CN107759607B - Triazole with anti-tumor activity and phenodiazine Zhuo compound and preparation method thereof - Google Patents
Triazole with anti-tumor activity and phenodiazine Zhuo compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of triazole with anti-tumor activity and phenodiazine Zhuo compounds and preparation method thereof, belong to medical synthesis technical field.Technical key point of the present invention are as follows:
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of triazole with anti-tumor activity and phenodiazine is tall and erect
Compound and preparation method thereof.
Background technique
The important heterocyclic compound with pharmacological activity of Benzodiazepines compound Shi ー kind, have calmness, hypnosis,
The effects of anti-epileptic, central of flaccid muscles, when it acts on human body, has the characteristics that rapid-action, safe.Central nervous system
It is middle to there is the binding site that there is high-affinity, stereospecificity and saturability to Benzodiazepine.And most of benzene phenodiazines
Tall and erect class drug is related to the affinity of binding site and their pharmacological action, and central action has with Benzodiazepine binding site
It closes.Further investigation also found distribution situation and the CNS inhibition neurotransmitter GABA of Benzodiazepine binding site
(GABA) distribution of GABAA receptor is almost the same.Electro physiology is it is demonstrated experimentally that Benzodiazepines can enhance GABA energy neurotransmission
Function and cynapse depression effect；The effect that GABA is combined with GABAA receptor can also be enhanced.
Triazole has certain physiological activity, in terms of as antiseptic medicine research, due to its efficient, hypotoxicity, secondary work
With small advantage, increasingly by the concern of scientist.In Benzodiazepine parent nucleus 1,2 upper introducing imidazoles or triazole ring etc.
The compound of heterocycle, is clinically widely applied, and mainly has alprazolam, estazolam, midazolam etc..At present for
1, the 2 introducing heterocycle modifications of Benzodiazepine parent nucleus and the derivative to the modification of 4,5 introducing heterocycles, document have more report
Road.This research obtains novel diazo in 2,3 introducing triazole rings of Benzodiazepine parent nucleus by design synthetic route
And benzodiazepine compound.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of novel triazoles with anti-tumor activity of molecular structure
And phenodiazine Zhuo compound and preparation method thereof.
A kind of triazole with anti-tumor activity and phenodiazine Zhuo compound, the compound are shown below:
A kind of preparation method of triazole with anti-tumor activity and phenodiazine Zhuo compound, it is characterised in that specific steps
Are as follows:
A, acylation reaction generation N- phenyl trimethicone acetamide occurs in pyridine or methylene chloride for aniline and pivaloyl chloride；
B, N- phenyl trimethicone acetamide activates under that action of n-butyl lithium occurs addition with 4- pyridine carboxaldehyde after ortho-hydrogens
Reaction obtains N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine；
C, N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine is aoxidized by manganese dioxide or chromium trioxide,
Secondary carbon and the hydroxyl connected generate carbonyl after sloughing a molecule hydrogen in its structure, obtain N- (2- (4- piperidone base) phenyl)
Pivaloyl amine；
D, N- (2- (4- piperidone base) phenyl) pivaloyl amine sloughs tertiary bytyry in acid condition and obtains 2- (4-
Piperidone base) aniline；2- (4- piperidone base) aniline occurs substitution reaction with Boc glycyl chlorine under DCC effect and generates N-
(2- (4- piperidone base) phenyl) Boc amino acetamide；
E, N- (2- (4- piperidone base) phenyl) Boc amino acetamide reacts in Isosorbide-5-Nitrae-dioxane or THF with HCl,
N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate is obtained at salt while sloughing Boc group；
F, N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate occurs ketoamine and is condensed under sodium methoxide effect
To tall and erect -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine；
G, tall and erect -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine and TMSN3Or NaN3Click is occurring
Reaction obtains
It further limits, the detailed process of step A are as follows: in reaction flask, aniline is added in pyridine, in room temperature condition
Under, pivaloyl chloride is slowly added dropwise, continues to react at room temperature after dripping, TLC monitors raw material fully reacting, to reaction solution
It is middle to be added a certain amount of HCl solution, strong stirring for a period of time after washed reaction liquid, be finally concentrated to get under vacuum conditions
N- phenyl trimethicone acetamide；Or in reaction flask, aniline and potassium carbonate are added in methylene chloride and stirred, in room temperature condition
Under, pivaloyl chloride is slowly added dropwise, continues to react at room temperature after dripping, TLC monitors raw material fully reacting, to reaction solution
It is middle to be added a certain amount of HCl solution, strong stirring for a period of time after washed reaction liquid, be finally concentrated to get N- under vacuum conditions
Phenyl trimethicone acetamide.
