CN107936032A - A kind of new diazepine tricyclic compounds and its preparation method and application - Google Patents
A kind of new diazepine tricyclic compounds and its preparation method and application Download PDFInfo
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- CN107936032A CN107936032A CN201711220442.7A CN201711220442A CN107936032A CN 107936032 A CN107936032 A CN 107936032A CN 201711220442 A CN201711220442 A CN 201711220442A CN 107936032 A CN107936032 A CN 107936032A
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- 0 *CC(Nc1ccccc1C(c1ccncc1)=O)=O Chemical compound *CC(Nc1ccccc1C(c1ccncc1)=O)=O 0.000 description 3
- UWNBNKSEQMRSLS-UHFFFAOYSA-N CC(C)(C)C(Nc(cccc1)c1C(c1ccncc1)=O)=O Chemical compound CC(C)(C)C(Nc(cccc1)c1C(c1ccncc1)=O)=O UWNBNKSEQMRSLS-UHFFFAOYSA-N 0.000 description 1
- RHTTVGJXQUBGLR-UHFFFAOYSA-N CC(C)(C)C(Nc1c(C(c2ccncc2)O)cccc1)=O Chemical compound CC(C)(C)C(Nc1c(C(c2ccncc2)O)cccc1)=O RHTTVGJXQUBGLR-UHFFFAOYSA-N 0.000 description 1
- LWJNWXYSLBGWDU-UHFFFAOYSA-N CC(C)(C)C(Nc1ccccc1)=O Chemical compound CC(C)(C)C(Nc1ccccc1)=O LWJNWXYSLBGWDU-UHFFFAOYSA-N 0.000 description 1
- BSNAZGSUFWMJLF-UHFFFAOYSA-N CN1C=CC(C(c(cccc2)c2N)=O)=CC1 Chemical compound CN1C=CC(C(c(cccc2)c2N)=O)=CC1 BSNAZGSUFWMJLF-UHFFFAOYSA-N 0.000 description 1
- MOPYXHGIWARXCY-UHFFFAOYSA-N Nc1ccccc1C(c1ccncc1)=O Chemical compound Nc1ccccc1C(c1ccncc1)=O MOPYXHGIWARXCY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of new diazepine tricyclic compounds and its preparation method and application, belong to medical synthesis technical field.Technical scheme main points are：A kind of new diazepine tricyclic compounds, has such as lower structure：
Description
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of new diazepine tricyclic compounds and its system
Preparation Method and application.
Background technology
Heterocyclic compound is one kind most huge in organic compound, accounts for more than 65%, and in distributed in nature
Quite varied, its chemical constitution is ever-changing, each there is special property and important use.Benzodiazepines compound is
A kind of important nitrogen-containing heterocycle compound, Benzodiazepines compound have good bioactivity, are widely used at present
Field of medicaments, is primarily used to as hypnotic and sedative, such as stable, librium, intrazepam etc..Benzodiazepines medicine
Thing is substantially safe, without serious side effect.However, high dose or while being shared with alcohol or other drugs are dangerous.
The problem of benzodiazepine is that easy produce relies on.This means the effect of same dose can be worse and worse, it is necessary to no
Disconnected ground dosage.Also imply that once disabling benzodiazepine often there is obvious rebound effect, generation takes several days or a few weeks
Restlessness, anxiety, insomnia.Equally, can all infringement be produced to memory when all benzodiazepines remain in vivo.For
The more preferable novel use for finding Benzodiazepines compound, we are by CAD, important oxygen-containing
Heterocycle structure furan nucleus and sulfur heterocyclic ring structure thiapyran ring are incorporated into Benzodiazepine structure, obtain a kind of structure novelization
Compound, the compound is with good antitumor activity and the activity for suppressing platelet aggregation after testing.
The content of the invention
The technical problem to be solved by the present invention is to provide a kind of new diazepine tricyclic compounds and preparation method thereof
And application.
A kind of new its molecular structure of diazepine tricyclic compounds is：Wherein R is O or S.
