CN110423224A - A kind of synthetic method of 2- aminopyrimidine type antiplatelet compound - Google Patents
A kind of synthetic method of 2- aminopyrimidine type antiplatelet compound Download PDFInfo
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- CN110423224A CN110423224A CN201910810281.XA CN201910810281A CN110423224A CN 110423224 A CN110423224 A CN 110423224A CN 201910810281 A CN201910810281 A CN 201910810281A CN 110423224 A CN110423224 A CN 110423224A
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of synthetic methods of 2- aminopyrimidine type antiplatelet compound, selecting salicylaldhyde A and 2- the bromoacetophenone B containing different substituents is raw material, using N-heterocyclic carbine as catalysts, the intermediate 1 of synthesizing new antiplatelet drug under alkaline condition, 3- cyclohexadione compounds C, then 1,3- cyclohexadione compounds C synthesizes flavone compound D in acid condition, and last flavone compound D and guanidine hydrochloride generate final product 2- aminopyrimidine type antiplatelet compound E under alkaline condition.Original synthetic method is reduced to three-step reaction by four steps by the present invention, considerably simplifies original synthetic method, to effectively reduce the price of its production cost and medicine, improves possibility for industrialized production.
Description
Technical field
The invention belongs to technical field of compound preparation, and in particular to a kind of 2- aminopyrimidine type antiplatelet compound
Synthetic method.
Background technique
It is about 40% in the morbidity and mortality of western countries, atherosclerosis thrombotic blood vessels disease.Blood is small
Plate plays key effect in thrombosis and hemostasis, and major physiological effect is the integrality of the maintenance circulatory system, and in blood
Pipe damage location is effectively made a response rapidly.It, will be by when the medicament contacts such as blood platelet and collagen, fibrin ferment and ADP
Activation.This activation plays key effect in Arterial thrombosis, mainly include platelet aggregation, densification, granule secretion and
Procoagulant activity.The population in the whole world nearly 50% has drug resistance to common antiplatelet drug at present, such as: aspirin and thiophene
Pyridines drug, to increase the risk of Relapse myocardial infarction and apoplexy.Therefore, develop novel antiplatelet drug and
Its synthetic method is studied to be of great significance.
Recent studies have shown that pyrimidine derivatives are a kind of effective antiplatelet drugs.Pyrimidine is in many bioprocess
It plays an important role, finds that pyrimidine ring has important chemistry and pharmacology meaning in nucleosides antibiosis alkaloids.Pyrimidine, especially alkane
Base sulfenyl substituted uracil compound, such as 2- propyl dithiocarbamate triazolo pyrimidine and pyrantel, due to its drug resistance with higher
It is concerned.Wherein the dual antiplatelet method of aspirin and thiopyridine Drug combination is although coronal in treatment recently
Progress is achieved in terms of superior mesenteric artery syndrome, but in acute stage and secondary prevention stage, atherosclerotic thrombotic disease is still
One of the main reason for morbidity and mortality.In addition, Indobufen can inhibit kidney as medicament for resisting platelet aggregation of new generation
Platelet aggregation caused by upper parathyrine, platelet activating factor, collagen and arachidonic acid.Clinical application includes that treatment lacks
Hemorrhagic brain soldier, myocardial infarction, Atrial fibrillation, the formation of phlebothrombosis, especially prevention and treatment arterial thrombus
It is formed, but is not also very sufficiently to the research of its anticoagulation.
It is currently available that the limitation of antiplatelet drug has caused the exploitation of novel drugs.Wherein mentioned from 2- aminopyrimidine
The compound taken provides foundation for different medicinal applications.Pyrimidine Type antiplatelet drug preparation method is mainly as follows at present:
1) 2011, Du Hongguang project was combined into 6- alkylamine -2,4- dialkyl (aryl) thiopyridine, and to being closed
At compound carried out viability examination.The results show that part of compounds plays the role of anti-platelet aggregation.
2) Giridhar seminar synthesized 4,6- diaryl -2- aminopyrimidine compounds with four-step reaction in 2012.
Found through experiment in vitro, the drug effect of aspirin only have 4- (2 '-hydroxyls -4 '-methoxyphenyl) -6- (2 ", 4 "-dichloro-benzenes
Base) -2-aminopyridine half.