Further limit, the detailed process of step B are as follows: in reaction flask, N- phenyl trimethicone acetamide be added to through
In the THF of Non-aqueous processing, nitrogen protection reaction system is placed under the conditions of 0 DEG C, and n-butyllithium solution is slowly added dropwise, and keeps temperature
At 5 DEG C hereinafter, stirring 2h after dripping, the THF solution dissolved with 4- pyridine carboxaldehyde is slowly dropped in reaction solution, makes reaction temperature
Degree is no more than 5 DEG C, drips rear reaction solution in peony；It is complete that the reaction was continued 3h, TLC monitor raw material unreacted, and reaction is made to exist
A certain amount of ice water quenching reaction is added after the reaction was continued 8h under the conditions of temperature is -20 DEG C~60 DEG C, then is extracted with ethyl acetate
Reaction solution obtains the crude product of N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine after organic phase is evaporated off, then passes through
Column chromatography for separation obtains sterling.
It further limits, the detailed process of step C are as follows: in reaction flask, N- (2- (hydroxyl (4- pyridyl group) methyl) benzene
Base) pivaloyl amine and MnO2It is added in chloroform, heating reflux reaction 10h, TLC monitor raw material fully reacting, and filtering is anti-
Liquid is answered, obtains N- (2- (4- piperidone base) phenyl) pivaloyl amine after filtrate concentration；Or in reaction flask, N- (2- (hydroxyl
Base (4- pyridyl group) methyl) phenyl) pivaloyl amine and CrO3It is added in chloroform, reacts at room temperature 5h, it is anti-that TLC monitors raw material
Should reaction solution be extracted with ethyl acetate after filtering, obtain N- (2- (4- piperidone base) phenyl) front three after organic phase is evaporated off completely
Yl acetamide.
It further limits, the detailed process of step D are as follows: in reaction flask, N- (2- (4- piperidone base) phenyl) front three
Yl acetamide is added in the mixed solution of ethyl alcohol and hydrochloric acid, is stirred to react at room temperature, is heated to after stirring 2h
Reflux, the reaction was continued 6h, TLC monitoring raw material fully reacting；Ethyl alcohol is evaporated off in vacuum concentration, then is adjusted instead with saturated sodium carbonate solution
Answering liquid pH is 7~8, then reaction solution is extracted with dichloromethane three times, is concentrated to get 2- (4- piperidone base) benzene after merging organic phase
The crude product of amine, then sterling is obtained through column chromatography for separation；Obtained 2- (4- piperidone base) aniline adding into dichloromethane,
Compound Boc glycyl chlorine and DCC are added, reacts 10h at room temperature, TLC monitors raw material fully reacting, and filtering is anti-
Liquid is answered to remove dicyclohexylurea, reaction solution is washed with 10% HCl solution and saturated sodium carbonate solution respectively again, after separating organic phase
It is concentrated to get N- (2- (4- piperidone base) phenyl) Boc amino acetamide crude product, then obtains sterling through column chromatography for separation.
It further limits, the detailed process of step E are as follows: in reaction flask, N- (2- (4- piperidone base) phenyl) Boc ammonia
Yl acetamide is added in Isosorbide-5-Nitrae-dioxane containing 4M HCl, is stirred to react 2h at room temperature, it is anti-that TLC monitors raw material
Should completely, filtering reacting liquid, filter cake is N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate；Or in reaction flask,
N- (2- (4- piperidone base) phenyl) Boc amino acetamide is added in the THF containing 4M HCl, is stirred under heated reflux condition
Reaction 2h is mixed, TLC monitors raw material fully reacting, filtering reacting liquid, and filter cake is N- (2- (4- piperidone base) phenyl) glycyl
Amine hydrochlorate.