A kind of preparation method of new diazepine tricyclic compounds, it is characterised in that concretely comprise the following steps：
A, acylation reaction generation occurs in pyridine for aniline and pivaloyl chlorideIn n-BuLi
Addition reaction occurs with 4- pyridine carboxaldehydes after the lower activation ortho-hydrogens of effect to obtain
B、By manganese dioxide, secondary carbon and the hydroxyl connected slough one point in its structure
Carbonyl is generated after sub- hydrogen, is obtainedUncle is sloughed in acid condition
Bytyry obtains
C、Substitution reaction generation occurs with Boc glycyls chlorine under DCC effectsReact, slough in Isosorbide-5-Nitrae-dioxane with HCl
Obtained while Boc groups into salt
D、Under sodium methoxide effect, ketoamine occurs and is condensed to yield React to obtain with lawesson reagent
E、Substitution reaction occurs with formaldehyde and dithyl sulfate to obtain
F、Oneself addition cyclization occurs to obtain
Further limit, the detailed process of step A is：In reaction bulb, aniline is added in pyridine, in room temperature condition
Under, pivaloyl chloride is slowly added dropwise, continues to react at ambient temperature after dripping, the reaction was complete for TLC monitoring raw material, to reaction solution
It is middle to add a certain amount of HCl solution, strong stirring for a period of time after washed reaction liquid, be finally concentrated to give under vacuum It is added in the THF through Non-aqueous processing, nitrogen protection reaction system, is placed under the conditions of 0 DEG C, delays
It is slow that n-butyllithium solution is added dropwise, less than 5 DEG C are maintained the temperature at, 2h is stirred after dripping, the THF solution dissolved with 4- pyridine carboxaldehydes
It is slowly dropped in reaction solution, reaction temperature is no more than 5 DEG C, it is in peony to drip rear reaction solution；The reaction was continued 3h, TLC
It is complete to monitor raw material unreacted, a certain amount of ice is added after the reaction was continued 8h under the conditions of making reaction be -30 DEG C~40 DEG C in temperature
Water quenching is gone out reaction, then reaction solution is extracted with ethyl acetate, and is obtained after organic phase is evaporated offCrude product, then
Sterling is obtained through column chromatography for separation.
Further limit, the detailed process of step B is：In reaction bulb,And MnO2Add
Into chloroform, the reaction was complete for heating reflux reaction 10h, TLC monitoring raw material, and filtering reacting liquid, obtains after filtrate concentration It is added in the mixed solution of ethanol and hydrochloric acid, in room temperature condition
Under be stirred reaction, be heated to flowing back after stirring 2h, the reaction was continued 5h, the reaction was complete for TLC monitoring raw material；Vacuum concentration is evaporated off
Ethanol, then adjust reaction solution pH with saturated sodium carbonate solution>7, then, after merging organic phase. with dichloromethane extractive reaction liquid three times
It is concentrated to giveCrude product, then obtain sterling through column chromatography for separation.
