CN110016036B - Pyrazolo [1,5-a ] pyrimidine compound and preparation method and application thereof - Google Patents
Pyrazolo [1,5-a ] pyrimidine compound and preparation method and application thereof Download PDFInfo
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- CN110016036B CN110016036B CN201910405532.6A CN201910405532A CN110016036B CN 110016036 B CN110016036 B CN 110016036B CN 201910405532 A CN201910405532 A CN 201910405532A CN 110016036 B CN110016036 B CN 110016036B
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Abstract
The invention discloses pyrazolo [1,5-a ] pyrimidine derivatives, and a preparation method and application thereof. The preparation method comprises the steps of carrying out Michael addition reaction on malonic diester and 3-aminopyrazole serving as raw materials to obtain pyrazolo [1,5-a ] pyrimidine-5, 7-diol, carrying out Friedel-crafts acylation reaction on pyrazolo [1,5-a ] pyrimidine-5, 7-diol and N, N-dimethylaniline serving as raw materials to obtain 5, 7-dichloro-pyrazolo [1,5-a ] pyrimidine, and synthesizing CMPS and NCPS by taking 5, 7-dichloro-pyrazolo [1,5-a ] pyrimidine and 1-methylpiperazine or N, N-dimethyl-1, 3-propanediamine as raw materials. The pyrazolo [1,5-a ] pyrimidine derivative is applied to the antibacterial field, so that the dosage of antibiotics can be reduced, the reasonable use of the antibiotics is promoted, and the problem of bacterial drug resistance caused by abuse of the antibiotics can be relieved.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pyrazolo [1,5-a ] pyrimidine derivative, a preparation method thereof and application thereof in inhibiting activity of escherichia coli.
Background
The abuse of antibiotics has caused a great threat to human beings, drug-resistant bacteria spread rapidly worldwide, and in order to protect human beings from the harm of drug-resistant bacteria, the research on novel antibacterial drugs and antibacterial methods which are not easy to generate drug resistance has been urgent.
Two important active units of pyrazole and pyrimidine simultaneously exist in a pyrazolo [1,5-a ] pyrimidine molecule, so the compound generally has good biological activity and is widely applied to the fields of medicines, pesticides and the like. Pyrazolo [1,5-a ] pyrimidine compounds may have altered biological activity by altering substituents at their 2,3,5,6,7, etc. positions. Therefore, it is also a subject of continuous research in the art to find pyrazolo [1,5-a ] pyrimidine derivatives having higher biological activity.
Disclosure of Invention
The invention aims to prepare a novel pyrazolo [1,5-a ] pyrimidine derivative which can obviously inhibit the activity of escherichia coli.
In order to achieve the purpose, the invention adopts the technical scheme that: pyrazolo [1,5-a ] pyrimidine derivative has a structural formula shown as (I),
wherein R is1Is composed of
R2Is halogen.
Preferably, said pyrazolo [1,5-a ] is]The pyrimidine derivative being R1Is composed of
R25-chloro-7- (4-methylpiperazin-1-yl) -pyrazolo [1,5-a ] as chlorine]A pyrimidine (CMPS) having the formula shown in (ii):
preferably, the pyrazolo [1,5-a ] is]The pyrimidine derivative being R1Is composed of
R2N being chlorine1- (5-chloro-pyrazolo [1, 5-a)]Pyrimidin-7-yl) -N3,N3-dimethyl-1, 3-propanediamine (NCPS) having the formula (iii):
a preparation method of pyrazolo [1,5-a ] pyrimidine derivatives comprises the following steps:
1) dissolving sodium ethoxide in EtOH and stirring, adding a proper amount of malonic diester and 3-aminopyrazole, heating and refluxing the mixture at 80 ℃ for 18-20 hours, cooling to room temperature, filtering, collecting precipitate, washing with EtOH, drying, dissolving in water, adjusting pH to 2 with HCl, filtering, collecting solid, and washing with water to obtain pyrazolo [1,5-a ] pyrimidine-5, 7-diol.
2) Pyrazolo [1, 5-a)]Dissolving pyrimidine-5, 7-diol in phosphoryl chloride, adding N, N-dimethylaniline, heating the mixture at 80 deg.C under reflux for 18-20 hr, removing excess phosphoryl chloride in vacuo, pouring the residue into cold water and adding CH2Cl2Extracting, collecting organic phase, sequentially washing with water and sodium chloride water solution, and passing the organic phase over anhydrous Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography to obtain compound 5, 7-dichloro-pyrazolo [1,5-a]A pyrimidine.
3) Reacting 5, 7-dichloro-pyrazolo [1,5-a ]]Mixing pyrimidine and a 2-propanol solution of 1-methylpiperazine, stirring, heating at 353K for 15 hours, and cooling to room temperature; extracting the obtained reaction product with ethyl acetate, collecting organic phase, washing the organic phase with water and sodium chloride aqueous solution, and adding anhydrous Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography to obtain 5-chloro-7- (4-methylpiperazin-1-yl) -pyrazolo [1,5-a]Pyrimidine (CMPS); preferred, 5, 7-dichloro-pyrazolo [1,5-a ]]Pyrimidine: 1-methylpiperazine ═ 1: 2.