It further limits, the detailed process of step F are as follows: in reaction flask, N- (2- (4- piperidone base) phenyl) amino
Acetamide hydrochloride and sodium methoxide are added in methanol, 2h are stirred to react at 50 DEG C, LCMS monitors raw material fully reacting, true
Reaction dissolvent is evaporated off under empty condition, adds a certain amount of water and methylene chloride, separates organic phase, 5- (4- pyrrole is obtained after concentration
Piperidinyl) tall and erect -2 (3H) -one of -1H- benzo [e] [1,4] phenodiazine.
Further limit, the detailed process of step G are as follows: in reaction flask, 5- (4- pyridyl group) -1H- benzo [e] [1,
4] tall and erect -2 (3H) -one of phenodiazine and TMSN3It is added in acetone, adds a certain amount of potassium carbonate, room temperature is anti-under nitrogen protection
2h, TLC is answered to monitor raw material fully reacting, reaction solution is extracted with dichloromethane after certain water is added, it is concentrated after merging organic phase,
It is obtained again through column chromatography for separationOr in reaction flask, 5- (4- pyridyl group) -1H- benzo [e] [Isosorbide-5-Nitrae] two
Nitrogen -2 (3H) -one of Zhuo and NaN3It is added in DMF, adds a certain amount of CuI and potassium carbonate, be heated under air conditions
120 DEG C, TLC monitors raw material fully reacting after reacting 6h, and reaction solution is extracted with dichloromethane after certain water is added, and merges organic phase
After be concentrated, then obtained through column chromatography for separation
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
In reaction flask, aniline (10g, 0.107mol) is added in pyridine 50mL, at room temperature, spy is slowly added dropwise
Valeric chloride (14.24g, 0.118mol) continues to react 3h at room temperature after dripping, and TLC monitors raw material fully reacting, to
Be added a certain amount of 6N HCl solution in reaction solution, strong stirring for a period of time after washed reaction liquid, finally under vacuum conditions
It is concentrated to get N- phenyl trimethicone acetamide (18g, yield:95.23%) .MS (ESI) m/z:177.1 (M+H+). HNMR:
(CDCl3) δ 7.38 (brs, 1H, NH), 7.55 (d, J=8Hz, 2H, Ar-H), 7.36 (t, J=8Hz, 2H, Ar-H), 7.20
(t, J=4Hz, 1H, Ar-H), 1.40 (s, 9H)
Embodiment 2
In reaction flask, methylene chloride is added in aniline (10g, 0.107mol) and potassium carbonate (27.6g, 0.20mol)
It is stirred in 50ml, at room temperature, pivaloyl chloride (14.24g, 0.118mol) is slowly added dropwise, continued after dripping in room temperature
Under the conditions of react 3h, TLC monitors raw material fully reacting, and a certain amount of 6N HCl solution, strong stirring one are added into reaction solution
Section the time after washed reaction liquid, be finally concentrated to get under vacuum conditions N- phenyl trimethicone acetamide (15.7g, yield:
82.78%) .MS (ESI) m/z:177.1 (M+H+).
Embodiment 3
In reaction flask, N- phenyl trimethicone acetamide (10g, 0.056mol) is added to the THF through Non-aqueous processing
In 100mL, nitrogen protection reaction system is placed under the conditions of 0 DEG C, n-butyllithium solution is slowly added dropwise, maintain the temperature at 5 DEG C with
Under, about 30min is added dropwise complete；After stirring 2h, the THF solution 50mL dissolved with 4- pyridine carboxaldehyde 12g, it is slowly dropped to reaction solution
In, so that reaction temperature is no more than 5 DEG C, drips rear reaction solution in peony；It is complete that the reaction was continued 3h, TLC monitor raw material unreacted
Entirely, make reaction that a certain amount of ice water quenching reaction be added after the reaction was continued 8h under the conditions of 60 DEG C of temperature, then use ethyl acetate
