CN107383074A - The preparation method of benzoxazine with platelet aggregation inhibitory activity and pyrazoles calcium composition - Google Patents
The preparation method of benzoxazine with platelet aggregation inhibitory activity and pyrazoles calcium composition Download PDFInfo
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- CN107383074A CN107383074A CN201710413874.3A CN201710413874A CN107383074A CN 107383074 A CN107383074 A CN 107383074A CN 201710413874 A CN201710413874 A CN 201710413874A CN 107383074 A CN107383074 A CN 107383074A
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- UFTNSBITDRJJJL-UHFFFAOYSA-N O=C1N2NC3=Nc(cccc4)c4OC3=C2CC1 Chemical compound O=C1N2NC3=Nc(cccc4)c4OC3=C2CC1 UFTNSBITDRJJJL-UHFFFAOYSA-N 0.000 description 2
- 0 **C1=NCC1 Chemical compound **C1=NCC1 0.000 description 1
- QDBGFOAHQDBAIU-UHFFFAOYSA-N BrCCC1=C2Oc(cccc3)c3N=C2NC1 Chemical compound BrCCC1=C2Oc(cccc3)c3N=C2NC1 QDBGFOAHQDBAIU-UHFFFAOYSA-N 0.000 description 1
- FPZMYAXGAYRMLE-UHFFFAOYSA-N BrCCC1=C2Oc(cccc3)c3N=C2NN1 Chemical compound BrCCC1=C2Oc(cccc3)c3N=C2NN1 FPZMYAXGAYRMLE-UHFFFAOYSA-N 0.000 description 1
- WYDZUYSRZFVBNA-POHAHGRESA-N NNC1=Nc2ccccc2O/C1=C\CCBr Chemical compound NNC1=Nc2ccccc2O/C1=C\CCBr WYDZUYSRZFVBNA-POHAHGRESA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/04—Calcium compounds
Abstract
The invention discloses the preparation method of a kind of benzoxazine with platelet aggregation inhibitory activity and pyrazoles calcium composition, belong to technical field of medicine synthesis.Technical scheme main points are：
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, relates generally to a kind of benzoxazine with platelet aggregation inhibitory activity
And the preparation method of pyrazoles-calcium composition.
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.Benzo oxazinyl material
(benzoxazinoid, Bx) is a kind of secondary metabolites being widely present in tall graminaceous plant, has the pest-resistant work of broad-spectrum disease resistance
Property.These compounds are represented with Ding Buwei, are the important compounds for studying insect and plant relationship.Based on benzoxazine
The important function of compound, in recent years people this kind of compound is conducted extensive research, having synthesized much has bioactivity
Compound.Pyrazoles possesses a variety of physiological actions, including analgesic, anti-inflammatory, bring down a fever, anti-arrhythmia, calmness, relaxed muscle,
Mental excitation, anti-spasm, monoamine oxidase inhibitor, anti-diabetic and antibacterial.Pyrazoles can be as in some medicine, agricultural chemicals
Mesosome, occupy highly important status in medical, agricultural chemicals research and development.Pyrazole compound is because its action spectrum is wide, drug effect
The features such as strong and receive more and more attention.Pyrazole compound has curative effect to the disease of many in medical applications；
On pesticides application, pyrazole compound has desinsection, sterilization and activity of weeding, and it is more to show efficient, less toxic and structure
Sample.Therefore, pyrazoles medicine has wide research and development prospect.Pyrazoles also can be as the side of some light-sensitive material monomers
Chain, have a wide range of applications.With reference to the advantage of two kinds of structures, we, which design, synthesizes a kind of new benzoxazine and pyrazoles-calcium
Complex, and platelet aggregation inhibitory activity test has been carried out to it.
The content of the invention
Present invention solves the technical problem that there is provided, a kind of synthetic method is simple, and molecular structure is novel, has anti-blood small
The benzoxazine of plate aggregation activity and the preparation method of pyrazoles-calcium composition.
The present invention adopts the following technical scheme that a kind of new lives with platelet aggregation-against to solve above-mentioned technical problem
Property benzoxazine and pyrazoles-calcium composition preparation method, it is characterised in that concretely comprise the following steps：
A, o-aminoanisole and carbon monoxide, make in palladium as catalyst, sodium carbonate as alkaline matter, toluene
For solvent, reaction obtains the benzoxazinone of Isosorbide-5-Nitrae-.
