazoline is very important nitrogenous five member ring heterocyclic compound, and it has a lot of excellent biological activity, such as antitumor, antibacterial, antiviral, antimycotic, tuberculosis, desinsection isoreactivity.It is a structural presence subunit with various pharmacological property, there is the active compound guide of general medicinal organism activity.In addition, because mostly pyrazoline is the conformation of the replacement on ring and molecule can be caused to have larger polytropy, thus, have chirality better biological activity potential quality! The application of pyrazoline compounds in organic synthesis and other field is more and more extensive, and chirality pyrazoline compounds has many biologies and pharmacological properties, facilitate the great development of medicine, for later drug development provides very large research space, development prospect is boundless, therefore building the heterocyclic system with pyrazoline structure to have great importance, is the focus be concerned in recent years.
Morpholine, as one of common pharmacophore important composition group, often can effectively improve the water-soluble of drug molecule, biological activity.Therefore, related compound is often applied in the exploitation of antitumor lead compound.
Based on this, naphthalene nucleus and pyrazoline are constructed in same a part by the present invention, meanwhile, introduce morpholine group, the a series of class of design and synthesis, containing the pyrazoline morpholine derivative of naphthalene nucleus skeleton, expects to have better biological activity, higher selectivity, lower toxicity.
Summary of the invention
Goal of the invention:
1. provide a class containing the pyrazoline morpholine derivative of naphthalene nucleus skeleton, to solve prior art Problems existing.
2. the preparation method of said derivative is provided.
3. provide a kind of said derivative preparing the application in antitumor drug.
Technical scheme a: class is containing the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it has such as formula the structure shown in X,
Wherein, described R 1be selected from H, CH 3, CH 2cH 3, OCH 3, OCH 2cH 3, F, Cl, Br; R 2be selected from H, CH 3, Cl, Br; R 3be selected from H, Cl.
One class is containing the building-up process of the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it has following general formula:
In formula I ~ formula V, described R 1be selected from H, CH 3, CH 2cH 3, OCH 3, OCH 2cH 3, F, Cl, Br; R 2be selected from H, CH 3, Cl, Br; R 3be selected from H, Cl.
The synthesis of the above-mentioned pyrazoline morpholine derivative containing naphthalene nucleus skeleton comprises the following steps:
Step 1: under 0 ± 5 DEG C of stirring action, is dissolved in structure in anhydrous methanol such as formula the compound shown in I, and drips SOCl 2, react under being transferred to 20 ± 10 DEG C of stirring actions, obtained structure is such as formula the compound shown in II; The mol ratio of each material is I: SOCl 3=1: 2 ~ 5, the reaction times is 6 ± 3h; Preferred mol ratio is 1: 4 further, and preferred temperature is respectively 0 DEG C, 20 DEG C, preferred reaction times 6h;
Step 2: under 20 ± 10 DEG C of stirring actions, in reaction vessel, add the compound of structure as shown in formula III successively, such as formula the compound shown in IV and dehydrated alcohol, dropwise drip the NaOH aqueous solution, obtained structure is such as formula the compound shown in V; The mol ratio of each material is III: IV: NaOH=1: 1: 3 ~ 10, NaOH aqueous solution massfraction is 20 ~ 50%, reaction times 4 ± 2h; Preferred mol ratio is 1: 1: 8 further, and preferred NaOH aqueous solution massfraction is 40%.Preferred temperature is 20 DEG C of preferred reaction times is 4h;
Step 3: under stirring, adds structure successively such as formula the compound shown in II, such as formula the compound shown in V and dehydrated alcohol, dropwise drip Glacial acetic acid in reaction vessel, extracts the target compound obtaining structure and show such as formula VI after back flow reaction; The mol ratio of each material is II: V: AcOH=1: 1 ~ 1.5: 5 ~ 20, and the reaction times is 6 ± 2h; Preferred mol ratio is 1: 1.2: 8 further, and the preferred reaction times is 6h;
Step 4: under stirring, add in reaction vessel successively structure such as formula the compound shown in VI and 1: 1 methyl alcohol, KOH water mixed liquid, dropwise dripping tetrahydrofuran (THF) to dissolving, extracting after back flow reaction and obtaining the target compound that structure shows such as formula VII; The mol ratio of each material is VI: KOH=1: 5 ~ 10, KOH aqueous solution massfraction is 20 ~ 60%, reaction times 4 ± 2h; Preferred mol ratio is 1: 1: 8 further, and preferred KOH aqueous solution massfraction is 45%, and the preferred reaction times is 4h;
Step 5: under 0 ± 5 DEG C of stirring action, structure is added successively such as formula the compound shown in VII, DMAP (DMAP), I-hydroxybenzotriazole (HOBT), anhydrous methylene chloride and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC.HCl) in reaction vessel, be transferred to 25 ± 10 DEG C and continue stirring reaction, extract the target compound obtaining structure and show such as formula VIII; The mol ratio of each material is VII:DMAP: HOBT: EDC.HCl=1: 2 ~ 2.5: 1 ~ 1.2: 1 ~ 1.5, reaction times 8 ± 3h; Preferred mol ratio is 1: 2.25: 1 ~ 1.1: 1 ~ 1.3 further, and preferred temperature is respectively 0 DEG C, 25 DEG C, and the preferred reaction times is 8h;
This preparation method has effectively integrated naphthalene nucleus skeleton, pyrazoline skeleton and these pharmacophoric groups of morpholine skeleton, and assay reproducibility is strong, good stability, the required condition of experiment reaction is comparatively simple, and experimental situation is gentle, productive rate is better, can produce in a large number in less input situation.