Reaction solution is extracted, obtains the crude product of N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine after organic phase is evaporated off,
Sterling (3.4g, yield:21.38%) .MS (ESI) m/z:285.4 (M+H is obtained through column chromatography for separation again+).HNMR:
(CDCl3) δ 8.94 (brs, 1H, NH), 8.27 (d, J=6Hz, 2H, Ar-H), 8.09 (d, J=8Hz, 1H, Ar-H), 7.24-
7.34 (m, 1H, Ar-H), 8.29 (d, J=6Hz, 2H, Ar-H), 7.22 (d, J=5.2Hz, 2H, Ar-H), 8.38 (d, J=
6Hz, 2H, Ar-H), 7.01 (d, J=3.6Hz, 2H, Ar-H), 5.65 (s, 1H), 1.04 (s, 9H)
Embodiment 4
In reaction flask, N- phenyl trimethicone acetamide (10g, 0.056mol) is added to the THF through Non-aqueous processing
In 100mL, nitrogen protection reaction system is placed under the conditions of 0 DEG C, n-butyllithium solution is slowly added dropwise, maintain the temperature at 5 DEG C with
Under, about 30min is added dropwise complete；After stirring 2h, the THF solution 50mL dissolved with 4- pyridine carboxaldehyde 12g, it is slowly dropped to reaction solution
In, so that reaction temperature is no more than 5 DEG C, drips rear reaction solution in peony；It is complete that the reaction was continued 3h, TLC monitor raw material unreacted
Entirely, make reaction that a certain amount of ice water quenching reaction be added after the reaction was continued 8h under the conditions of -20 DEG C of temperature, then use ethyl acetate
Reaction solution is extracted, obtains the crude product of N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine after organic phase is evaporated off,
Sterling (12.7g, yield:79.21%) .MS (ESI) m/z:285.4 (M+H is obtained through column chromatography for separation again+)。
Embodiment 5
In reaction flask, N- phenyl trimethicone acetamide (10g, 0.056mol) is added to the THF through Non-aqueous processing
In 100mL, nitrogen protection reaction system is placed under the conditions of 0 DEG C, n-butyllithium solution is slowly added dropwise, maintain the temperature at 5 DEG C with
Under, about 30min is added dropwise complete；After stirring 2h, the THF solution 50mL dissolved with 4- pyridine carboxaldehyde 12g, it is slowly dropped to reaction solution
In, so that reaction temperature is no more than 5 DEG C, drips rear reaction solution in peony；It is complete that the reaction was continued 3h, TLC monitor raw material unreacted
Entirely, make reaction that a certain amount of ice water quenching reaction be added after the reaction was continued 8h under the conditions of 10 DEG C of temperature, then use ethyl acetate
Reaction solution is extracted, obtains the crude product of N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine after organic phase is evaporated off,
Sterling (13.3g, yield:83.23%) .MS (ESI) m/z:285.4 (M+H is obtained through column chromatography for separation again+)。
Embodiment 6
In reaction flask, N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine (6g, 0.021mol)
And MnO2(9.2g, 0.021mol) is added in chloroform 50mL, and heating reflux reaction 10h, TLC monitor raw material fully reacting, mistake
Filter reaction solution, filtrate concentration after obtain N- (2- (4- piperidone base) phenyl) pivaloyl amine (4.8g, yield:
82.11%) .MS (ESI) m/z:283.4 (M+H+).MS(ESI)m/z:283.4(M+H+).HNMR:(CDCl3)δ11.35
(brs, 1H, NH), 8.77-8.79 (m, 3H, Ar-H), 7.60 (t, J=7.6Hz, 1H, Ar-H), 7.50-7.49 (m, 3H, Ar-
), H 7.03 (t, J=7.2Hz, 1H, Ar-H), 1.06 (s, 9H)
Embodiment 7
In reaction flask, N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine (6g, 0.021mol)
And CrO3(2.1g, 0.021mol) is added in chloroform 50mL, reacts at room temperature 5h, TLC monitors raw material fully reacting, after filtering
Reaction solution is extracted with ethyl acetate, be evaporated off after organic phase obtain N- (2- (4- piperidone base) phenyl) pivaloyl amine (5.4g,
Yield:92.30%) .MS (ESI) m/z:283.4 (M+H+).