3) Okuda project has been combined into a large amount of tricyclic 2- substitution 4- alkyl amino -5,6- dihydrobenzo azepine [5,4-d]
Pyrimidine, many of alkyl and aryl all can be used as 2- bit substituent.And it is small to the anti-blood of the five rings pyrimidine Type compound of synthesis
Plate activity is assessed, and result of study shows that some of products and aspirin have comparable effect.It should by research
Seminar has found influence of the newly synthesized compound to collagen-induced platelet aggregation, has obtained several effects better than Ah Si
Woods, promises to be antiplatelet compound.
But process made above needs multi-step, in multi step organic synthesis, since the yield of each step reaction is lower than
Theoretical yield, per more steps, gross production rate is necessarily influenced by cumulative reaction step.Therefore, reaction step is reduced for improving
The yield of final product has great function.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound, this method will
Largely simplify original four-step reaction synthetic method, the valence of its production cost and medicine can be effectively reduced in the present invention
Lattice improve possibility for industrialized production.
The present invention is realized especially by following technical scheme:
A kind of synthetic method of 2- aminopyrimidine type antiplatelet compound, by by flavone compound, guanidine hydrochloride and
Alkali soluble is stirred to react at 65 DEG C of temperature in solvent, after reaction, reaction solution is poured into the trash ice containing acetic acid, mistake
Filter obtains yellow solid, obtains target product through washing, recrystallizing methanol.
The alkali is selected from potassium hydroxide, and the solvent is selected from methanol.
In another aspect of this invention, the preparation method of above-mentioned flavone compound is provided, by by 1,3- diones
Compound and the concentrated sulfuric acid are dissolved in solvent, are stirred to react at 100 DEG C of temperature, after reaction, are down to room to reacting liquid temperature
Temperature pours into reaction solution in trash ice, through flavone compound is obtained by filtration.
The solvent is selected from glacial acetic acid.
In another aspect of this invention, the preparation method of above-mentioned 1,3- cyclohexadione compounds is provided, by by adjacent hydroxyl
Benzaldehyde, 2- bromoacetophenone, aza ring carbene precursor and alkali soluble are stirred to react, instead in solvent at 80 DEG C~130 DEG C of temperature
After answering, it is concentrated under reduced pressure, is purified with silica gel column chromatography to crude product, obtain 1,3- cyclohexadione compounds.
The salicylaldhyde and 2- bromoacetophenone contains different substituents；The salicylaldhyde and 2- bromobenzene
The molar ratio of ethyl ketone is 1:1~1:1.3.
The solvent is selected from one of acetonitrile, toluene, DMF, THF or paraxylene kind.
The alkali is selected from one of potassium hydroxide, sodium hydroxide, cesium carbonate, triethylamine or pyridine kind；The alkali with
The molar ratio of salicylaldhyde is 0.5~1.
The aza ring carbene precursor is selected from one of L1~L4 kind, the aza ring carbene precursor and o-hydroxy
The molar ratio of formaldehyde is 0.02~0.2, and preferred molar ratio is 0.02,0.05,0.1 or 0.2, and wherein the structural formula of L1~L4 is such as
Under:
The invention has the benefit that
The method of the present invention will largely simplify original four-step reaction synthetic method, and the present invention can be effectively reduced
The price of its production cost and medicine.
Specific embodiment
Below in conjunction with specific embodiment of the present invention, technical solution of the present invention is clearly and completely described, is shown
So, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the reality in the present invention
Example is applied, every other embodiment obtained by those of ordinary skill in the art without making creative efforts all belongs to
In the scope of protection of the invention.
The present invention provides a kind of new method of synthesizing new 2- aminopyrimidine type antiplatelet compound, by by adjacent hydroxyl
Benzaldehyde and 2- bromoacetophenone compound react under N-heterocyclic carbine catalysis, obtain 1,3- cyclohexadione compounds, so
1,3- cyclohexadione compounds synthesize flavone compound in acid condition afterwards, and last flavone compound and guanidine hydrochloride are in alkalinity
Under the conditions of generate final product 2- aminopyrimidine type antiplatelet compound.