Beneficial effect: the present invention has obvious restraining effect to human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549) and liver cancer cell (HepG2), its action effect and positive control drug Celecoxib roughly the same, part should be better than positive control drug containing the pyrazoline morpholine derivative performance of naphthalene nucleus skeleton, and these derivatives show quite people's renal epithelial cell (293T) or are better than the cytotoxicity of positive control medicine Celecoxib simultaneously.Therefore, this kind of pyrazoline morpholine derivative containing naphthalene nucleus skeleton disclosed by the invention has better biological activity, higher selectivity and lower toxicity.
Embodiment
A detailed embodiment of the present invention is as follows:
Step 1: under 0 ± 5 DEG C of stirring action, is dissolved in structure such as formula the compound shown in I in the anhydrous methanol in round-bottomed flask, and dropwise drips SOCl 2, after 10 ± 5min, be transferred to 20 ± 10 DEG C and continue stirring 6 ± 3h, filter, dry, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the compound shown in II.
Step 2: under 20 ± 10 DEG C of stirring actions, the compound of structure as shown in formula III is added successively, such as formula the compound shown in IV and dehydrated alcohol in round-bottomed flask, dropwise drip 5 ~ 50%NaOH aqueous solution, after reaction 4 ± 2h, filter, the solid obtained uses distilled water, cold ethanol, distilled water wash successively, dry, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the compound shown in V.
Step 3: under stirring, structure is added successively such as formula the compound shown in II, such as formula the compound shown in V and dehydrated alcohol in reaction vessel, dropwise drip Glacial acetic acid, backflow, TLC follows the tracks of reaction, after reaction 6 ± 2h, cooling, filter, the solid obtained uses distilled water, cold ethanol, distilled water wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the target compound shown in VI by the solid crude product obtained.
Step 4: under stirring, add in reaction vessel successively structure such as formula the compound shown in VI and 1: 1 methyl alcohol, 20 ~ 60%KOH aqueous solution liquid, dropwise drip tetrahydrofuran (THF) to dissolve completely to compound, backflow, TLC follows the tracks of reaction, after reaction 4 ± 2h, acidifying, extraction, revolves steaming, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the compound shown in VII.
Step 5: under 0 ± 5 DEG C of stirring action, structure is added successively such as formula the compound shown in VII, DMAP, I-hydroxybenzotriazole and anhydrous methylene chloride in reaction vessel, after 10 ± 5min, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, be transferred to 25 ± 10 DEG C to continue to stir, TLC follows the tracks of reaction, and after 8 ± 3h, reaction solution uses saturated KHSO successively 4the aqueous solution, saturated Na 2cO 3, saturated common salt water washing, revolve steaming afterwards, the solid crude product obtained be dissolved in dehydrated alcohol recrystallization and obtain structure such as formula the compound shown in VIII.
Embodiment one:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-phenyl-4,5-pyrazoline) phenyl) ketone (compound 80)
Under 0 DEG C of stirring action, intermediate 55, DMAP, I-hydroxybenzotriazole and anhydrous methylene chloride that step 4 obtains is added successively in reaction vessel, after 10 ± 5min, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, be transferred to 25 DEG C to continue to stir, TLC follows the tracks of reaction (developping agent V acOEt: V normal hexane=2: 1), after 8 ± 3h, reaction solution uses saturated KHSO successively 4the aqueous solution, saturated Na 2cO 3, saturated common salt water washing, revolve steaming afterwards, the solid crude product obtained be dissolved in dehydrated alcohol recrystallization and obtain target compound 80.
Obtain crystal, productive rate 86.9%. 1H NMR(DMSO-d 6，400MHz)δ：8.33(s，1H，ArH)，8.02(d，J＝7.9Hz，1H，ArH)，7.87(d，J＝8.3Hz，1H，ArH)，7.78(d，J＝6.8Hz，2H，ArH)，7.70～7.58(m，2H，ArH)，7.46～7.35(m，4H，ArH)，7.29～7.20(m，3H，ArH)，6.96(d，J＝8.4Hz，2H，ArH)，6.26(s，1H，CH)，4.22(dd，J 1＝12.6，J 2＝12.3Hz，1H，CH 2)，3.55(s，4H，CH 2)，3.45(s，4H，CH 2)，3.13(d，J＝14.6Hz，1H，CH 2).ESI-MS：462.6[M+H] +，C 30H 27N 3O 2.
Embodiment two:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(4-methylphenyl)-4,5-pyrazolines) phenyl) ketone (compound 81)
Preparation method's reference example one.Obtain crystal, productive rate 88.3%. 1H NMR(DMSO-d 5，400MHz)δ：8.31(s，1H，ArH)，8.01(d，J＝7.9Hz，1H，ArH)，7.86(d，J＝8.2Hz，1H，ArH)，7.68～7.59(m，4H，ArH)，7.40(t，J＝7.5Hz，1H，ArH)，7.27～7.20(m，5H，ArH)，6.94(d，J＝8.3Hz，2H，ArH)，6.22(s，1H，CH)，4.19(dd，J 1＝12.6，J 2＝12.4Hz，1H，CH)，3.54(s，4H，CH 2)，3.45(s，4H，CH 2)，3.36(s，3H，CH 3)，3.08(d，J＝13.9Hz，1H，CH 2).ESI-MS：476.6[M+H] +，C 31H 29N 3O 2.