Embodiment 8
In reaction flask, N- (2- (4- piperidone base) phenyl) pivaloyl amine (4.2g, 0.0154mol) is added to
It in the mixed solution of ethyl alcohol 35mL and hydrochloric acid 14mL, is stirred to react at room temperature, is heated to flowing back after stirring 2h,
The reaction was continued 6h, TLC monitoring raw material fully reacting；Ethyl alcohol is evaporated off in vacuum concentration, then adjusts reaction solution with saturated sodium carbonate solution
PH is 7~8, then reaction solution is extracted with dichloromethane three times, is concentrated to get 2- (4- piperidone base) aniline after merging organic phase
Crude product, then sterling (2.5g, yield:83%) .MS (ESI) m/z:199.2 (M+H is obtained through column chromatography for separation+).HNMR:
(CDCl3) δ 8.75-8.76 (m, 2H, Ar-H), 7.44 (d, 2H, Ar-H), 7.43 (d, 2H, Ar-H), 6.75 (d, 1H, J=
8Hz,Ar-H),6.57-6.61(m,1H,Ar-H),6.32(brs,2H,NH).
Embodiment 9
In reaction flask, 2- (4- piperidone base) aniline (2g, 0.01mol) is added in methylene chloride 50mL, then plus
Enter Boc glycyl chlorine (3.8g, 0.02mol) and DCC (4.12g, 0.02mol), reacts 7h, TLC prison at room temperature
Control raw material fully reacting, filtering reacting liquid remove dicyclohexylurea, reaction solution again respectively with 10% HCl solution and saturated sodium carbonate
Solution washing, is concentrated to get N- (2- (4- piperidone base) phenyl) Boc amino acetamide crude product after separating organic phase, then through column layer
Analyse isolated sterling (2.2g.yield:60%) .MS (ESI) m/z:356.4 (M+H+).HNMR:(CDCl3)δ 11.46
(brs, 1H, NH), 8.79 (t, 3H, J=4Hz, Ar-H), 8.72 (d, 1H, J=4Hz, Ar-H), 7.45-7.61 (m, 4H, Ar-
), H 5.36 (brs, 1H, NH), 4.00 (d, J=8Hz, 2H), 1.45 (s, 9H)
Embodiment 10
In reaction flask, N- (2- (4- piperidone base) phenyl) Boc amino acetamide (2g, 0.0056mol) is added to
In Isosorbide-5-Nitrae-dioxane containing 4M HCl, it is stirred to react 2h at room temperature, TLC monitors raw material fully reacting, and filtering is anti-
Liquid is answered, filter cake is N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate (1.2g, yield:75%) .MS (ESI) m/
z: 256.4(M+H+).HNMR:(CDCl3) δ 8.66 (t, 3H, J=4Hz, Ar-H), 8.43 (d, 1H, J=4Hz, Ar-H),
7.38-7.61 (m, 4H, Ar-H), 7.23 (brs, 1H, NH), 3.85 (d, J=8Hz, 2H), 1.53 (s, 2H)
Embodiment 11
In reaction flask, N- (2- (4- piperidone base) phenyl) Boc amino acetamide (2g, 0.0056mol) is added to
In THF containing 4M HCl, 2h is stirred to react under heated reflux condition, TLC monitors raw material fully reacting, filtering reacting liquid, filter
Cake is N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate (1.5g, yield:93.56%) .MS (ESI) m/z:
256.4 (M+H+).
Embodiment 12
In reaction flask, N- (2- (4- piperidone base) phenyl) glycyl amine hydrochlorate (700mg, 2.41mmol) and
Sodium methoxide (155.8mg, 2.88mmol) is added in methanol 20mL, and 2h, LC-MS monitoring reaction are stirred to react under the conditions of 50 DEG C
Completely, reaction dissolvent is evaporated off under vacuum conditions, adds a certain amount of water and methylene chloride, separates organic phase, after concentration
To -2 (3H) -one (450mg, yield:78.81%) .MS (ESI) m/ of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine Zhuo
z: 238.3(M+H+).HNMR:(CDCl3) δ 9.37 (brs, 1H, NH), 8.68 (s, 2H, Ar-H), 7.54 (d, 1H, J=8Hz,
Ar-H),7.45(s,2H,Ar-H),7.20-7.27(m,3H,Ar-H),4.38(s,2H).
Embodiment 13
In reaction flask, tall and erect -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [Isosorbide-5-Nitrae] phenodiazine (300mg,
1.26mmol) and TMSN3(130mg, 1.52mmol) is added in acetone 20mL, add potassium carbonate (170mg,
1.26mmol), 2h is reacted at room temperature under nitrogen protection, and TLC monitors raw material fully reacting, reaction solution is poured into water 50mL, uses
Methylene chloride 20mL extracts reaction solution three times, merges organic phase, solvent is evaporated off and obtains(299mg,
Yield:90.55%) MS (ESI) m/z:262.1 (M+H+).HNMR:(DMSO-d6)δ11.79(s,1H,NH),8.68(s,
2H,Ar-H), 7.88(m,2H,Ar-H),7.58(m,1H,Ar-H),6.68-7.22(m,3H,Ar-H),4.22(s,1H).