Further limit, the detailed process of step C is：In reaction bulb,It is added to dichloromethane
In, compound Boc glycyls chlorine and DCC are added, reacts 10h at ambient temperature, the reaction was complete for TLC monitoring raw material, mistake
Filter reaction solution and remove dicyclohexylurea, reaction solution is washed with 10% HCl solution and saturated sodium carbonate solution, separated organic respectively again
It is concentrated to give after phaseCrude product, then obtain sterling through column chromatography for separation；It is added in Isosorbide-5-Nitrae-dioxane containing 4M HCl, at ambient temperature stirring reaction
The reaction was complete for 2h, TLC monitoring raw material, filtering reacting liquid, and filter cake is
Further limit, the detailed process of step D is：In reaction bulb,And first
Sodium alkoxide is added in methanol, and the reaction was complete for stirring reaction 2h, LCMS monitoring raw material at ambient temperature, is evaporated off under vacuum
Reaction dissolvent, adds a certain amount of water and dichloromethane, separates organic phase, is obtained after concentration It is added to lawesson reagent in toluene, under nitrogen protection heating reflux reaction 2h, LCMS monitoring raw materials
The reaction was complete, and the mixed solution (DCM of saturated sodium carbonate solution, reaction solution dichloromethane and methanol is added after reaction solution cooling：
MeOH=5:1) extraction is multiple, is concentrated after merging organic phase, then obtained through column chromatography for separation
Further limit, the detailed process of step E is：In reaction bulb,Add in formalin, add triethylamine, be heated to one section of back flow reaction
After time, dithyl sulfate is slowly added dropwise at reflux, drips postcooling to room temperature, is added into reaction solution a certain amount of
Water and the concentrated sulfuric acid, then reaction solution is slowly dropped in ice n-heptanol solution, there is solid precipitation, suction filtration obtains
Further limit, the detailed process of step F is：In reaction bulb,Add in DMSO, a certain amount of palladium is added, in 130 DEG C of reaction temperatures
Under the conditions of, 10h is reacted, the reaction was complete for TLC monitoring raw material, and reaction solution is cooled to room temperature, and a certain amount of water is added into reaction solution,
Stirring has solid precipitation at ambient temperature, and suction filtration obtains
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
In reaction bulb, aniline (20g, 0.21mol) is added in pyridine 90mL, at ambient temperature, spy is slowly added dropwise
Valeric chloride (28g, 0.23mol), continues to react 4h at ambient temperature after dripping, and the reaction was complete for TLC monitoring raw material, to reaction
Add the HCl solution of a certain amount of 6N in liquid, adjust reaction solution pH as neutrality, strong stirring for a period of time after washed reaction liquid,
Finally it is concentrated to give under vacuum(35g,yield:94%)；.HNMR:(CDCl3)δ7.35(brs,1H,
), NH 7.53 (d, J=8Hz, 2H, Ar-H), 7.31 (t, J=8Hz, 2H, Ar-H), 7.09 (t, J=4Hz, 1H, Ar-H), 1.35
(s,9H).
Embodiment 2
In reaction bulb,(20g, 0.113mol) is added in the THF150mL through Non-aqueous processing, nitrogen
Reaction system is protected, is placed under the conditions of 0 DEG C, n-butyllithium solution 60mL is slowly added dropwise, maintain the temperature at less than 5 DEG C, about 30min
It is added dropwise complete；After stirring 4h, the THF solution 100mL dissolved with 4- pyridine carboxaldehydes 24g (0.224mol), reaction is slowly dropped to
In liquid, reaction temperature is set to be no more than 5 DEG C, it is in peony to drip rear reaction solution；The reaction was continued 5h, TLC monitoring raw material unreacted
Completely, a certain amount of frozen water is added under the conditions of making reaction be 10 DEG C in temperature after the reaction was continued 8h and is quenched reaction, then with acetic acid second
Ester extractive reaction liquid, obtains after organic phase is evaporated offCrude product, then obtain sterling through column chromatography for separation