4) Reacting 5, 7-dichloro-pyrazolo [1,5-a ]]Mixing pyrimidine and N, N-dimethyl-1, 3-propane diamine in 2-propanol, stirring, heating at 353K for 15 hr, and cooling to room temperature; extracting the obtained reaction product with ethyl acetate, collecting organic phase, washing the organic phase with water and sodium chloride aqueous solution, and adding anhydrous Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography to obtain N1- (5-chloro-pyrazolo [1,5-a ]]Pyrimidin-7-yl) -N3,N3-dimethyl-1, 3-propanediamine (NCPS). Preferred, 5, 7-dichloro-pyrazolo [1,5-a ]]Pyrimidine N, N-dimethyl-1, 3-propanediamine ═ 1: 2.
The pyrazolo [1,5-a ] pyrimidine derivative prepared by the invention is applied to the preparation of antibacterial drugs. Preferably, the antibiotic is antibacterial. More preferably, the bacterium is Escherichia coli.
The preparation method comprises the steps of firstly, taking malonic diester and 3-aminopyrazole as raw materials, carrying out Michael addition reaction to obtain pyrazolo [1,5-a ] pyrimidine-5, 7-diol, then taking pyrazolo [1,5-a ] pyrimidine-5, 7-diol and N, N-dimethylaniline as raw materials, carrying out Friedel-crafts acylation reaction to obtain 5, 7-dichloro-pyrazolo [1,5-a ] pyrimidine, and finally taking 5, 7-dichloro-pyrazolo [1,5-a ] pyrimidine and 1-methylpiperazine or N, N-dimethyl-1, 3-propanediamine as raw materials to synthesize CMPS and NCPS.
The invention has the beneficial effects that: the pyrazolo [1,5-a ] pyrimidine derivatives CMPS and NCPS provided by the invention both have certain inhibition effect on escherichia coli, and the inhibition rate can reach 28% and 52%. The invention applies CMPS and NCPS to the antibacterial field, thereby reducing the dosage of antibiotics, promoting the reasonable use of the antibiotics and relieving the problem of bacterial drug resistance caused by the abuse of the antibiotics.
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FIG. 1 shows the growth inhibition of Escherichia coli by CMPS and NCPS concentrations.
Detailed Description
The technical solution of the present invention is explained in detail by specific examples below.
Example 15-chloro-7- (4-methylpiperazin-1-yl) -pyrazolo [1,5-a ] pyrimidine (CMPS)
The reaction formula is as follows:
the preparation method comprises the following steps:
1. synthesis of pyrazolo [1,5-a ] pyrimidine-5, 7-diol
50mmol of sodium ethoxide are dissolved in 100mL of EtOH and stirred, and then 20mmol of malonic diester and 20mmol of 3-aminopyrazole are added. The mixture was heated to reflux at 80 ℃ for 18-20 hours to form a precipitate. After cooling to room temperature, the precipitate was collected by filtration and washed with EtOH and dried under vacuum. After drying, the product was dissolved in 100mL of water and the resulting solution was adjusted to pH 2 with 12mol/L HCl. The solid is collected by filtration and washed with water to obtain pyrazolo [1,5-a ] pyrimidine-5, 7-diol.
2. Synthesis of 5, 7-dichloro-pyrazolo [1,5-a ] pyrimidines
10mmol of pyrazolo [1,5-a ]]Pyrimidine-5, 7-diol was dissolved in 20mL of phosphorus oxychloride, followed by the addition of 1.0mL of N, N-dimethylaniline. The mixture is heated to reflux at 80 ℃ for 18-20 hours, cooled, excess phosphorus oxychloride removed in vacuo, the residue poured into cold water and washed with CH2Cl2Extracting, collecting organic phase, washing with water and sodium chloride aqueous solution in sequence, and adding anhydrous Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography (hexane: ethyl acetate 10: 1) to obtain 5, 7-dichloro-pyrazolo [1,5-a ] compound]Pyrimidine, yield: 36 percent.
3. 5-chloro-7- (4-methylpiperazin-1-yl) -pyrazolo [1,5-a ] pyrimidine (CMPS)
5.0mmol of 5, 7-dichloro-pyrazolo [1,5-a ]]Mixing pyrimidine with 50mL of 2-propanol solution containing 10mmol of 1-methylpiperazine, stirring, heating at 353K for 15 hours, and cooling to room temperature; extracting the obtained reaction product with ethyl acetate, collecting organic phase, washing the organic phase with water and sodium chloride aqueous solution, and adding anhydrous Na2SO4Drying, vacuum concentration, and purification by silica gel column chromatography (hexane: ethyl acetate 10: 1) gave compound CMPS.
CMPS has the following properties: yellow powder, yield: 67%, melting point: 114 ℃ and 116 ℃.