Embodiment three:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(3,4-Dimethvl-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 82)
Preparation method's reference example one.Obtain crystal, productive rate 64.8%. 1H NMR(DMSO-d 6，400MHz)δ：8.30(s，1H，ArH)，8.02(d，J＝7.8Hz，1H，ArH)，7.87(d，J＝8.1Hz，1H，ArH)，7.69～7.59(m，3H，ArH)，7.48(d，J＝7.7Hz，1H，ArH)，7.41(t，J＝7.0Hz，1H，ArH)，7.27～7.16(m，4H，ArH)，6.96(d，J＝8.8Hz，2H，ArH)，6.23(s，1H，CH)，4.18(dd，J 1＝12.6，J 2＝12.4Hz，1H，CH 2)，3.54(s，4H，CH 2)，3.45(s，4H，CH 2)，3.11(d，J＝11.9Hz，1H，CH 2)，2.24(s，6H，CH 3).ESI-MS：490.6[M+H] +，C 32H 31N 3O 2.
Embodiment four:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(4-Ethyl-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 83)
Preparation method's reference example one.Obtain crystal, productive rate 77.8%. 1H NMR(DMSO-d 6，400MHz)δ：8.32(s，1H，ArH)，8.02(d，J＝7.9Hz，1H，ArH)，7.87(d，J＝8.2Hz，2H，ArH)，7.70～7.60(m，4H，ArH)，7.41(t，J＝7.6Hz，1H，ArH)，7.27～7.24(m，4H，ArH)，6.94(d，J＝8.4Hz，2H，ArH)，6.24(s，1H，CH)，4.19(dd，J 1＝12.6，J 2＝12.3Hz，1H，CH 2)，3.54(s，4H，CH 2)，3.45(s，4H，CH 2)，3.09(d，J＝15.9Hz，1H)，2.62(dd，J 1＝7.5，J 2＝7.6Hz，2H，CH 2)，1.17(t，J＝7.6Hz，3H，CH 3).ESI-MS：490.6[M+H] +，C 32H 31N 3O 2.
Embodiment five:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(4-methoxyl group-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 84)
Preparation method's reference example one.Obtain crystal, productive rate 84.3%. 1H NMR(DMSO-d 6，400MHz)δ：8.30(s，1H，ArH)，7.86(d，J＝7.8Hz，1H，ArH)，7.71(d，J＝8.0Hz，1H，ArH)，7.67～7.59(m，4H，ArH)，7.40(t，J＝7.3Hz，1H，ArH)，7.24(d，J＝7.0Hz，3H，ArH)，6.98～6.92(m，4H，ArH)，6.18(s，1H，CH)，4.18(dd，J 1＝10.4，J 2＝13.5Hz，1H，CH 2)，3.78(s，3H，CH 3)，3.54(s，4H，CH 2)，3.45(s，4H，CH 2)，3.08(d，J＝10.2Hz，1H，CH 2).ESI-MS：492.6[M+H] +，C 31H 29N 3O 3.
Embodiment six:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(4-oxyethyl group-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 85)
Preparation method's reference example one.Obtain crystal, productive rate 90.7%. 1H NMR(DMSO-d 6，400MHz)δ：8.03(s，1H，ArH)，8.02(d，J＝8.1Hz，1H，ArH)，7.86(d，J＝8.2Hz，1H，ArH)，7.70-7.60(m，4H，ArH)，7.40(t，J＝4.9Hz，1H，ArH)，7.24(d，J＝8.6Hz，3H，ArH)，6.94(t，J＝9.1Hz，4H，ArH)，6.19(s，1H，CH)，4.17(t，J＝14.8Hz，1H，CH 2)，4.05(t，J＝9.4Hz，2H，CH 2)，3.54(s，4H，CH 2)，3.40(s，4H，CH 2)，3.07(d，J＝＝15.6Hz，1H，CH 2)，1.32(t，J＝13.8Hz，3H，CH 3).ESI-MS：506.6[M+H] +，C 32H 31N 3O 3.
Embodiment seven:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(the fluoro-phenyl of 4-)-4,5-pyrazolines) phenyl) ketone (compound 86)
Preparation method's reference example one.Obtain crystal, productive rate 80.2%. 1H NMR(DMSO-d 6，400MHz)δ：8.03(s，1H，ArH)，8.02(d，J＝8.1Hz，1H，ArH)，7.88-7.80(m，3H，ArH)，7.69-7.60(m，2H，ArH)，7.41(t，J＝7.3Hz，1H，ArH)，7.27-7.18(m，5H，ArH)，6.96(d，J＝8.2Hz，2H，ArH)，6.26(s，1H，CH)，4.20(dd，J 1＝13.0，J 2＝12.5Hz，1H，CH 2)，3.54(s，4H，CH 2)，3.45(s，4H，CH 2)，3.12(d，J＝14.2Hz，1H，CH 2).ES0-MS：480.6[M+H] +，C 32H 26FN 3O 2.
Embodiment eight:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(the bromo-phenyl of 4-)-4,5-pyrazolines) phenyl) ketone (compound 87)
Preparation method's reference example one.Obtain crystal, productive rate 76.7%. 1H NMR(DMSO-d 5，400MHz)δ：8.03(s，1H，ArH)，8.01(d，J＝7.0Hz，1H，ArH)，7.87(d，J＝8.5Hz，1H，ArH)，7.72～7.59(m，6H，ArH)，7.41(t，J＝7.0Hz，1H，ArH)，7.27～7.17(m，3H，ArH)，6.96(d，J＝8.6Hz，2H，ArH)，6.28(s，1H，CH)，4.18(dd，J 1＝12.5，J 2＝12.6Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.45(s，4H，CH 2)，3.11(d，J＝13.3Hz，1H，CH 2).ESI-MS：541.5[M+H] +，C 30H 26BrN 3O 2.