(20g,yield:62%) .MS (ESI) m/z:285.4(M+H+),1HNMR:(CDCl3)δ8.99(brs,1H,NH),8.31(d,J
=6Hz, 2H, Ar-H), 8.11 (d, J=8Hz, 1H, Ar-H), 7.29-7.34 (m, 1H, Ar-H), 8.31 (d, J=6Hz, 2H,
), Ar-H 7.22 (d, J=5.2Hz, 2H, Ar-H), 8.31 (d, J=6Hz, 2H, Ar-H), 7.07 (d, J=3.6Hz, 2H, Ar-
H),5.79(s,1H),1.04(s,9H).。
Embodiment 3
In reaction bulb,(6g, 0.021mol) and MnO2(9.2g, 0.021mol) is added
Into chloroform 50mL, the reaction was complete for heating reflux reaction 7h, TLC monitoring raw material, and filtering reacting liquid, obtains after filtrate concentration(5.5g,yield:92.59%) .MS (ESI) m/z:283.4(M+H+).1HNMR:(CDCl3)δ
(11.33 brs, 1H, NH), 8.77-8.79 (m, 3H, Ar-H), 7.60 (t, J=7.6Hz, 1H, Ar-H), 7.46-7.49 (m,
3H, Ar-H), 7.06 (t, J=7.2Hz, 1H, Ar-H), 1.04 (s, 9H)
Embodiment 4
In reaction bulb,(4.2g, 0.0154mol) is added to ethanol 40mL and hydrochloric acid
In the mixed solution of 15mL, reaction is stirred at ambient temperature, be heated to flowing back after stirring 4h, the reaction was continued 3h, TLC prisons
Controlling raw material, the reaction was complete；Ethanol is evaporated off in vacuum concentration, then it is 7~8 to adjust reaction solution pH with saturated sodium carbonate solution, then uses dichloro
Methane 30mL extractive reactions liquid three times, is concentrated to give after merging organic phaseCrude product, then through column chromatography for separation
Obtain sterling (2.4g, yield:80%) .MS (ESI) m/z:199.2(M+H+),1HNMR:(CDCl3)δ8.75-8.76(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 5
In reaction bulb,(2g, 0.01mol) is added in dichloromethane 50mL, adds chemical combination
Thing Boc glycyls chlorine (3.8g, 0.02mol) and DCC (4.12g, 0.02mol), react 10h, TLC monitoring at ambient temperature
The reaction was complete for raw material, and filtering reacting liquid removes dicyclohexylurea, and reaction solution is molten with 10% HCl solution and saturated sodium carbonate respectively again
Liquid washs, and is concentrated to give after separating organic phaseCrude product, then obtain sterling through column chromatography for separation
(2.5g.yield:70%) .MS (ESI) m/z:356.4(M+H+).1HNMR:(CDCl3)δ11.46(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 6
In reaction bulb,(2g, 0.0056mol) is added to 1 containing 4M HCl,
In 4- dioxane, the reaction was complete for stirring reaction 2h, TLC monitoring raw material at ambient temperature, filtering reacting liquid, and filter cake is(1.2g,yield:75%) MS (ESI) m/z:256.4(M+H+),1HNMR:(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 7
In reaction bulb,(700mg, 2.41mmol) and sodium methoxide (155.8mg,
2.88mmol) it is added in methanol 20mL, the reaction was complete for stirring reaction 2h, LCMS monitoring compound 7 at ambient temperature, true
Reaction dissolvent is evaporated off under empty condition, adds a certain amount of water and dichloromethane, separates organic phase, is obtained after concentration(450mg,yield:78.81%) .MS (ESI) m/z:238.3(M+H+).1HNMR:(CDCl3)δ9.37
(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 8
In reaction bulb,(300mg, 1.26mmol) and lawesson reagent (614mg, 1.52mmol)
It is added in toluene 20mL, under nitrogen protection heating reflux reaction 2h, the reaction was complete for LCMS monitoring raw material, after reaction solution cooling
Add the mixed solution (DCM of saturated sodium carbonate solution, reaction solution dichloromethane and methanol：MeOH=5:1) extraction is multiple, closes
And concentrated after organic phase, then obtained through column chromatography for separation(250mg.yield:78.13%) .MS (ESI)
m/z:254.3(M+H+).
Embodiment 9
In reaction bulb,It is water-soluble that 2.4g (0.01mol) adds the formaldehyde that mass concentration is 50%
In liquid 20g, triethylamine 6g is added, is heated to flowing back, dimethyl suflfate 2.5g is slowly added dropwise at reflux after reacting 3h
(0.02mol), continues to stir 10min after dripping, and reaction solution is cooled to room temperature, and water 10mL and the concentrated sulfuric acid are added into reaction solution
10g, is then slowly dropped to reaction solution in n-heptanol solution under the conditions of 0 DEG C, there is solid precipitation, suction filtration obtains2.6g, yield 93%.
