CN110016036A - Pyrazolo [1,5-a] pyrimidines and its preparation method and application - Google Patents

Pyrazolo [1,5-a] pyrimidines and its preparation method and application Download PDF

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CN110016036A
CN110016036A CN201910405532.6A CN201910405532A CN110016036A CN 110016036 A CN110016036 A CN 110016036A CN 201910405532 A CN201910405532 A CN 201910405532A CN 110016036 A CN110016036 A CN 110016036A
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pyrazolo
pyrimidine
chloro
pyridine derivatives
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CN110016036B (en
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余声
徐亮
王新
王晓芳
刘彬
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Liaoning University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Communicable Diseases (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses pyrazolo [1,5-a] pyridine derivatives and its preparation method and application.Preparation method is to obtain pyrazolo [1,5-a] pyrimidine -5,7- glycol through Michael addition reaction using diester malonate and 3- amino-pyrazol as raw material; with the pure and mild N of pyrazolo [1,5-a] pyrimidine -5,7- bis-; accelerine obtains 5 through Fu Ke-acylation reaction for raw material; 7- bis- chloro- pyrazolo [1,5-a] pyrimidine, with 5; the chloro- pyrazolo [1 of 7- bis-; 5-a] pyrimidine and 1- methyl piperazine or N, N- dimethyl -1,3- propane diamine is Material synthesis CMPS and NCPS.Pyrazolo [1,5-a] pyridine derivatives of the invention are applied to antibacterial field, the dosage of antibiotic can be reduced, promote the reasonable employment of antibiotic, can be relieved abuse of antibiotics bring bacterial drug resistance problem.

Description

Pyrazolo [1,5-a] pyrimidines and its preparation method and application
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of pyrazolo [1,5-a] pyridine derivatives and its preparation Method and the application in terms of inhibiting E. coli Activity.
Background technique
The abuse of antibiotic causes great threat to the mankind, and drug tolerant bacteria is worldwide spread rapidly, To make the mankind avoid the harm by drug-fast bacteria, the research of the novel antibacterials for being not likely to produce drug resistance and antibiotic method is It is extremely urgent.
Pyrazoles and the important activity unit of two class of pyrimidine are existed simultaneously in pyrazolo [1,5-a] pyrimidines molecules, therefore this kind of Compound generally has good bioactivity, has a wide range of applications in fields such as medicine, pesticides.Pyrazolo [1,5-a] is phonetic Acridine compound can be by the change of its 2,3,5,6,7 equal positions substituent group, to change its bioactivity.So having to find The project that pyrazolo [1, the 5-a] pyridine derivatives of more high bioactivity and this field are constantly studied.
Summary of the invention
A kind of new it is an object of the invention to prepare, the pyrazolo [1,5-a] that can significantly inhibit E. coli Activity is phonetic Pyridine analog derivative.
To achieve the goals above, the technical scheme adopted by the invention is that: pyrazolo [1,5-a] pyridine derivatives, With the structural formula as shown in (I),
Wherein, R1ForR2For halogen.
Preferably, pyrazolo [1, the 5-a] pyridine derivatives are R1ForR2For the chloro- 7- of 5- of chlorine (4- thyl-piperazin pyrrolidinyl)-[1,5-a] pyrimidine (CMPS) has the structural formula as shown in (II):
Preferably, pyrazolo [1, the 5-a] pyridine derivatives are R1ForR2For the N '-(5- of chlorine Chloro- pyrazolo [1,5-a] pyrimidine -7- piperazine pyrrolidinyl)-N, N- Dimethyl-propyl -1,3- diamine (NCPS), with such as (III) structural formula shown in:
A kind of preparation method of pyrazolo [1,5-a] pyridine derivatives, includes the following steps:
1) sodium ethoxide is dissolved in EtOH and is stirred, suitable diester malonate and 3- amino-pyrazol is added, by mixture It is heated to reflux at 80 DEG C 18-20 hours, after being cooled to room temperature, sediment is collected by filtration and is washed with EtOH, dissolved after dry Yu Shuizhong is adjusted to pH=2 with HCl, solid is collected by filtration, is washed with water, and obtains pyrazolo [1,5-a] pyrimidine -5,7- glycol.