B, for the benzoxazinone of Isosorbide-5-Nitrae-under lawesson reagent effect, toluene obtains the benzoxazine sulphur of Isosorbide-5-Nitrae-as solvent, reaction
Ketone.
C, 1,4- benzoxazines thioketones under ethylenediamine effect by enol form change to obtain compound 2H- benzos [b] [1,
4] oxazine mercaptan.
D, [1,4] oxazines mercaptan obtain 2H- benzos [b] with bromo propionic aldehyde under triethylamine effect
E、Substitution reaction occurs with hydrazine hydrate and obtains compound
F、Issued in Oxygen Condition and be born from body cyclization, obtain compound
G、With carbon monoxide, in palladium as catalyst, sodium carbonate as alkaline matter,
Toluene obtains as solvent, reaction
H, compoundComplexation reaction is carried out with calcium chloride to obtain
Further limit, step A detailed process is：In autoclave, o-aminoanisole, a certain amount of palladium
Added with a certain amount of sodium carbonate in toluene, after the gas in nitrogen displacement reactor, be passed through an oxidation under vacuum
Carbon makes the pressure in reactor reach 0.2MPa；Slowly rise temperature is to 50 DEG C, and TLC monitoring raw material reactions are complete after reacting 4h,
Filtering reacting liquid, solvent being evaporated off under vacuum, residue is added in dichloromethane, then with pure water washing three times, it is organic
Mutually after anhydrous sodium sulfate drying, solvent is evaporated off and obtains the benzoxazinone of Isosorbide-5-Nitrae-.
Further limit, step B detailed process is：Added in reaction bulb 1,4- benzoxazinones, lawesson reagent and
Toluene, 10h is heated to reflux, reaction solution is added in frozen water and cooled down, with dichloromethane extraction three times, merge organic phase, decompression is steamed
Dichloromethane is distillated, obtains the benzoxazine thioketones of Isosorbide-5-Nitrae-.
Further limit, step C detailed process is：In reaction bulb, the benzoxazine thioketones of Isosorbide-5-Nitrae-is added in acetone,
A certain amount of diethylamine is added, after adding some time of flowing back, TLC monitoring raw material reactions are complete, and solvent is evaporated off and obtains chemical combination
Thing 2H- benzos [b] [1,4] oxazine mercaptan.
Further limit, step D detailed process is：In reaction bulb, 2H- benzos [b], [Isosorbide-5-Nitrae] oxazines mercaptan adds
Into DMF, a certain amount of triethylamine and bromo propionic aldehyde is added, it is anti-to be warming up to 110 DEG C of reaction 1h, TLC monitoring raw materials
Should be complete, reaction solution is poured into frozen water, there are a large amount of solids to separate out, filters reaction solution, filter cake is sterling compound
Further limit, step E detailed process is：In reaction bulb,It is added to DMSO
In, a certain amount of hydrazine hydrate is added, is heated to 60 DEG C, TLC monitoring raw material reactions are complete, and reaction solution is poured into water, and have big
Measure solid to separate out, filter reaction solution, filter cake is sterling compound
Further limit, step F detailed process is：In reaction bulb,It is added to DMSO
In, in O2100 DEG C are heated under atmosphere, is monitored after reacting 3h through TLC, raw material reaction is complete, and reaction solution is poured into water, and has big
Measure solid to separate out, filter reaction solution, filter cake is sterling compound
Further limit, step A detailed process is：In autoclave,A certain amount of vinegar
Sour palladium and a certain amount of sodium carbonate are added in toluene, after the gas in nitrogen displacement reactor, are passed through one under vacuum
Carbonoxide makes the pressure in reactor reach 0.2MPa；Slowly rise temperature is to 50 DEG C, and TLC monitoring raw materials have reacted after reacting 4h
Entirely, filtering reacting liquid, solvent is evaporated off under vacuum, residue is added in dichloromethane, then with pure water washing three times, is had
Machine mutually after anhydrous sodium sulfate drying, is evaporated off solvent and obtained
Further preferably, step L detailed process is：Nitrogen is passed through into the ultrasonic response container for being provided with agitating device
Gas, then add dissolved withDichloromethane solution, after adding ammoniacal liquor, in 25 DEG C to ultrasonic response
The methanol solution dissolved with calcium chloride is added dropwise in container, agitating device and ultrasonic generator, ultrasonic wave are opened during dropwise addition
The setpoint frequency of generating means is 80KHz, and it is clear state to drip rear solution, stops stirring, keeps ultrasonic generator
Work on, be cooled to 0 DEG C of standing reaction solution, open the steam vent on ultrasonic response container, keep the nitrogen that is passed through from row
Stomata is discharged, and nitrogen is discharged ultrasonic response container with reaction dissolvent, there is a clear crystal precipitation, and crystallization is complete after 5h, takes out
Reaction solution is filtered, filter cake is washed repeatedly to wash away unnecessary stannous chloride with methanol, and filter cake obtains after drying at room temperature
In the preparation method of benzoxazine of the present invention with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Synthetic route be：
The present invention has synthesized a kind of benzoxazine with platelet aggregation inhibitory activity and pyrazoles-calcium composition, and finding should
Compound has good action effect to suppressing platelet aggregation.