Embodiment 10
In reaction bulb,It is water-soluble that 2.53g (0.01mol) adds the formaldehyde that mass concentration is 50%
In liquid 20g, triethylamine 6g is added, is heated to flowing back, dimethyl suflfate 2.5g is slowly added dropwise at reflux after reacting 3h
(0.02mol), continues to stir 10min after dripping, and reaction solution is cooled to room temperature, and water 10mL and the concentrated sulfuric acid are added into reaction solution
10g, is then slowly dropped to reaction solution in n-heptanol solution under the conditions of 0 DEG C, there is solid precipitation, suction filtration obtains26.5g, yield 90%；1HNMR:(400M, CDCl3)δ8.69-8.68(m,2H),7.95-7.94(m,
2H), 7.66 (s, 1H), 7.29 (d, J=8.0Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.65 (d, J=8.0Hz, 1H),
5.25(s,1H),5.19-5.17(m,2H),4.39(s,1H),2.48-2.47(m,1H),1.31(s,3H),MS(ESI)m/z:
296.5(M+H+)。
Embodiment 11
In reaction bulb,2.8g (0.01mol) is added in DMSO10mL, adds palladium
0.15g, reacts 10h under the conditions of 130 DEG C of reaction temperatures, and the reaction was complete for TLC monitoring raw material, and reaction solution is cooled to room temperature, to anti-
Addition frozen water 30mL in liquid is answered, stirring at ambient temperature has solid precipitation, and suction filtration obtains23g, yield
For 83.6%；1HNMR:(400M, CDCl3)δ8.84(s,1H),8.71(s,1H),7.98-7.95(m,2H),7.45-7.42(m,
2H), 6.95 (d, J=8.0Hz, 1H), 4.25 (s, 1H), 3.62-3.60 (m, 2H), 2.95-2.91 (m, 4H), 2.00-1.96
(m,4H),MS(ESI)m/z:280.3(M+H+)。
Embodiment 12
In reaction bulb,2.95g (0.01mol) is added in DMSO10mL, adds palladium
0.15g, reacts 10h under the conditions of 130 DEG C of reaction temperatures, and the reaction was complete for TLC monitoring raw material, and reaction solution is cooled to room temperature, to anti-
Addition frozen water 30mL in liquid is answered, stirring at ambient temperature has solid precipitation, and suction filtration obtains21g, yield
For 71.1%；1HNMR:(400M, CDCl3)δ8.87(s,1H),8.69(s,1H),7.98-7.96(m,2H),7.45-7.43(m,
2H), 6.95 (d, J=8.0Hz, 1H), 4.25 (s, 1H), 3.57-3.56 (m, 2H), 2.95-2.92 (m, 4H), 2.01-1.98
(m,4H),MS(ESI)m/z:296.4(M+H+)。
Embodiment 13
Platelet aggregation inhibitory activity is tested
Select healthy male rabbit, random packet.If normal and ticlopidine control group, gastric infusion, dosage 30mg/
kg-1.Normal group gives the CMC-Na that equivalent mass concentration is 0.5%.2h after administration, is injected intraperitoneally 40mg/kg-1Penta bar
Than appropriate sodium (1mL/kg-1) anesthesia, collection rabbit hearts position blood, with the sodium citrate anti-freezing that mass concentration is 3.8%, difference
Platelet rich plasma (PRP) and platelet poor plasma (PPP) are prepared, by adenosine diphosphate (ADP) (final concentration：1.5μmol/L-1) add
With induced platelet aggregation, relative light transmission is detected at 37 DEG C 5 minutes, maximum effect during observation be used to calculate induction
Maximum platelet aggregation rate and inhibiting rate.Inhibiting rate (%)=(aggregation of aggregation maximum-test group of control group is maximum
Value)/control group aggregation maximum * 100%.
As seen from the above table, the compounds for resisting platelet aggregation effect that we synthesizeIt is better than
Embodiment 14
Antitumor activity is tested
Growth period lung cell A549 is collected, the active anticancer of compound is measured with MTS methods, by cell with appropriate dense
(every milliliter 4 × 10 of degree4A cell) be added in 96 porocyte culture plates (containing 10% tire calf serum obtain nutrient solution be made into it is single thin
Born of the same parents' suspension), culture 24 it is small when after, 37 DEG C, volumetric concentration be 5% CO2Under the conditions of compound effects 72 with various concentrations
Hour, then the mixture of MTS (final mass concentration 2mg/mL) and DMS (final 30 μM of molar concentration) are directly added into containing thin
In the culture medium of born of the same parents, continue to put incubator incubation 4h.After acting on 4h, abandoning supernatant, 150 μ LDMSO are added per hole, are vibrated, carefully
Born of the same parents' survival rate is measured by its absorptivity of metabolin to MTS effects under enzyme linked immunological monitor 490nm wavelength.