2) pyrazolo [1,5-a] pyrimidine -5,7- glycol is dissolved in phosphoryl chloride phosphorus oxychloride, n,N-Dimethylaniline is then added, Mixture is heated to reflux 18-20 hours at 80 DEG C, excessive phosphoryl chloride phosphorus oxychloride is removed in a vacuum, residue is poured into cold water And use CH2Cl2Extraction, takes organic phase, is successively washed with water and sodium-chloride water solution, then by organic phase through anhydrous Na2SO4It is dry Dry, vacuum concentration purifies through silica gel column chromatography, obtains compound 5,7- bis- chloro- pyrazolo [1,5-a] pyrimidine.
3) 5,7-, bis- chloro- pyrazolo [1,5-a] pyrimidine and the 2- propanol solution of 1- methyl piperazine are mixed and stirred for, 353K is cooled to room temperature after heating 15 hours；Gained reactant is extracted with ethyl acetate, and takes organic phase, gained organic phase water and Anhydrous Na is used after sodium-chloride water solution washing2SO4Dry, vacuum concentration purifies through silica gel column chromatography, obtains 5- chloro- 7- (4- first Base-piperazine pyrrolidinyl)-[1,5-a] pyrimidine (CMPS)；Preferably, 5,7- bis- chloro- pyrazolo [1,5-a] pyrimidine: 1- methyl piperazine Piperazine=1:2.
4) the 2- propanol solution of bis- chloro- pyrazolo [1,5-a] pyrimidine of 5,7- and N, N- dimethyl -1,3- propane diamine is mixed And stir, it is cooled to room temperature after 353K is heated 15 hours；Gained reactant is extracted with ethyl acetate, and takes organic phase, and gained has Machine uses anhydrous Na after mutually being washed with water and sodium-chloride water solution2SO4Dry, vacuum concentration purifies through silica gel column chromatography, obtains N '- (the chloro- pyrazolo of 5- [1,5-a] pyrimidine -7- piperazine pyrrolidinyl)-N, N- Dimethyl-propyl -1,3- diamine (NCPS).It is preferred that , 5,7- bis- chloro- pyrazolo [1,5-a] pyrimidines: N, N- dimethyl -1,3- propane diamine=1:2.
Application of pyrazolo [1,5-a] pyridine derivatives prepared by the present invention in preparation antibacterials.Preferably, institute Stating antibacterial is antibacterium.It is furthermore preferred that the bacterium is Escherichia coli.
The present invention, first using diester malonate and 3- amino-pyrazol as raw material through Michael addition reaction obtain pyrazolo [1, 5-a] then pyrimidine -5,7- glycol is raw material through Fu with the pure and mild n,N-Dimethylaniline of pyrazolo [1,5-a] pyrimidine -5,7- bis- Gram-acylation reaction obtains 5,7- bis- chloro- pyrazolo [1,5-a] pyrimidine, finally with 5,7-, bis- chloro- pyrazolo [1,5-a] pyrimidine with 1- methyl piperazine or N, N- dimethyl -1,3- propane diamine are Material synthesis CMPS and NCPS.
The beneficial effects of the present invention are: pyrazolo [1,5-a] pyridine derivatives CMPS provided by the invention and NCPS pairs Escherichia coli have certain inhibiting effect, and inhibiting rate is up to 28% and 52%.CMPS and NCPS is applied to antibacterial by the present invention Field promotes the reasonable employment of antibiotic to reduce the dosage of antibiotic, alleviates abuse of antibiotics bring bacterial drug resistance Problem.
Detailed description of the invention
Fig. 1 is inhibition situation of CMPS, NCPS concentration to Escherichia coli Growth.
Specific embodiment
Technical solution of the present invention is described in detail below by specific example.