Embodiment 14
In reaction flask, tall and erect -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [Isosorbide-5-Nitrae] phenodiazine (300mg,
1.26mmol) and NaN3(99mg, 1.52mmol) is added in DMF20mL, adds CuI (71.5mg, 0.50mmol) and carbon
Sour potassium (68.97mg, 0.50mmol) is heated to 120 DEG C under air conditions, and TLC monitors raw material fully reacting after reacting 6h,
Reaction solution is extracted with dichloromethane after certain water is added, and is concentrated after merging organic phase, then obtain through column chromatography for separation(258mg, yield:77.8%) .MS (ESI) m/z:262.1 (M+H+).
Embodiment 15
Anti-tumor activity test
Growth period breast cancer cell MCF-7 and liver cancer HepG2 is collected, the anticancer activity of compound is measured with MTS method,
By cell with (every milliliter 4 × 10 of debita spissitudo4A cell) it is added in 96 porocyte culture plates and (must be trained containing 10% tire calf serum
Nutrient solution is made into individual cells suspension), after culture 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of with various concentration
Compound effects 72 hours, then by the mixing of MTS (final mass concentration 2mg/mL) and DMS (30 μM of final molar concentration)
Object is directly added into celliferous culture medium, continues to set incubator incubation 4h.After acting on 4h, liquid is discarded supernatant, every hole is added 150
μ LDMSO, oscillation, cell survival rate pass through its suction to the metabolin of MTS effect under enzyme linked immunological monitor 490nm wavelength
Yield measurement.
Preliminary biological activity test shows that the compound has inhibition to make breast cancer cell MCF-7 and liver cancer HepG2
With, but it is better than the inhibiting effect to breast cancer cell MCF-7 to the inhibiting effect of hepatocellular carcinoma H22.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of triazole with anti-tumor activity and phenodiazine Zhuo compound, it is characterised in that its molecular structural formula are as follows:
2. the preparation method of a kind of triazole with anti-tumor activity described in claim 1 and phenodiazine Zhuo compound, special
Sign is specific steps are as follows:
A, acylation reaction generation N- phenyl trimethicone acetamide occurs in pyridine or methylene chloride for aniline and pivaloyl chloride；
B, N- phenyl trimethicone acetamide activates under that action of n-butyl lithium occurs addition reaction with 4- pyridine carboxaldehyde after ortho-hydrogens
Obtain N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine；
C, N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine is aoxidized by manganese dioxide or chromium trioxide, knot
Secondary carbon and the hydroxyl connected generate carbonyl after sloughing a molecule hydrogen on structure, obtain N- (2- (4- pyriconyl) phenyl) front three
Yl acetamide；
D, N- (2- (4- pyriconyl) phenyl) pivaloyl amine sloughs tertiary bytyry in acid condition and obtains 2- (4- pyridine
Ketone group) aniline；2- (4- pyriconyl) aniline occurs substitution reaction with Boc glycyl chlorine under DCC effect and generates N- (2-
(4- pyriconyl) phenyl) Boc amino acetamide；
E, N- (2- (4- pyriconyl) phenyl) Boc amino acetamide is reacted in Isosorbide-5-Nitrae-dioxane or THF with HCl, is sloughed
N- (2- (4- pyriconyl) phenyl) glycyl amine hydrochlorate is obtained at salt while Boc group；
F, N- (2- (4- pyriconyl) phenyl) glycyl amine hydrochlorate occurs ketoamine and is condensed to yield 5- under sodium methoxide effect
(4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine -2 (3H) -one of Zhuo；
G, tall and erect -2 (3H) -one of 5- (4- pyridyl group) -1H- benzo [e] [1,4] phenodiazine and TMSN3Or NaN3Click reaction is occurring
It obtains
3. the preparation method of a kind of triazole with anti-tumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that the detailed process of step A are as follows: in reaction flask, aniline is added in pyridine, at room temperature, is slowly added dropwise
Pivaloyl chloride continues to react at room temperature after dripping, and TLC monitors raw material fully reacting, is added into reaction solution certain
The HCl solution of amount, strong stirring for a period of time after washed reaction liquid, be finally concentrated to get N- phenyl trimethicone under vacuum conditions
Acetamide；Or in reaction flask, aniline and potassium carbonate are added in methylene chloride and stirred, at room temperature, spy is slowly added dropwise
Valeric chloride continues to react at room temperature after dripping, and TLC monitors raw material fully reacting, is added into reaction solution a certain amount of
HCl solution, strong stirring for a period of time after washed reaction liquid, be finally concentrated to get N- phenyl trimethicone second under vacuum conditions
Amide.