Specific reaction equation is as follows:
Embodiment 1
Reaction route:
- 5 methoxybenzaldehyde of 2- hydroxyl (4.0mmol), 2- bromo- 1- (4- methoxyl group are sequentially added in 50mL pressure bottle
Phenyl) ethane (4.8mmol) and L1 (0.2mmol), KOH and toluene (10mL), flow back under the conditions of 110 DEG C, instead in air
Answer 5h.After reaction, the solid that will obtain is concentrated under reduced pressure with Rotary Evaporators, uses silica gel column chromatography later, ethyl acetate/
N-hexane is that the in the mixed solvent of 1:8 purifies crude product, obtains 1,3- cyclohexadione compounds C1, yield 83%；It will
C1 (3.0mmol) and the concentrated sulfuric acid (3.0ml) are dissolved in glacial acetic acid (15.0ml), are stirred to react at 100 DEG C of temperature, reaction terminates
Afterwards, it is down to room temperature to reacting liquid temperature, reaction solution is poured into trash ice, intermediate flavone compound D1 is obtained by filtration, produced
Rate is 65%；D1 (1.5mmol), guanidine hydrochloride (7.5mmol) and potassium hydroxide (0.8g) are dissolved in methanol (25ml), in temperature
It is stirred to react at 65 DEG C, after reaction, reaction solution is poured into the trash ice containing acetic acid, yellow solid is obtained by filtration, through water
It washes, recrystallizing methanol obtains final product E1.Finally obtained target product is weighed and records data.Finally obtain the production of product
Rate is 67%.
The nuclear magnetic data characterization of compound prepared by embodiment 1 are as follows:
1H NMR(CDCl3,400MHz):δ3.86(s,6H,OCH3),5.48(s,2H,NH2),7.24-7.26(d,2H,
ArH),7.30-7.32(d,2H,ArH),7.36-7.38(d,2H,ArH),7.49(s,1H,ArH),8.06(s,1H,pyri)
.MS m/z；324.05(M+1).Anal.Calcd for C18H17N3O3:C,66.86；H,5.30；N,13.0.Found:C,
66.84；H,5.32；N,13.10.
Embodiment 2
Reaction route:
- 5 methoxybenzaldehyde of 2- hydroxyl (4.0mmol), the bromo- 1- of 2- (2- chlorphenyl) are sequentially added in 50mL pressure bottle
Ethane (4.8mmol) and L1 (0.2mmol), KOH and toluene (10mL) flow back under the conditions of 110 DEG C in air, react 5h.
After reaction, the solid that will obtain is concentrated under reduced pressure with Rotary Evaporators, uses silica gel column chromatography later, ethyl acetate/just oneself
Alkane is that the in the mixed solvent of 1:8 purifies crude product, obtains 1,3- cyclohexadione compounds C2, yield 76%；By C2
(3.0mmol) and the concentrated sulfuric acid (3.0ml) are dissolved in glacial acetic acid (15.0ml), are stirred to react at 100 DEG C of temperature, reaction terminates
Afterwards, it is down to room temperature to reacting liquid temperature, reaction solution is poured into trash ice, intermediate flavone compound D2 is obtained by filtration, produced
Rate is 60%；D2 (1.5mmol), guanidine hydrochloride (7.5mmol) and potassium hydroxide (0.8g) are dissolved in methanol (25ml), in temperature
It is stirred to react at 65 DEG C, after reaction, reaction solution is poured into the trash ice containing acetic acid, yellow solid is obtained by filtration, through water
It washes, recrystallizing methanol obtains final product E2, yield 61%.
The nuclear magnetic data characterization of compound prepared by embodiment 2 are as follows:
1H NMR(CDCl3,400MHz):δ3.81(s,3H,OCH3),5.24(s,2H,NH2),6.97(s,1H,ArH),
7.0-7.02(m,1H,ArH),7.39-7.42(m,3H,ArH),7.50-7.52(m,1H,ArH),7.60-7.62(m,1H,
ArH),7.83(s,1H,pyri),13.09(br,1H,OH)；MS m/z；328.1(M+1)；Anal.Calcd for
C17H14ClN3O2:C,62.30；H,4.31；N,12.82.Found:C,62.33；4.38；N,12.86.