Embodiment nine:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(3-methylphenyl)-4,5-pyrazolines) phenyl) ketone (compound 88)
Preparation method's reference example one.Obtain crystal, productive rate 79.1%. 1H NMR(DMSO-d 6，400MHz)δ：8.32(s，1H，ArH)，8.02(d，J＝8.2Hz，1H，ArH)，7.87(d，J＝8.2Hz，1H，ArH)，7.72～7.49(m，6H，ArH)，7.44～7.14(m，6H，ArH)，6.96(d，J＝8.2Hz，1H，ArH)，6.85(d，J＝8.2Hz，1H，ArH)，6.25(s，1H，CH)，4.20(dd，J 1＝12.9，J 2＝12.7Hz，1H，CH 2)，3.55(s，3H，CH 2)，3.45(s，3H，CH 2)，3.10(d，J＝13.8Hz，1H，CH 2)，2.33(s，3H，CH 3).ESI-MS：476.6[M+H] +，C 31H 29N 3O 2.
Embodiment ten:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(the chloro-phenyl of 3-)-4,5-pyrazolines) phenyl) ketone (compound 89)
Preparation method's reference example one.Obtain crystal, productive rate 93.2%. 1H NMR(DMSO-d 6，400MHz)δ：8.30(s，1H，ArH)，8.01(d，J＝7.0Hz，1H，ArH)，7.86(d，J＝8.4Hz，1H，ArH)，7.73～7.59(m，6H，ArH)，7.40(t，J＝7.0Hz，1H，ArH)，7.27～7.17(m，3H，ArH)，6.96(d，J＝8.6Hz，2H，ArH)，6.31(s，1H，CH)，4.18(dd，J 1＝12.5，J 2＝12.6Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.45(s，4H，CH 2)，3.11(d，J＝13.3Hz，1H，CH 2).ESI-MS：497.0[M+H] +，C 30H 26ClN 3O 2.
Embodiment 11:
The preparation of morpholino (4-(5-(Alpha-Naphthyl)-3-(the bromo-phenyl of 3-)-4,5-pyrazolines) phenyl) ketone (compound 90)
Preparation method's reference example one.Obtain crystal, productive rate 84.7%. 1H NMR(DMSO-d 6，400MHz)δ：7.87(s，1H，ArH)，7.75(d，J＝7.8Hz，1H，ArH)，7.69(s，1H，ArH)，7.63(t，J＝7.2Hz，2H，ArH)，7.57(d，J＝7.8Hz，1H，ArH)，7.43-7.35(m，2H，ArH)，7.27(d，J＝8.5Hz，2H，ArH)，7.15(s，1H，ArH)，6.99(d，J＝8.2Hz，2H，ArH)，6.31(s，1H，CH)，4.19(dd，J 1＝13.0，J 2＝12.5Hz，1H，CH 2)，3.55(s，4H，CH 2)，3.45(s，4H，CH 2)，3.15(d，J＝14.9Hz，1H，CH 2).ESI-MS：541.5[M+H] +，C 30H 26BrN 3O 2.
Embodiment 12:
The preparation of morpholino (4-(5-(betanaphthyl)-3-phenyl-4,5-pyrazoline) phenyl) ketone (compound 91)
Preparation method's reference example one.Obtain crystal, productive rate 85.8%. 1H NMR(DMSO-d 6，400MHz)δ：7.88(d，J＝5.0Hz，4H，ArH)，7.79(d，J＝7.0Hz，2H，ArH)，7.52-738(m，6H，ArH)，7.25(d，J＝8.7Hz，2H，ArH)，7.08(d，J＝8.7Hz，2H，ArH)，5.70(dd，J 1＝6.1，J 2＝6.2Hz，1H，CH)，4.07-4.00(m，1H，CH 2)，3.52(d，J＝3.8Hz，4H，CH 2)，3.43(s，4H，CH 2)，3.26(d，J＝6.2Hz，1H，CH 2).ESI-MS：462.6[M+H] +，C 30H 27N 3O 2.
Embodiment 13:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(4-methylphenyl)-4,5-pyrazolines) phenyl) ketone (compound 92)
Preparation method's reference example one.Obtain crystal, productive rate 91.7%. 1H NMR(DMSO-d 6，400MHz)δ：7.93-7.87(m，4H，ArH)，7.69(d，J＝7.8Hz，2H，ArH)，7.52-7.49(m，2H，ArH)，7.40(d，J＝8.5Hz，1H，ArH)，7.27(t，J＝7.7Hz，4H，ArH)，7.06(d，8.1Hz，2H，ArH)，5.58(dd，J 1＝6.1，J 2＝6.2Hz，1H，CH)，4.06-3.98(m，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.24(d，J＝6.2Hz，1H，CH 2)，2.34(s，3H，CH 3).ESI-MS：476.6[M+H] +，C 31H 29N 3O 2.
Embodiment 14:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(3,4-Dimethvl-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 93)
Preparation method's reference example one.Obtain crystal, productive rate 84.8%. 1H NMR(DMSO-d 6，400MHz)δ：7.90-7.86(m，4H，ArH)，7.61(s，1H，ArH)，7.52-7.49(m，3H，ArH)，7.49(s，1H，ArH)，7.26-7.20(m，3H，ArH)，7.06(d，J＝8.6Hz，2H，ArH)，5.67(dd，J 1＝5.9，J 2＝6.1Hz，1H，CH)，4.00(dd，J 1＝12.3，J 2＝11.4Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.20(dd，J 1＝6.0，J 2＝5.9Hz，1H，CH 2)，2.56(d，J＝6.1Hz，6H，CH 3).ESI-MS：490.6[M+H] +，C 32H 31N 3O 2.