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 autoclave, o-aminoanisole 12.3g (0.1mol), palladium 2.5g and sodium carbonate 20g are added toluene
In 100mL, after the gas in nitrogen displacement reactor, being passed through carbon monoxide under vacuum makes pressure in reactor
Reach 0.2MPa；Slowly rise temperature is to 50 DEG C, and TLC monitoring raw material reactions are complete after reacting 4h, filtering reacting liquid, in vacuum
Under the conditions of be evaporated off solvent, residue is added in dichloromethane 100mL, then washed three times with pure water 50mL, and organic phase is through anhydrous
After sodium sulphate 50g is dried, solvent is evaporated off and obtains the benzoxazinone 14g of Isosorbide-5-Nitrae-
Embodiment 2
The benzoxazinone 15g (0.1mol) of Isosorbide-5-Nitrae-, lawesson reagent 30g and toluene 200mL are added in reaction bulb, is heated back
10h is flowed, reaction solution is added in frozen water 200mL, with dichloromethane 100mL extractions three times, merges organic phase, is evaporated under reduced pressure out two
Chloromethanes, obtain the benzoxazine thioketones 16g of Isosorbide-5-Nitrae-
Embodiment 3
In reaction bulb, the benzoxazine thioketones 16.5g of Isosorbide-5-Nitrae-is added in acetone 200mL, diethylamine 50mL is added, adds
After heat backflow a period of time, TLC monitoring raw material reactions are complete, and solvent is evaporated off and obtains compound 2H- benzos [b] [Isosorbide-5-Nitrae] oxazine sulphur
Alcohol 16g
Embodiment 4
In reaction bulb, 2H- benzos [b], [Isosorbide-5-Nitrae] oxazine mercaptan 16g is added in DMF100mL, adds triethylamine
30mL and bromo propionic aldehyde 12g (0.1mol), it is warming up to 110 DEG C of reaction 1h, TLC monitoring raw material reactions completely, reaction solution is poured into
In frozen water, there are a large amount of solids to separate out, filter reaction solution, filter cake is sterling compound26g；
Embodiment 5
In reaction bulb,28g (0.1mol) is added in DMSO50mL, adds hydrazine hydrate
50mL, 60 DEG C are heated to, TLC monitoring raw material reactions are complete, and reaction solution is poured into water, there are a large amount of solids to separate out, filters reaction
Liquid, filter cake are sterling compound25g
Embodiment 6
In reaction bulb,28g (0.1mol) is added in DMSO50mL, in O2Add under atmosphere
Heat monitors to 100 DEG C after reacting 3h through TLC, and raw material reaction is complete, and reaction solution is poured into water, and has a large amount of solids to separate out, and filters
Reaction solution, filter cake are sterling compound27g；1H NMR(400MHz,DMSO-d6) δ:7.28-7.27
(m, 1H), 7.16 (t, J=4Hz, 1H), 6.99-6.97 (m, 2H), 3.34-3.32 (m, 2H), 2.46-2.42 (m, 2H),
2.01-2.00(m,2H)；MS-ESI(m/z):281.1[M+H+]。
Embodiment 7
In autoclave,28g, palladium 2.8g and sodium carbonate 20g are added in toluene 100mL,
After the gas in nitrogen displacement reactor, being passed through carbon monoxide under vacuum reaches the pressure in reactor
0.2MPa；Slowly rise temperature is to 50 DEG C, and TLC monitoring raw material reactions are complete after reacting 4h, filtering reacting liquid, under vacuum
Solvent is evaporated off, residue is added in dichloromethane, then with pure water washing three times, organic phase is steamed after anhydrous sodium sulfate drying
Except solvent obtains20g；1H NMR(400MHz,DMSO-d6)δ:7.28-7.27(m, 2H),7.16
(t, J=4Hz, 1H), 7.01-7.00 (m, 1H), 2.24 (d, J=4Hz, 2H), 2.22 (d, J=4Hz, 2H), 2.01 (s,
1H)；MS-ESI(m/z):228.3[M+H+]。
Embodiment 8
Nitrogen is passed through into the ultrasonic response container for being provided with agitating device, is then added dissolved with compound45g dichloromethane solution 500mL, after adding ammoniacal liquor 100mL, hold in 25 DEG C to ultrasonic response