Embodiment 3
Reaction route:
- 4 methoxybenzaldehyde of 2- hydroxyl (4.0mmol), 2- bromo- 1- (2,4- dichloro are sequentially added in 50mL pressure bottle
Phenyl) ethane (4.8mmol) and L1 (0.2mmol), KOH and toluene (10mL), flow back under the conditions of 110 DEG C, instead in air
Answer 5h.After reaction, the solid that will obtain is concentrated under reduced pressure with Rotary Evaporators, uses silica gel column chromatography later, ethyl acetate/
N-hexane is that the in the mixed solvent of 1:8 purifies crude product, obtains 1,3- cyclohexadione compounds C3, yield 90%；It will
C3 (3.0mmol) and the concentrated sulfuric acid (3.0ml) are dissolved in glacial acetic acid (15.0ml), are stirred to react at 100 DEG C of temperature, reaction terminates
Afterwards, it is down to room temperature to reacting liquid temperature, reaction solution is poured into trash ice, intermediate flavone compound D3 is obtained by filtration, produced
Rate is 71%；D3 (1.5mmol), guanidine hydrochloride (7.5mmol) and potassium hydroxide (0.8g) are dissolved in methanol (25ml), in temperature
It is stirred to react at 65 DEG C, after reaction, reaction solution is poured into the trash ice containing acetic acid, yellow solid is obtained by filtration, through water
It washes, recrystallizing methanol obtains final product E3.Finally obtained target product is weighed and records data.Finally obtain the production of product
Rate is 74%.
The nuclear magnetic data characterization of compound prepared by embodiment 3 are as follows:
1H NMR(CDCl3,400MHz):δ3.84(s,3H,OCH3),5.15(s,2H,NH2),6.48-6.51(m,2H,
ArH),7.33(s,1H,pyri),7.36e7.38(dd,1H,ArH),7.52-7.53(m,1H,ArH),7.56-7.58(d,1H,
ArH),7.67-7.69(dd,1H,ArH),13.19(s,1H,OH)；13C NMR(CDCl3,400MHz):δ55.48,101.89,
105.84,107.69,110.34,127.60,128.66,130.28,131.79,132.94,135.56,136.12,160.05,
163.19,163.90,164.05,165.55；MS m/z；362.1(M+1)；Anal.Calcd for C17H13Cl2N3O2:C,
56.37；H,3.62；N,11.60.Found:C,56.44；H,3.56；N,11.68.
Embodiment 4
Reaction route:
It is same as Example 1, the difference is that substituting the bromo- 1- of 2- (4- methoxy using the bromo- 1- of 2- (3- chlorphenyl) ethane
Base phenyl) ethane, three-step reaction yield is followed successively by 92%, 75% and 77%, nuclear-magnetism and mass spectrometric data and existing consistent.
Embodiment 5
Reaction route:
It is same as Example 1, the difference is that substituting the bromo- 1- of 2- (4- methoxy using the bromo- 1- of 2- (4- fluorophenyl) ethane
Base phenyl) ethane, three-step reaction yield is followed successively by 62%, 55% and 15%, nuclear-magnetism and mass spectrometric data and existing consistent.
Embodiment 6
Reaction route:
It is same as Example 3, the difference is that substituting the bromo- 1- (2,4- of 2- using the bromo- 1- of 2- (3- aminomethyl phenyl) ethane
Dichlorophenyl) ethane, three-step reaction yield is followed successively by 62%, 55% and 15%, nuclear-magnetism and mass spectrometric data and existing consistent.
Embodiment 7
Reaction route:
It is same as Example 3, the difference is that substituting the bromo- 1- of 2- (2,4- bis- using the bromo- 1- of 2- (3- chlorphenyl) ethane
Chlorphenyl) ethane, three-step reaction yield is followed successively by 72%, 65% and 65%, nuclear-magnetism and mass spectrometric data and existing consistent.
Embodiment 8
Reaction route:
It is same as Example 3, the difference is that substituting the bromo- 1- of 2- (2,4- bis- using the bromo- 1- of 2- (4- fluorophenyl) ethane
Chlorphenyl) ethane, three-step reaction yield is followed successively by 70%, 60% and 62%, nuclear-magnetism and mass spectrometric data and existing consistent.