4. the preparation method of a kind of triazole with anti-tumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that the detailed process of step B are as follows: in reaction flask, N- phenyl trimethicone acetamide is added to through Non-aqueous processing
In THF, nitrogen protection reaction system is placed under the conditions of 0 DEG C, n-butyllithium solution is slowly added dropwise, maintain the temperature at 5 DEG C hereinafter,
2h is stirred after dripping, the THF solution dissolved with 4- pyridine carboxaldehyde is slowly dropped in reaction solution, and reaction temperature is made to be no more than 5
DEG C, rear reaction solution is dripped in peony；It is complete that the reaction was continued 3h, TLC monitor raw material unreacted, makes reaction in temperature -20
DEG C~40 DEG C under the conditions of a certain amount of ice water quenching reaction is added after the reaction was continued 8h, then reaction solution is extracted with ethyl acetate, steams
Except the crude product for obtaining N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) pivaloyl amine after organic phase, then through column chromatography for separation
Obtain sterling.
5. the preparation method of a kind of triazole with anti-tumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that the detailed process of step C are as follows: in reaction flask, N- (2- (hydroxyl (4- pyridyl group) methyl) phenyl) trimethyl
Acetamide and MnO2It is added in chloroform, heating reflux reaction 10h, TLC monitor raw material fully reacting, filtering reacting liquid, filtrate
N- (2- (4- pyriconyl) phenyl) pivaloyl amine is obtained after concentration；Or in reaction flask, N- (2- (hydroxyl (4- pyridine
Base) methyl) phenyl) pivaloyl amine and CrO3It is added in chloroform, reacts at room temperature 5h, TLC monitors raw material fully reacting, mistake
Reaction solution is extracted with ethyl acetate after filter, obtains N- (2- (4- pyriconyl) phenyl) pivaloyl amine after organic phase is evaporated off.
6. the preparation method of a kind of triazole with anti-tumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that the detailed process of step D are as follows: in reaction flask, N- (2- (4- pyriconyl) phenyl) pivaloyl amine is added
Enter into the mixed solution of ethyl alcohol and hydrochloric acid, be stirred to react at room temperature, be heated to flowing back after stirring 2h, continues anti-
5h, TLC is answered to monitor raw material fully reacting；Ethyl alcohol is evaporated off in vacuum concentration, then adjusts reaction solution pH > 7 with saturated sodium carbonate solution, then
Reaction solution is extracted with dichloromethane three times, the crude product of 2- (4- pyriconyl) aniline is concentrated to get after merging organic phase, then through column
Chromatography obtains sterling；Obtained 2- (4- pyriconyl) aniline adding into dichloromethane, compound Boc is added
Glycyl chlorine and DCC react 10h at room temperature, and TLC monitors raw material fully reacting, and filtering reacting liquid removes two hexamethylenes
Urea, reaction solution are washed with 10% HCl solution and saturated sodium carbonate solution respectively again, are concentrated to get N- (2- after separating organic phase
(4- pyriconyl) phenyl) Boc amino acetamide crude product, then sterling is obtained through column chromatography for separation.
7. the preparation method of a kind of triazole with anti-tumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that the detailed process of step E are as follows: in reaction flask, N- (2- (4- pyriconyl) phenyl) Boc amino acetamide
It being added in Isosorbide-5-Nitrae-dioxane containing 4M HCl, is stirred to react 2h at room temperature, TLC monitors raw material fully reacting,
Filtering reacting liquid, filter cake are N- (2- (4- pyriconyl) phenyl) glycyl amine hydrochlorate；Or in reaction flask, N- (2-
(4- pyriconyl) phenyl) Boc amino acetamide is added in the THF containing 4M HCl, is stirred to react under heated reflux condition
2h, TLC monitor raw material fully reacting, filtering reacting liquid, and filter cake is N- (2- (4- pyriconyl) phenyl) amino acetamide hydrochloric acid
Salt.