The methanol solution 500mL dissolved with calcium chloride 50g is slowly added dropwise in device, opens agitating device during dropwise addition and ultrasonic wave fills
Put, the setpoint frequency of ultrasonic generator is 80KHz, and it is clear state to drip rear solution, stops stirring, keeps ultrasonic wave
Generating means works on, and slow cooling to 0 DEG C of standing reaction solution, opens the steam vent on ultrasonic response container, keeps logical
The nitrogen entered is discharged from steam vent, nitrogen is discharged ultrasonic response container with a certain amount of reaction dissolvent, gradually has colourless
Crystal is separated out, and crystallization is complete after 5h, filters reaction solution, and filter cake is washed repeatedly to wash away unnecessary tin salt with methanol, and filter cake exists
Obtained after drying at room temperature55g。
Embodiment 9
Platelet aggregation inhibitory activity is tested
From 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, 40mg/kg is injected intraperitoneally-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 synthesize is suitable with ticlopidine.
Embodiment above describes the general principle of the present invention, main features and advantages, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (9)
1. the preparation method of benzoxazine and pyrazoles-calcium composition with platelet aggregation inhibitory activity, it is characterised in that specific
Step is：
A, o-aminoanisole and carbon monoxide, in palladium as catalyst, sodium carbonate is as alkaline matter, and toluene is as molten
Agent, reaction obtain the benzoxazinone of Isosorbide-5-Nitrae-；
B, for the benzoxazinone of Isosorbide-5-Nitrae-under lawesson reagent effect, toluene obtains the benzoxazine thioketones of Isosorbide-5-Nitrae-as solvent, reaction；
C, 1,4- benzoxazines thioketones changes to obtain compound 2H- benzos [b] [1,4] Evil under ethylenediamine effect by enol form
Piperazine mercaptan；
D, [1,4] oxazines mercaptan obtain 2H- benzos [b] with bromo propionic aldehyde under triethylamine effect
E、Substitution reaction occurs with hydrazine hydrate and obtains compound
F、Issued in Oxygen Condition and be born from body cyclization, obtain compound
G、With carbon monoxide, make in palladium as catalyst, sodium carbonate as alkaline matter, toluene
For solvent, reaction obtains
H, compoundComplexation reaction is carried out with calcium chloride to obtain
2. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that step A detailed process is：In autoclave, o-aminoanisole, a certain amount of palladium and one
Quantitative sodium carbonate is added in toluene, and after the gas in nitrogen displacement reactor, being passed through carbon monoxide under vacuum makes
Pressure in reactor reaches 0.2MPa；Slowly rise temperature is to 50 DEG C, and TLC monitoring raw material reactions are complete after reacting 4h, filtering
Reaction solution, solvent being evaporated off under vacuum, residue is added in dichloromethane, then with pure water washing three times, organic phase warp
After anhydrous sodium sulfate drying, solvent is evaporated off and obtains the benzoxazinone of Isosorbide-5-Nitrae-；Described step B detailed process is：In reaction bulb
Middle addition Isosorbide-5-Nitrae-benzoxazinone, lawesson reagent and toluene, are heated to reflux 10h, reaction solution are added in frozen water and cooled down, uses dichloro
Methane extracts three times, merges organic phase, is evaporated under reduced pressure out dichloromethane, obtains Isosorbide-5-Nitrae-benzoxazine thioketones.
3. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that step C detailed process is：In reaction bulb, the benzoxazine thioketones of Isosorbide-5-Nitrae-is added in acetone, then added
Enter a certain amount of diethylamine, after adding some time of flowing back, TLC monitoring raw material reactions are complete, and solvent is evaporated off and obtains compound 2H-
Benzo [b] [1,4] oxazine mercaptan.
4. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that step D detailed process is：In reaction bulb, 2H- benzos [b], [Isosorbide-5-Nitrae] oxazine mercaptan is added to
In DMF, a certain amount of triethylamine and bromo propionic aldehyde is added, is warming up to 110 DEG C of reaction 1h, TLC monitoring raw material reactions completely,
Reaction solution is poured into frozen water, has a large amount of solids to separate out, and filters reaction solution, filter cake is sterling compound
5. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that step E detailed process is：In reaction bulb,It is added in DMSO, then adds
Enter a certain amount of hydrazine hydrate, be heated to 60 DEG C, TLC monitoring raw material reactions are complete, and reaction solution is poured into water, there are a large amount of solids to analyse
Go out, filter reaction solution, filter cake is sterling compound
6. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that step F detailed process is：In reaction bulb,It is added in DMSO,
O2100 DEG C are heated under atmosphere, is monitored after reacting 3h through TLC, raw material reaction is complete, and reaction solution is poured into water, and has a large amount of solid
Body separates out, and filters reaction solution, filter cake is sterling compound
7. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that step G detailed process is：In autoclave,A certain amount of palladium
Added with a certain amount of sodium carbonate in toluene, after the gas in nitrogen displacement reactor, be passed through an oxidation under vacuum
Carbon makes the pressure in reactor reach 0.2MPa；Slowly rise temperature is to 50 DEG C, and TLC monitoring raw material reactions are complete after reacting 4h,
Filtering reacting liquid, solvent being evaporated off under vacuum, residue is added in dichloromethane, then with pure water washing three times, it is organic
Mutually after anhydrous sodium sulfate drying, solvent is evaporated off and obtains
8. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that step H detailed process is：Nitrogen is passed through into the ultrasonic response container for being provided with agitating device,
Then add dissolved withDichloromethane solution, after adding ammoniacal liquor, in 25 DEG C to ultrasonic response container
The middle methanol solution being added dropwise dissolved with calcium chloride, opens agitating device and ultrasonic generator during dropwise addition, ultrasonic wave occurs
The setpoint frequency of device is 80KHz, and it is clear state to drip rear solution, stops stirring, keeps ultrasonic generator to continue
Work, 0 DEG C of standing reaction solution is cooled to, opens the steam vent on ultrasonic response container, keeps the nitrogen that is passed through from steam vent
Discharge, nitrogen is discharged ultrasonic response container with reaction dissolvent, there is a clear crystal precipitation, crystallization is complete after 5h, filters anti-
Liquid is answered, filter cake is washed repeatedly to wash away unnecessary stannous chloride with methanol, and filter cake obtains after drying at room temperature
9. the preparation of the benzoxazine according to claim 1 with platelet aggregation inhibitory activity and pyrazoles-calcium composition
Method, it is characterised in that the specific synthetic route in preparation process is：
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| CN1528763A (en) * | 2003-10-14 | 2004-09-15 | 四川大学 | Binuclear macrocyclic polyamine metal complex and its use |
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| CN103755730A (en) * | 2014-01-28 | 2014-04-30 | 广西师范大学 | Marbofloxacin-calcium chelate and synthetic method and application thereof |
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2017
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| CN1528763A (en) * | 2003-10-14 | 2004-09-15 | 四川大学 | Binuclear macrocyclic polyamine metal complex and its use |
| CN1546450A (en) * | 2003-12-04 | 2004-11-17 | 上海交通大学 | Alkannin derivatives as immune inhibitors and metal complexes thereof |
| CN1556095A (en) * | 2003-12-31 | 2004-12-22 | 赤峰制药（集团）有限责任公司 | Tetracycline derivatives |
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Application publication date: 20171124 |