Embodiment 9
Reaction route:
It is same as Example 3, the difference is that using the bromo- 1- of 2- (3- methoxyphenyl) ethane substitution the bromo- 1- of 2- (2,
4- dichlorophenyl) ethane, three-step reaction yield is followed successively by 60%, 65% and 52%, nuclear-magnetism and mass spectrometric data and existing consistent.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
Understand without departing from the principles and spirit of the present invention can to these examples carry out it is a variety of variation, modification, replacement and
Modification, the scope of the present invention is defined by the appended.
Claims (9)
1. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound, which is characterized in that by by flavone compound,
Guanidine hydrochloride and alkali soluble are stirred to react at 65 DEG C of temperature in solvent, after reaction, reaction solution are poured into containing the broken of acetic acid
In ice, yellow solid is obtained by filtration, obtains target product through washing, recrystallizing methanol.
2. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 1, which is characterized in that
The alkali is selected from potassium hydroxide；The solvent is selected from methanol.
3. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 1, which is characterized in that
The flavone compound the preparation method comprises the following steps: by the way that 1,3- cyclohexadione compounds and the concentrated sulfuric acid are dissolved in solvent, in temperature
It is stirred to react at 100 DEG C of degree, after reaction, is down to room temperature to reacting liquid temperature, reaction solution is poured into trash ice, through filtering
To flavone compound.
4. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 3, which is characterized in that
The solvent is selected from glacial acetic acid.
5. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 3, which is characterized in that
The 1,3- cyclohexadione compounds the preparation method comprises the following steps: by will be before salicylaldhyde, 2- bromoacetophenone, N-heterocyclic carbine
Body and alkali soluble are stirred to react at 80 DEG C~130 DEG C of temperature in solvent, after reaction, are concentrated under reduced pressure, are used silica gel column chromatography
Method purifies crude product, obtains 1,3- cyclohexadione compounds.
6. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 5, which is characterized in that
The salicylaldhyde and 2- bromoacetophenone contains different substituents；The salicylaldhyde and 2- bromoacetophenone rubs
You are than being 1:1~1:1.3.
7. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 5, which is characterized in that
The solvent is selected from one of acetonitrile, toluene, DMF, THF or paraxylene kind.
8. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 5, which is characterized in that
The alkali is selected from one of potassium hydroxide, sodium hydroxide, cesium carbonate, triethylamine or pyridine kind；The alkali and o-hydroxy
The molar ratio of formaldehyde is 0.5~1.
9. a kind of synthetic method of 2- aminopyrimidine type antiplatelet compound according to claim 5, which is characterized in that
The aza ring carbene precursor is selected from one of L1~L4 kind, and the aza ring carbene precursor and salicylaldhyde rub
You are than being 0.02~0.2, and preferred molar ratio is 0.02,0.05,0.1 or 0.2, and wherein the structural formula of L1~L4 is as follows:
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| US20030194634A1 (en) * | 2002-03-08 | 2003-10-16 | Tomoki Nagai | Novel anthracene derivative and radiation-sensitive resin composition |
| CN105085433A (en) * | 2014-05-19 | 2015-11-25 | 中国科学院上海药物研究所 | Substituted-amide phenolic compound, preparation method, pharmaceutical composition and application thereof |
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2019
- 2019-08-29 CN CN201910810281.XA patent/CN110423224B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030194634A1 (en) * | 2002-03-08 | 2003-10-16 | Tomoki Nagai | Novel anthracene derivative and radiation-sensitive resin composition |
| CN105085433A (en) * | 2014-05-19 | 2015-11-25 | 中国科学院上海药物研究所 | Substituted-amide phenolic compound, preparation method, pharmaceutical composition and application thereof |
Non-Patent Citations (3)
| Title |
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| MARIEL MARDER，等: "Detection of Benzodiazepine Receptor Ligandsin Small Libraries of Flavone Derivatives Synthesizedby Solution Phase Combinatorial Chemistry", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
| MOHAN PADMANABAN，等: "N-Heterocyclic Carbene-Catalyzed Cross-Coupling of Aromatic Aldehydes with Activated Alkyl Halides", 《ORGANIC LETTERS》 * |
| RAJANI GIRIDHAR，等: "Assessment of antiplatelet activity of 2-aminopyrimidines", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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