The chloro- 7- of 1 5- of embodiment (4- thyl-piperazin pyrrolidinyl)-[1,5-a] pyrimidine (CMPS)
Reaction equation is as follows:
The preparation method is as follows:
1, the synthesis of pyrazolo [1,5-a] pyrimidine -5,7- glycol
50mmol sodium ethoxide is dissolved in 100mL EtOH and is stirred, 20mmol diester malonate and 20mmol is then added 3- amino-pyrazol.Mixture is heated to reflux 18-20 hours at 80 DEG C, forms precipitating.After being cooled to room temperature, it is heavy to be collected by filtration Starch is simultaneously washed with EtOH, dry under vacuum.Dried product exhibited is dissolved in 100mL water, acquired solution 12mol/L HCl tune It saves to pH=2.Solid is collected by filtration, is washed with water, obtains pyrazolo [1,5-a] pyrimidine -5,7- glycol.
2, the synthesis of 5,7- bis- chloro- pyrazolo [1,5-a] pyrimidine
10mmol pyrazolo [1,5-a] pyrimidine -5,7- glycol is dissolved in 20mL phosphoryl chloride phosphorus oxychloride, 1.0mL N is then added, Accelerine.Mixture is heated to reflux 18-20 hours at 80 DEG C, it is cooling, excessive phosphoryl chloride phosphorus oxychloride is removed in vacuum, it will be residual Excess pours into cold water and uses CH2Cl2Extraction, takes organic phase, uses anhydrous Na after successively being washed with water and sodium-chloride water solution2SO4 Dry, vacuum concentration is purified by silica gel column chromatography (hexane: ethyl acetate=10:1), obtains compound 5, the chloro- pyrazoles of 7- bis- And [1,5-a] pyrimidine, yield: 36%.
3, the chloro- 7- of 5- (4- thyl-piperazin pyrrolidinyl)-[1,5-a] pyrimidine (CMPS)
Bis- chloro- pyrazolo [1,5-a] pyrimidine of 5.0mmol 5,7- and 50mL are contained to the 2- third of 10mmol 1- methyl piperazine Alcoholic solution is mixed and stirred for, and 353K is cooled to room temperature after heating 15 hours；Gained reactant is extracted with ethyl acetate, and takes organic Phase, gained organic phase water and sodium-chloride water solution use anhydrous Na after washing2SO4Dry, vacuum concentration passes through silica gel column chromatography Method (hexane: ethyl acetate=10:1) purifying, obtains compound CMPS.
CMPS has the property that yellow powder, yield: 67%, fusing point: 114-116 DEG C.
Embodiment 2N '-(the chloro- pyrazolo of 5- [1,5-a] pyrimidine -7- piperazine pyrrolidinyl)-N, Dimethyl-propyl -1 N-, 3- diamine (NCPS)
Reaction equation is as follows:
The preparation method is as follows:
1, the synthesis of pyrazolo [1,5-a] pyrimidine -5,7- glycol
With embodiment 1
2, the synthesis of 5,7- bis- chloro- pyrazolo [1,5-a] pyrimidine
With embodiment 1
3, N '-(the chloro- pyrazolo of 5- [1,5-a] pyrimidine -7- piperazine pyrrolidinyl)-N, N- Dimethyl-propyl -1,3- binary Amine (NCPS)
Bis- chloro- pyrazolo [1,5-a] pyrimidine of 5.0mmol 5,7- and 50mL are contained into 10mmol N, N- dimethyl -1,3- The 2- propanol solution of propane diamine is mixed and stirred for, and 353K is cooled to room temperature after heating 15 hours；Gained reactant ethyl acetate Extraction, uses anhydrous Na after taking organic phase, gained organic phase water and sodium-chloride water solution to wash2SO4Dry, vacuum concentration passes through Silica gel column chromatography (hexane: ethyl acetate=10:1) purifying, obtains compound N CPS.
NCPS has the property that yellow powder, yield: 58%, fusing point: 91-93 DEG C.