Preliminary biological activity test shows, such compoundThe inhibitory action of A549 is better than
Basic principle, main features and advantages embodiment above describes the present invention, 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 the original of the present invention
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (9)
1. a kind of new diazepine tricyclic compounds and its preparation method and application, it is characterised in that its molecular structure is：
Wherein R is O or S.
A kind of 2. preparation method of the new diazepine tricyclic compounds described in claim 1, it is characterised in that specific step
Suddenly it is：
A, acylation reaction generation occurs in pyridine for aniline and pivaloyl chlorideActed in n-BuLi
Addition reaction occurs with 4- pyridine carboxaldehydes after lower activation ortho-hydrogens to obtain
B、By manganese dioxide, secondary carbon and the hydroxyl connected slough a molecular hydrogen in its structure
Carbonyl is generated after gas, is obtainedTertiary butyryl is sloughed in acid condition
Base obtains
C、Substitution reaction generation occurs with Boc glycyls chlorine under DCC effectsReact, slough in Isosorbide-5-Nitrae-dioxane with HCl
Obtained while Boc groups into salt
D、Under sodium methoxide effect, ketoamine occurs and is condensed to yield React to obtain with lawesson reagent
E、Substitution reaction occurs with formaldehyde and dithyl sulfate to obtain
F、Oneself addition cyclization occurs to obtain
A kind of 3. preparation method of new diazepine tricyclic compounds according to claim 2, it is characterised in that step
Suddenly the detailed process of A is：In reaction bulb, aniline is added in pyridine, at ambient temperature, pivaloyl chloride is slowly added dropwise, dripped
Continuing to react at ambient temperature after adding, the reaction was complete for TLC monitoring raw material, and a certain amount of HCl solution is added into reaction solution,
Strong stirring for a period of time after washed reaction liquid, be finally concentrated to give under vacuum Add
Into the THF through Non-aqueous processing, nitrogen protection reaction system, is placed under the conditions of 0 DEG C, n-butyllithium solution is slowly added dropwise, keep
Temperature stirs 2h below 5 DEG C after dripping, and the THF solution dissolved with 4- pyridine carboxaldehydes is slowly dropped in reaction solution, makes anti-
Temperature is answered to be no more than 5 DEG C, it is in peony to drip rear reaction solution；The reaction was continued 3h, TLC monitoring raw material unreacted are complete, make anti-
A certain amount of frozen water is added after the reaction was continued 8h under the conditions of should being -30 DEG C~40 DEG C in temperature and reaction is quenched, then use ethyl acetate
Extractive reaction liquid, obtains after organic phase is evaporated offCrude product, then obtain sterling through column chromatography for separation.
A kind of 4. preparation method of new diazepine tricyclic compounds according to claim 2, it is characterised in that step
Suddenly the detailed process of B is：In reaction bulb,And MnO2It is added in chloroform, heating reflux reaction
The reaction was complete for 10h, TLC monitoring raw material, and filtering reacting liquid, obtains after filtrate concentration It is added in the mixed solution of ethanol and hydrochloric acid, is stirred reaction at ambient temperature, stirs 2h
After be heated to flowing back, the reaction was complete for the reaction was continued 5h, TLC monitoring raw material；Ethanol is evaporated off in vacuum concentration, then molten with saturated sodium carbonate
Liquid adjusts reaction solution pH>7, then, be concentrated to give after merging organic phase with dichloromethane extractive reaction liquid three times
Crude product, then obtain sterling through column chromatography for separation.