Embodiment 15:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(4-Ethyl-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 94)
Preparation method's reference example one.Obtain crystal, productive rate 74.9%. 1H NMR(DMSO-d 6，400MHz)δ：7.94-7.86(m，4H，ArH)，7.72(d，J＝8.2Hz，2H，ArH)，7.53-7.48(m，2H，ArH)，7.42-7.39(m，1H，ArH)，7.27(dd，J 1＝8.2，J 2＝8.3Hz，4H，ArH)，7.07(d，J＝8.8Hz，2H，ArH)，5.68(dd，J 1＝6.0，J 2＝6.2Hz，1H，CH)，4.02(dd，J 1＝12.4，J 2＝12.2Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.44(s，4H，CH 2)，3.22(dd，J 1＝6.2，J 2＝6.1Hz，1H，CH 2)，2.64(dd，J 1＝7.5，J 2＝7.6Hz，2H，CH 2)，1.19(t，J＝7.6Hz，3H，CH 3).ESI-MS：490.6[M+H] +，C 32H 31N 3O 2.
Embodiment 16:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(4-methoxyl group-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 95)
Preparation method's reference example one.Obtain crystal, productive rate 90.2%. 1H NMR(DMSO-d 6，400MHz)δ：δ：7.87(s，4H，ArH)，7.74(d，J＝8.8Hz，2H，ArH)，7.50(t，3.8Hz，2H，ArH)，7.42-7.39(m，1H，ArH)，7.24(d，J＝8.8Hz，2H，ArH)，7.03(dd，J 1＝8.8，J 2＝8.9Hz，4H，ArH)，5.65(dd，J 1＝6.1，J 2＝6.2Hz，1H，CH)，4.01(dd，J 1＝12.3，J 2＝12.1Hz，1H，CH 2)，3.80(s，3H，CH 3)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.23(d，J＝6.2Hz，1H，CH 2).ESI-MS：492.6[M+H] +，C 31H 29N 3O 3.
Embodiment 17:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(4-oxyethyl group-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 96)
Preparation method's reference example one.Obtain crystal, productive rate 79.8%. 1H NMR(DMSO-d 6，400MHz)δ：7.93～7.85(m，4H，ArH)，7.72(d，J＝8.8Hz，2H，ArH)，7.49(t，J＝3.8Hz，2H，ArH)，7.40(d，J＝8.5Hz，1H，ArH)，7.24(d，J＝8.8Hz，2H，ArH)，7.05～6.97(m，4H，ArH)，5.65(s，1H，CH)，4.10-3.95(m，3H，CH 2)，3.54(s，4H，CH 2)，3.45(s，4H，CH 2)，3.11(dd，J 1＝7.5，J 2＝7.6Hz，1H，CH 2)，1.34(t，J＝6.9Hz，3H，CH 3).ESI-MS：506.6[M+H] +，C 32H 31N 3O 3.
Embodiment 18:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(the fluoro-phenyl of 4-)-4,5-pyrazolines) phenyl) ketone (compound 97)
Preparation method's reference example one.Obtain crystal, productive rate 70.8%. 1H NMR(DMSO-d 6，400MHz)δ：7.84～7.82(m，6H，ArH)，7.50(d，J＝6.0Hz，2H，ArH)，7.40(d，J＝6.2Hz，1H，ArH)，7.31～7.24(m，4H，ArH)，7.07(d，J＝6.1Hz，2H，ArH)，5.70(dd，J 1＝11.5，J 2＝13.6Hz，1H，CH)，4.03(dd，J 1＝10.5，J 2＝12.1Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.22(d，J＝11.5Hz，1H，CH 2).ESI-MS：480.6[M+H] +，C 30H 26FN 3O 2.
Embodiment 19:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(the chloro-phenyl of 4-)-4,5-pyrazolines) phenyl) ketone (compound 98)
Preparation method's reference example one.Obtain crystal, productive rate 70.1%. 1H NMR(DMSO-d 6，400MHz)δ：8.03(s，1H，ArH)，8.01(d，J＝7.0Hz，1H，ArH)，7.87(d，J＝8.5Hz，1H，ArH)，7.72～7.59(m，6H，ArH)，7.41(t，J＝7.0Hz，1H，ArH)，7.27～7.17(m，3H，ArH)，6.96(d，J＝8.6Hz，2H，ArH)，6.28(s，1H，CH)，4.18(dd，J 1＝12.5，J 2＝12.6Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.45(s，4H，CH 2)，3.11(d，J＝13.3Hz，1H，CH 2).ESI-MS：497.0[M+H] +，C 30H 26ClN 3O 2.
Embodiment 20:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(3,4-Dichloro-phenyl)-4,5-pyrazolines) phenyl) ketone (compound 99)
Preparation method's reference example one.Obtain crystal, productive rate 93.2%. 1H NMR(DMSO-d 6，400MHz)δ：7.77(s，1H，ArH)，7.75(d，J＝8.5Hz，4H，ArH)，7.70(d，J＝6.5Hz，1H，ArH)，7.69(d，J＝5.9Hz，1H，ArH)，7.48(t，J＝6.9Hz，2H，ArH)，7.40(d，J＝6.0Hz，1H，ArH)，7.25(d，J＝7.0Hz，2H，ArH)，7.10(d，J＝5.8Hz，2H，ArH)，5.75(dd，J 1＝11.5，J 2＝13.6Hz，1H，CH)，4.03(dd，J 1＝10.5，J 2＝12.1Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.29(d，J＝10.3Hz，1H，CH 2).ESI-MS：531.5[M+H] +，C 30H 25Cl 2N 3O 2.