8. the preparation method of a kind of triazole with anti-tumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that the detailed process of step F are as follows: in reaction flask, N- (2- (4- pyriconyl) phenyl) amino acetamide hydrochloric acid
Salt and sodium methoxide are added in methanol, and 2h is stirred to react at 50 DEG C, and LCMS monitors raw material fully reacting, steams under vacuum conditions
Except reaction dissolvent, a certain amount of water and methylene chloride are added, separates organic phase, 5- (4- pyridyl group) -1H- benzene is obtained after concentration
And tall and erect -2 (3H) -one of [e] [1,4] phenodiazine.
9. the preparation method of a kind of triazole with anti-tumor activity according to claim 2 and phenodiazine Zhuo compound,
It is characterized in that the detailed process of step G are as follows: in reaction flask, 5- (4- pyridyl group) -1H- benzo [e] [Isosorbide-5-Nitrae] phenodiazine Zhuo -2
(3H) -one and TMSN3It is added in acetone, adds a certain amount of potassium carbonate, react at room temperature 2h, TLC prison under nitrogen protection
Raw material fully reacting is controlled, reaction solution is extracted with dichloromethane after certain water is added, and is concentrated after merging organic phase, then through column chromatography point
From obtainingOr in reaction flask, 5- (4- pyridyl group) -1H- benzo [e] [Isosorbide-5-Nitrae] phenodiazine Zhuo -2 (3H) -
Ketone and NaN3It is added in DMF, adds a certain amount of CuI and potassium carbonate, 120 DEG C are heated under air conditions, react 6h
TLC monitors raw material fully reacting afterwards, and reaction solution is extracted with dichloromethane after certain water is added, and is concentrated after merging organic phase, then pass through
Column chromatography for separation obtains
10. simultaneously phenodiazine Zhuo compound is preparing anti-tumor drug to triazole with anti-tumor activity as described in claim 1
In application.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102762569A (en) * | 2009-11-05 | 2012-10-31 | 葛兰素史克有限责任公司 | Benzodiazepine bromodomain inhibitor |
| CN103827120A (en) * | 2011-09-01 | 2014-05-28 | 拜耳知识产权有限责任公司 | 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine |
| CN105189514A (en) * | 2013-02-22 | 2015-12-23 | 拜耳医药股份有限公司 | Pyrrolo- and pyrazolo-triazolodiazepines as bet-protein inhibitors for treating hyperproliferative diseases |
| CN105899212A (en) * | 2013-08-06 | 2016-08-24 | 翁科埃斯克斯有限公司 | Method of treating diffuse large B-cell lymphoma (DLBCL) using a beta-bromodomain inhibitor |
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| JPH09157261A (en) * | 1995-12-07 | 1997-06-17 | Yoshitomi Pharmaceut Ind Ltd | Phenylazole compound and benzotriazolodiazepine compound |
| JP5844358B2 (en) * | 2010-06-22 | 2016-01-13 | グラクソスミスクライン エルエルシー | Bromodomain inhibitors containing benzotriazolodiazepine compounds |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102762569A (en) * | 2009-11-05 | 2012-10-31 | 葛兰素史克有限责任公司 | Benzodiazepine bromodomain inhibitor |
| CN103827120A (en) * | 2011-09-01 | 2014-05-28 | 拜耳知识产权有限责任公司 | 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine |
| CN105189514A (en) * | 2013-02-22 | 2015-12-23 | 拜耳医药股份有限公司 | Pyrrolo- and pyrazolo-triazolodiazepines as bet-protein inhibitors for treating hyperproliferative diseases |
| CN105899212A (en) * | 2013-08-06 | 2016-08-24 | 翁科埃斯克斯有限公司 | Method of treating diffuse large B-cell lymphoma (DLBCL) using a beta-bromodomain inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors;Steven G. Smith et al.;《Chemistry & Biology》;20140522;第21卷;第573-583页 |
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