A kind of 5. preparation method of new diazepine tricyclic compounds according to claim 2, it is characterised in that step
Suddenly the detailed process of C is：In reaction bulb,It is added in dichloromethane, adds compound Boc ammonia
Base chloroacetic chloride and DCC, react 10h at ambient temperature, and the reaction was complete for TLC monitoring raw material, and filtering reacting liquid removes dicyclohexylurea,
Reaction solution is washed with 10% HCl solution and saturated sodium carbonate solution respectively again, is concentrated to give after separating organic phaseCrude product, then obtain sterling through column chromatography for separation；Add
Enter into Isosorbide-5-Nitrae-dioxane containing 4M HCl, the reaction was complete for stirring reaction 2h, TLC monitoring raw material at ambient temperature, mistake
Reaction solution is filtered, filter cake is
A kind of 6. preparation method of new diazepine tricyclic compounds according to claim 2, it is characterised in that step
Suddenly the detailed process of D is：In reaction bulb,It is added to sodium methoxide in methanol, in room
The reaction was complete for stirring reaction 2h, LCMS monitoring raw material under the conditions of temperature, and reaction dissolvent is evaporated off under vacuum, adds a certain amount of
Water and dichloromethane, separate organic phase, obtained after concentration And lawesson reagent
It is added in toluene, under nitrogen protection heating reflux reaction 2h, the reaction was complete for LCMS monitoring raw material, is added after reaction solution cooling
Mixed solution (the DCM of saturated sodium carbonate solution, reaction solution dichloromethane and methanol：MeOH=5:1) extraction is multiple, is associated with
Concentrate after machine phase, then obtained through column chromatography for separation
A kind of 7. preparation method of new diazepine tricyclic compounds according to claim 2, it is characterised in that step
Suddenly the detailed process of E is：In reaction bulb,Add in formalin, then
Triethylamine is added, after being heated to back flow reaction for a period of time, dithyl sulfate is slowly added dropwise at reflux, drips rear cold
But to room temperature, a certain amount of water and the concentrated sulfuric acid are added into reaction solution, reaction solution is then slowly dropped to ice n-heptanol solution
In, there is solid precipitation, suction filtration obtains
A kind of 8. preparation method of new diazepine tricyclic compounds according to claim 2, it is characterised in that step
Suddenly the detailed process of F is：In reaction bulb,Add in DMSO, add
A certain amount of palladium, under the conditions of 130 DEG C of reaction temperatures, reacts 10h, the reaction was complete for TLC monitoring raw material, and reaction solution is cooled to
Room temperature, a certain amount of water is added into reaction solution, and stirring at ambient temperature has solid precipitation, and suction filtration obtains
9. a kind of new diazepine tricyclic compounds as claimed in claim 1 is preparing medicament for resisting platelet aggregation and is resisting
Application in tumour medicine.
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| CN115322160A (en) * | 2022-08-04 | 2022-11-11 | 温州医科大学 | A kind of preparation method of 5-aryl-1,4-benzodiazepine-2-one compounds |
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| CN102190631A (en) * | 2010-03-10 | 2011-09-21 | 中国人民解放军63975部队 | Preparation method of benzodiazepine compound |
| CN102933236A (en) * | 2010-04-15 | 2013-02-13 | 斯皮罗根发展有限公司 | Pyrrolobenzodiazepines and conjugates thereof |
| CN103086986A (en) * | 2011-11-01 | 2013-05-08 | 上海医药工业研究院 | Preparation method and application of 1,4-benzodiazepine-N-nitrosamine intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102190631A (en) * | 2010-03-10 | 2011-09-21 | 中国人民解放军63975部队 | Preparation method of benzodiazepine compound |
| CN102933236A (en) * | 2010-04-15 | 2013-02-13 | 斯皮罗根发展有限公司 | Pyrrolobenzodiazepines and conjugates thereof |
| CN103086986A (en) * | 2011-11-01 | 2013-05-08 | 上海医药工业研究院 | Preparation method and application of 1,4-benzodiazepine-N-nitrosamine intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115322160A (en) * | 2022-08-04 | 2022-11-11 | 温州医科大学 | A kind of preparation method of 5-aryl-1,4-benzodiazepine-2-one compounds |
| CN115322160B (en) * | 2022-08-04 | 2024-05-31 | 温州医科大学 | A preparation method of 5-aryl-1,4-benzodiazepine-2-one compounds |
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