Embodiment 21:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(the bromo-phenyl of 4-)-4,5-pyrazolines) phenyl) ketone (compound 100)
Preparation method's reference example one.Obtain crystal, productive rate 80.2%. 1H NMR(DMSO-d 6，400MHz)δ：7.72-7.68(m，4H，ArH)，7.66(s，2H，ArH)，7.63(s，2H，ArH)，7.53-7.41(m，2H，ArH)，7.39(d，J＝8.0Hz，1H，ArH)，7.25(d，J＝8.8Hz，2H，ArH)，7.08(d，J＝8.6Hz，2H，ArH)，5.73(dd，J 1＝6.6Hz，J 2＝6.3Hz，1H，CH)，4.03(dd，J 1＝12.5，J 2＝12.4Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.26(d，J＝6.4Hz，1H，CH 2).ESI-MS：541.5[M+H] +，C 30H 26BrN 3O 2.
Embodiment 22:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(3-methylphenyl)-4,5-pyrazolines) phenyl) ketone (compound 101)
Preparation method's reference example one.Obtain crystal, productive rate 85.8%.m.p.270-272℃； 1H NMR(DMSO-d 6，400MHz)δ：7.93-7.85(m，4H，ArH)，7.65(s，1H，ArH)，7.57(d，J＝7.8Hz，1H，ArH)，7.50(t，J＝7.6Hz，2H，ArH)，7.39(d，J＝8.6Hz，1H，ArH)，7.33(t，J＝7.6Hz，1H，ArH)，7.26-7.20(m，3H，ArH)，7.07(d，J＝8.7Hz，2H，ArH)，5.70(dd，J 1＝6.0，J 2＝6.1Hz，1H，CH)，4.02(dd，J 1＝12.4，J 2＝12.2Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.23(dd，J 1＝6.1，J 2＝6.0Hz，1H，CH 2)，2.35(s，3H，CH 3).ESI-MS：476.6[M+H] +，C 31H 29N 3O 2.
Embodiment 23:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(the chloro-phenyl of 3-)-4,5-pyrazolines) phenyl) ketone (compound 102)
Preparation method's reference example one.Obtain crystal, productive rate 88.7%. 1H NMR(DMSO-d 6，400MHz)δ：7.98(s，1H，ArH)，7.94～7.86(m，4H，ArH)，7.77(d，J＝7.8Hz，1H，ArH)，7.59(d，J＝7.8Hz，1H，ArH)，7.53～7.23(m，6H，ArH)，7.11～7.01(m，2H，ArH)，5.74(dd，J 1＝6.1，J 2＝6.2Hz，1H，CH)，4.02(dd，J 1＝12.5，J 2＝12.4Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.27(dd，J 1＝6.2，J 2＝6.0Hz，1H，CH 2).ESI-MS：497.0[M+H] +，C 30H 26ClN 3O 2.
Embodiment 24:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(the bromo-phenyl of 3-)-4,5-pyrazolines) phenyl) ketone (compound 103)
Preparation method's reference example one.Obtain crystal, productive rate 84.8%. 1H NMR(DMSO-d 6，400MHz)δ：8.03(s，1H，ArH)，8.01(d，J＝6.4Hz，1H，ArH)，7.84～7.82(m，3H，ArH)，7.62(d，J＝8.5Hz，2H，ArH)，7.42(t，J＝6.4Hz，1H，ArH)，7.30(t，J＝7.0Hz，5H，ArH)，6.96(t，J＝7.6Hz，2H，ArH)，6.26(s，1H，CH)，4.20(dd，J 1＝10.5，J 2＝11.6Hz，1H，CH 2)，3.54(s，4H，CH 2)，3.45(s，4H，CH 2)，3.12(d，J＝11.3Hz，1H，CH 2).ESI-MS：541.5[M+H] +，C 30H 26BrN 3O 2.
Embodiment 25:
The preparation of morpholino (4-(5-(betanaphthyl)-3-(the chloro-phenyl of 2-)-4,5-pyrazolines) phenyl) ketone (compound 104)
Preparation method's reference example one.Obtain crystal, productive rate 84.3%. 1H NMR(DMSO-d 6，400MHz)δ：7.78(s，1H，ArH)，7.74(d，J＝8.5Hz，4H，ArH)，7.69(d，J＝6.2Hz，1H，ArH)，7.67(d，J＝5.4Hz，1H，ArH)，7.49(t，J＝6.6Hz，2H，ArH)，7.41(d，J＝6.3Hz，2H，ArH)，7.25(d，J＝7.0Hz，2H，ArH)，7.10(d，J＝5.8Hz，2H，ArH)，5.75(dd，J 1＝11.5，J 2＝13.6Hz，1H，CH)，4.03(dd，J 1＝10.5，J 2＝12.1Hz，1H，CH 2)，3.53(s，4H，CH 2)，3.43(s，4H，CH 2)，3.29(d，J＝11.2Hz，1H，CH 2).ESI-MS：497.0[M+H] +，C 30H 26ClN 3O 2.
Embodiment 26:
Containing the pyrazoline morpholine derivative anti tumor activity in vitro of naphthalene nucleus skeleton about the research of anti-tumour cell proliferative
Adopt MTT [3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures pyrazoline morpholine derivative containing naphthalene nucleus skeleton to the half-inhibition concentration (IC of human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549) and liver cancer cell (HepG2) 50).