3 compound concentration of embodiment inhibits the influence of Escherichia coli effect to it
7 5mL are taken to connect lid centrifuge tube, packet is tightened with cotton cord again with brown paper.9 empty conical flasks are taken, are sealed respectively with tampon Good bottleneck, brown paper are tightened with cotton thread again after wrapping up.Physiological saline 150mL is taken, loaded in 250mL conical flask, takes a 10mL The effective brown paper of liquid relief wrap.It will be stand-by after 121 DEG C of high pressure steam sterilization 15min of the above article.
Escherichia coli bacteria liquid concentration used is 1 × 107cfu/mL。
CMPS is dissolved in physiological saline, the CMPS solution that preparation concentration is 3.97 μm of ol/L.
NCPS is dissolved in physiological saline, the NCPS solution that preparation concentration is 3.94 μm of ol/L.
Method: it after super-clean bench ultraviolet sterilization 30min, is tested around the alcolhol burner lighted.It, will be under aseptic condition It after heart pipe marks, is loaded by table 1 into centrifuge tube, then pipettes the physiological saline that 9.9mL sterilization treatment is crossed with pipette and set In in sterilized conical flask, 100 μ L are then taken from each group solution respectively, are placed in the conical flask equipped with 9.9mL physiological saline It is interior, it shakes up, then take the 100 μ L of solution after dilution in solid culture primary surface respectively, is smoothened, marked again with glass rake It moves into 37 DEG C of incubators and is inverted culture 18h, carry out bacterium colony counting later and calculate bacteriostasis rate, as a result as shown in Figure 1.
1 compound concentration of table inhibits the sample packing table of the influence experiment of Escherichia coli effect to it
As shown in Figure 1.CMPS and NCPS have been investigated to the inhibition situation of Escherichia coli, can have been obtained by Fig. 1, the two is to large intestine bar Bacterium has certain inhibiting effect, and situation is inhibited to have concentration dependent, and bacteriostasis rate has with concentration to be positively correlated.It is in concentration When 0.3mmol/L, it is 52% to the inhibiting rate of Escherichia coli that CMPS, which is 28%, NCPS to the inhibiting rate of Escherichia coli, compare and Speech, NCPS are stronger to Escherichia coli inhibiting effect.

Claims (8)

  1. Pyrazolo 1. [1,5-a] pyridine derivatives, which is characterized in that pyrazolo [1, the 5-a] pyridine derivatives have The structural formula as shown in (I),
    Wherein, R1ForR2For halogen.
  2. 2. pyrazolo [1,5-a] pyridine derivatives according to claim 1, which is characterized in that the pyrazolo [1,5- A] pyridine derivatives are R1ForR2It is phonetic for the chloro- 7- of 5- (4- thyl-piperazin pyrrolidinyl)-[1,5-a] of chlorine Pyridine (CMPS).
  3. 3. pyrazolo [1,5-a] pyridine derivatives according to claim 1, which is characterized in that the pyrazolo [1,5- A] pyridine derivatives are R1ForR2For N '-(the chloro- pyrazolo of 5- [1,5-a] pyrimidine -7- piperazine pyrroles of chlorine Alkyl)-N, N- Dimethyl-propyl -1,3- diamine (NCPS).