(1) preparation of nutrient solution (/L): 1. suspension cell: DMEM cultivates one bag, powder (10.4g), new-born calf serum 100mL, penicillin solution (2 × 10 -5u/mL) 0.5mL, Streptomycin Solution (2 × 10 -5u/mL) 0.5mL, after adding tri-distilled water dissolving, with the NaHCO of 5.6% 3solution adjust pH, to 7.2-7.4, is finally settled to 1000mL.Filtration sterilization.2. attached cell: the same, then add NaHCO 32.00g, HEPES 2.38g.
(2) preparation of D-Hanks damping fluid (often liter): NaCl 8.00g, KCl 0.40g, Na 2hPO 412H 2o0.06g, KH 2pO 40.06g, NaHCO 30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of liquid is tested: dissolved by a small amount of tri-distilled water of test sample and be made into storing solution, i.e. 10 times of preparation storing solutions of empirically maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.Storing solution is stored in-20 DEG C of refrigerators for subsequent use.
(5) cultivation of human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549) and liver cancer cell (HepG2): be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/mL Streptomycin sulphate) in DMEM nutrient solution, is placed in 37 DEG C, 5%CO 2cultivate in incubator, go down to posterity once every 3-4d.When going down to posterity, nutrient solution in former bottle is transferred in centrifuge tube, the centrifugal 5min of 1000rpm, discard original fluid, add equivalent fresh medium, piping and druming evenly, pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).
(6) cell incubation: the tumour cell in vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 10 5individual/mL.In 96 well culture plates, every hole adds cell suspension 100 μ L, puts 37 DEG C, 5%CO 224h is cultivated in incubator.After cultivating 24h, add liquid by design respectively.
(7) dosing: join in each hole by test liquid respectively according to the concentration gradient of ultimate density, each concentration establishes 6 parallel holes.Experiment is divided into drug test group (adding the test medicine of different concns respectively), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in 37 DEG C, 5%CO 248h is cultivated in incubator.The activity of positive control medicine measures according to the method for test sample.
(8) mensuration of survivaling cell: in 96 orifice plates after having cultivated 48h, every hole adds MTT40 μ L (being made into 4mg/mL with D-Hanks damping fluid).After placing 4h at 37 DEG C, remove supernatant liquor.Every hole adds 150 μ LDMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, automatic microplate reader is utilized to detect the optical density(OD) (OD value) in each hole at 490nm wavelength place.
Half-inhibition concentration (IC 50) be defined as drug level when the tumor cell survival of 50%.According to the optical density(OD) (OD value) measured, make the typical curve of inhibitory rate of cell growth, typical curve is tried to achieve the drug level of its correspondence.
The IC recorded 50be shown in Table 1.
The listed pyrazoline morpholine derivative containing naphthalene nucleus skeleton of table 1 the present invention is to the suppression IC of tumour cell 50value (μM)
a6 parallel tests, experimental result is averaged, and error is between 5-10%
From above-mentioned experiment: the pyrazoline morpholine derivative containing naphthalene nucleus skeleton of the present invention has obvious restraining effect to human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549) and liver cancer cell (HepG2), especially best to liver cancer cell (HepG2), contrast positive control drug Celecoxib shows quite or is better than the inhibit activities of positive control medicine.Therefore, the pyrazoline morpholine derivative containing naphthalene nucleus skeleton of the present invention can be applied to and prepare antitumor drug.
Embodiment 27:
The present invention tests new synthetic compound 80-104 to the cytotoxicity of people's renal epithelial cell (293T), cytotoxicity result as table 2, using Celecoxib as positive control.The toxicity suppressor T cell survival rate of each compound to 50% time concentration (CC 50) represent.
Experimental technique:
(1) cultivator renal epithelial cell (293T) is tending towards fusion until reach its logarithmic growth end of term cell, digests cell dispersion, be mixed with 1 × 10 with cell culture fluid with cell dissociation buffer 4the cell suspension of individual/mL.Get 96 well culture plates, in every hole, add the cell suspension of 100 μ L.Horizontally rotating culture plate gently makes cell be evenly dispersed in the surface in ware hole.
(2) be placed in containing 5%CO2 cell culture incubator, at 37 ± 2 DEG C of temperature, cultivate 24h.Discard original fluid, every hole adds the blank liquid of 100 μ L, negative controls, positive control solution, the test sample vat liquor of 100% and 50% concentration.Often organize and at least establish 8 holes.Note: lixiviate stoste or make the serial lixiviate diluent of thinner with substratum.When adopting 0.9% sodium chloride injection lixiviate, use 2 times of concentrated substratum when diluting lixiviate.
(3) be placed in containing 5%CO 2in incubator, cultivate at 37 ± 2 DEG C of temperature.Cultivate 48h.
(4) after date between each cultivation, every hole adds MTT solution 20 μ L, is placed in containing 5%CO 2in incubator, at 37 ± 2 DEG C of temperature, cultivate 5h.
(5) discard liquid in hole, every hole adds 200 μ LDMSO respectively, and culture plate is placed 10min, and level is rocked and made solution colour in hole even.
(6) measure absorbancy by microplate reader, wavelength adopts 490nm.
The CC recorded 50be shown in Table 2.
The listed pyrazoline morpholine derivative containing naphthalene nucleus skeleton of table 2 the present invention is to the suppression CC of 293T cell 50value (μM)
a6 parallel tests, experimental result is averaged, and error is between 5-10%
From above-mentioned experiment: the pyrazoline morpholine derivative containing naphthalene nucleus skeleton of the present invention shows quite people's renal epithelial cell (293T) or is better than the cytotoxicity of positive control medicine, can be applied to and prepare antitumor drug.
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple equivalents to technical scheme of the present invention, these equivalents all belong to protection scope of the present invention.It should be noted that in addition, each the concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode.In order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.