  4. 4. a kind of preparation method of pyrazolo [1,5-a] pyridine derivatives, which comprises the steps of:
    1) sodium ethoxide is dissolved in EtOH and is stirred, suitable diester malonate and 3- amino-pyrazol is added, by mixture 80 It is heated to reflux at DEG C 18-20 hours, after being cooled to room temperature, sediment is collected by filtration and is washed with EtOH, be dissolved in water after dry In, it is adjusted to pH=2 with HCl, solid is collected by filtration, is washed with water, pyrazolo [1,5-a] pyrimidine -5,7- glycol is obtained；
    2) pyrazolo [1,5-a] pyrimidine -5,7- glycol is dissolved in phosphoryl chloride phosphorus oxychloride, n,N-Dimethylaniline is then added, will mixed It closes object to be heated to reflux at 80 DEG C 18-20 hours, removes excessive phosphoryl chloride phosphorus oxychloride in a vacuum, residue is poured into cold water and is used in combination CH2Cl2Extraction, takes organic phase, is successively washed with water and sodium-chloride water solution, then by organic phase through anhydrous Na2SO4It is dry, very Sky concentration, purifies through silica gel column chromatography, obtains compound 5,7- bis- chloro- pyrazolo [1,5-a] pyrimidine；
    3) 5,7-, bis- chloro- pyrazolo [1,5-a] pyrimidine and the 2- propanol solution of 1- methyl piperazine are mixed and stirred for, in 353K plus Heat is cooled to room temperature after 15 hours；The extraction of gained reactant ethyl acetate, takes organic phase, gained organic phase water and sodium chloride water Anhydrous Na is used after solution washing2SO4Dry, vacuum concentration purifies through silica gel column chromatography, obtains the chloro- 7- of 5- (4- thyl-piperazin pyrrole Cough up alkyl)-[1,5-a] pyrimidine (CMPS)；
    4) the 2- propanol solution of bis- chloro- pyrazolo [1,5-a] pyrimidine of 5,7- and N, N- dimethyl -1,3- propane diamine is mixed and is stirred It mixes, is cooled to room temperature after 353K is heated 15 hours；Gained reactant is extracted with ethyl acetate, and takes organic phase, gained organic phase Anhydrous Na is used after being washed with water and sodium-chloride water solution2SO4Dry, vacuum concentration purifies through silica gel column chromatography, obtains N '-(5- Chloro- pyrazolo [1,5-a] pyrimidine -7- piperazine pyrrolidinyl)-N, N- Dimethyl-propyl -1,3- diamine (NCPS).
  5. 5. the preparation method according to claim 4, which is characterized in that in molar ratio, 5,7- bis- chloro- pyrazolos [1,5-a] Pyrimidine: 1- methyl piperazine=1:2；5,7- bis- chloro- pyrazolo [1,5-a] pyrimidine: N, N- dimethyl -1,3- propane diamine=1:2.
  6. 6. application of pyrazolo [1,5-a] pyridine derivatives described in claim 1,2 or 3 in preparation antibacterials.
  7. 7. application according to claim 6, which is characterized in that the antibacterial is antibacterium.
  8. 8. application according to claim 7, which is characterized in that the bacterium is Escherichia coli.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671709A (en) * 2002-05-29 2005-09-21 拜尔农作物科学股份公司 Pyrazolopyrimidines and the use thereof for controlling harmful organisms
CN1839136A (en) * 2003-06-27 2006-09-27 拜尔农作物科学股份公司 Pyrazolopyrimidines
US20080021045A1 (en) * 2003-12-10 2008-01-24 Bayer Cropscience Aktiengesellschsft 7-Amino-5-Halopyrazolopyrimidines with a Fungicidal Action
WO2017210678A1 (en) * 2016-06-03 2017-12-07 An2H Discovery Limited Pyrazolopyrimidine derivatives and the compositions and methods of treatment regarding the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671709A (en) * 2002-05-29 2005-09-21 拜尔农作物科学股份公司 Pyrazolopyrimidines and the use thereof for controlling harmful organisms
CN1839136A (en) * 2003-06-27 2006-09-27 拜尔农作物科学股份公司 Pyrazolopyrimidines
US20080021045A1 (en) * 2003-12-10 2008-01-24 Bayer Cropscience Aktiengesellschsft 7-Amino-5-Halopyrazolopyrimidines with a Fungicidal Action
WO2017210678A1 (en) * 2016-06-03 2017-12-07 An2H Discovery Limited Pyrazolopyrimidine derivatives and the compositions and methods of treatment regarding the same

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Title
THOMAS NOVINSON ET AL.: "Synthesis and antifungal properties of certain 7-alkylaminopyrazolo[1,5-a]pyrimidines", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
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