Claims (8)

1. a class is containing the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it has such as formula the structure shown in X,
Wherein, described R 1be selected from H, CH 3, CH 2cH 3, OCH 3, OCH 2cH 3, F, Cl, Br; R 2be selected from H, CH 3, Cl, Br; R 3be selected from H, Cl.
2. prepare a method for the pyrazoline morpholine derivative containing naphthalene nucleus skeleton, it is characterized in that, the described pyrazoline morpholine derivative containing naphthalene nucleus skeleton has such as formula the structure shown in X,
Wherein, described R 1be selected from H, CH 3, CH 2cH 3, OCH 3, OCH 2cH 3, F, Cl, Br; R 2be selected from H, CH 3, Cl, Br; R 3be selected from H, Cl.
Its building-up process, has following general formula:
Described method comprises the steps:
(wherein, described R 1be selected from H, CH 3, CH 2cH 3, OCH 3, OCH 2cH 3, F, Cl, Br; R 2be selected from H, CH 3, Cl, Br; R 3be selected from H, Cl.)
Step 1: under 0 ± 5 DEG C of stirring action, is dissolved in structure in anhydrous methanol such as formula the compound shown in I, and drips SOCl 2, react under being transferred to 20 ± 10 DEG C of stirring actions, obtained structure is such as formula the compound shown in II;
Step 2: under 20 ± 10 DEG C of stirring actions, in reaction vessel, add the compound of structure as shown in formula III successively, such as formula the compound shown in IV and dehydrated alcohol, dropwise drip the NaOH aqueous solution, obtained structure is such as formula the compound shown in V;
Step 3: under stirring, adds structure successively such as formula the compound shown in II, such as formula the compound shown in V and dehydrated alcohol, dropwise drip Glacial acetic acid in reaction vessel, extracts the target compound obtaining structure and show such as formula VI after back flow reaction;
Step 4: under stirring, add in reaction vessel successively structure such as formula the compound shown in VI and 1: 1 methyl alcohol, KOH water mixed liquid, dropwise dripping tetrahydrofuran (THF) to dissolving, extracting after back flow reaction and obtaining the target compound that structure shows such as formula VII;
Step 5: under 0 ± 5 DEG C of stirring action, structure is added successively such as formula the compound shown in VII, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, DMAP, I-hydroxybenzotriazole and anhydrous methylene chloride in reaction vessel, react under being transferred to 25 ± 10 DEG C of stirring actions, extract the target compound obtaining structure and show such as formula VIII.
3. preparation as claimed in claim 2 is containing the method for the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it is characterized in that, described step 1 is further:
Under 0 ± 5 DEG C of stirring action, structure is dissolved in such as formula the compound shown in I in the anhydrous methanol in round-bottomed flask, and dropwise drips SOCl 2, after 10 ± 5min, be transferred to 20 ± 10 DEG C and continue stirring 6 ± 3h, filter, dry, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the compound shown in II.
4. preparation as claimed in claim 2 is containing the method for the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it is characterized in that, described step 2 is further:
Under 20 ± 10 DEG C of stirring actions, the compound of structure as shown in formula III is added successively, such as formula the compound shown in IV and dehydrated alcohol in round-bottomed flask, dropwise drip 5 ~ 50%NaOH aqueous solution, after reaction 4 ± 2h, filter, the solid obtained uses distilled water, cold ethanol, distilled water wash successively, dry, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the compound shown in V.
5. preparation as claimed in claim 2 is containing the method for the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it is characterized in that, described step 3 is further:
Under stirring, structure is added successively such as formula the compound shown in II, such as formula the compound shown in V and dehydrated alcohol in reaction vessel, dropwise drip Glacial acetic acid, backflow, TLC follows the tracks of reaction, after reaction 6 ± 2h, cooling, filter, the solid obtained uses distilled water, cold ethanol, distilled water wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the target compound shown in VI by the solid crude product obtained.
6. preparation as claimed in claim 2 is containing the method for the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it is characterized in that, described step 4 is further:
Under stirring, add in reaction vessel successively structure such as formula the compound shown in VI and 1: 1 methyl alcohol, 20 ~ 60%KOH aqueous solution liquid, dropwise drip tetrahydrofuran (THF) to dissolve completely to compound, backflow, TLC follows the tracks of reaction, after reaction 4 ± 2h, acidifying, extraction, revolves steaming, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains structure such as formula the compound shown in VII.
7. preparation as claimed in claim 2 is containing the method for the pyrazoline morpholine derivative of naphthalene nucleus skeleton, and it is characterized in that, described step 5 is further:
Under 0 ± 5 DEG C of stirring action, structure is added successively such as formula the compound shown in VII, DMAP, I-hydroxybenzotriazole and anhydrous methylene chloride in reaction vessel, after 10 ± 5min, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, be transferred to 25 ± 10 DEG C to continue to stir, TLC follows the tracks of reaction, and after 8 ± 3h, reaction solution uses saturated KHSO successively 4the aqueous solution, saturated Na 2cO 3, saturated common salt water washing, revolve steaming afterwards, the solid crude product obtained be dissolved in dehydrated alcohol recrystallization and obtain structure such as formula the compound shown in VIII.
8. the pyrazoline morpholine derivative containing naphthalene nucleus skeleton had such as formula the structure shown in X is preparing the application in antitumor drug,
Wherein, described R 1be selected from H, CH 3, CH 2cH 3, OCH 3, OCH 2cH 3, F, Cl, Br; R 2be selected from H, CH 3cl, Br; R 3be selected from H, Cl.
CN201510268943.7A 2015-05-20 2015-05-20 Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs Pending CN104829534A (en)

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