Example 2N1- (5-chloro-pyrazolo [1, 5-a)]Pyrimidin-7-yl) -N3,N3-dimethyl-1, 3-propanediamine (NCPS)
The reaction formula is as follows:
the preparation method comprises the following steps:
1. synthesis of pyrazolo [1,5-a ] pyrimidine-5, 7-diol
Same as example 1
2. Synthesis of 5, 7-dichloro-pyrazolo [1,5-a ] pyrimidines
Same as example 1
3、N1- (5-chloro-pyrazolo [1, 5-a)]Pyrimidin-7-yl) -N3,N3-dimethyl-1, 3-propanediamine (NCPS)
5.0mmol of 5, 7-dichloro-pyrazolo [1,5-a ]]Pyrimidine and 50mL of 2-propanol solution containing 10mmol of N, N-dimethyl-1, 3-propane diamine are mixed and stirred, heated for 15 hours at 353K and then cooled to room temperature; extracting the obtained reaction product with ethyl acetate, collecting organic phase, washing the organic phase with water and sodium chloride aqueous solution, and adding anhydrous Na2SO4Drying, vacuum concentration, and purification by silica gel column chromatography (hexane: ethyl acetate 10: 1) gave the compound NCPS.
NCPS has the following properties: yellow powder, yield: 58%, melting point: 91-93 ℃.
EXAMPLE 3 Effect of Compound concentration on its Escherichia coli-inhibiting Effect
7 pieces of 5mL centrifuge tubes with covers are taken, wrapped with kraft paper and then tied up with cotton ropes. Taking 9 hollow conical bottles, sealing the bottle openings with cotton plugs respectively, and tightening with cotton threads after kraft paper is wrapped. 150mL of physiological saline was taken and placed in a 250mL conical flask, and a 10mL pipette was wrapped with Kraft paper. Sterilizing the above materials with high pressure steam at 121 deg.C for 15 min.
The concentration of the Escherichia coli liquid is 1 × 107cfu/mL。
CMPS was dissolved in physiological saline to prepare a CMPS solution having a concentration of 3.97. mu. mol/L.
NCPS was dissolved in physiological saline to prepare a NCPS solution having a concentration of 3.94. mu. mol/L.
The method comprises the following steps: after 30min of superclean uv sterilization, experiments were performed around the lit alcohol lamps. Under aseptic conditions, labeling a centrifuge tube, adding samples into the centrifuge tube according to table 1, transferring 9.9mL of sterilized normal saline into a sterilized conical flask by using a pipette, then respectively taking 100 mu L of each group of solution, placing the solution into the conical flask filled with 9.9mL of normal saline, shaking up, respectively taking 100 mu L of diluted solution onto the surface of a solid culture medium, uniformly coating the solution with a glass rake, labeling, transferring the solution into a 37 ℃ incubator, inversely culturing for 18h, then counting colonies and calculating the bacteriostasis rate, wherein the result is shown in fig. 1.
TABLE 1 sample dispensing table for experiment of influence of concentration of compound on inhibition effect of Escherichia coli
As shown in fig. 1. The inhibition conditions of CMPS and NCPS on the escherichia coli are examined, and the inhibition conditions can be obtained from figure 1, wherein the CMPS and the NCPS have certain inhibition effects on the escherichia coli, the inhibition conditions have concentration dependence, and the bacteriostasis rate and the concentration have positive correlation. At a concentration of 0.3mmol/L, the inhibition rate of CMPS to Escherichia coli is 28%, and the inhibition rate of NCPS to Escherichia coli is 52%, compared with that the inhibition effect of NCPS to Escherichia coli is stronger.
Claims (1)
1. Pyrazolo [1,5-a]The application of the pyrimidine derivatives in preparing anti-Escherichia coli medicines is characterized in that the pyrazolo [1,5-a ] is]The pyrimidine derivative being N1- (5-chloro-pyrazolo [1, 5-a)]Pyrimidin-7-yl) -N3,N3-dimethyl-1, 3-propanediamine NCPS having the formula (iii):
the preparation method of the NCPS comprises the following steps:
1) 50mmol of sodium ethoxide are dissolved in 100mL of EtOH and stirred, and then 20mmol of malonic diester and 20mmol of 3-aminopyrazole are added; heating and refluxing the mixture at 80 deg.C for 18-20 hr to form precipitate; after cooling to room temperature, the precipitate was collected by filtration and washed with EtOH and dried under vacuum; after drying the product was dissolved in 100mL of water and the resulting solution was adjusted to pH =2 with 12mol/L HCl; filtering and collecting solid, washing with water to obtain pyrazolo [1,5-a ] pyrimidine-5, 7-diol;
2) 10mmol of pyridineAzolo [1,5-a ]]Dissolving pyrimidine-5, 7-diol in 20mL of phosphorus oxychloride, and then adding 1.0mL of N, N-dimethylaniline; the mixture is heated to reflux at 80 ℃ for 18-20 hours, cooled, excess phosphorus oxychloride removed in vacuo, the residue poured into cold water and washed with CH2Cl2Extracting, collecting organic phase, washing with water and sodium chloride aqueous solution in sequence, and adding anhydrous Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography to obtain compound 5, 7-dichloro-pyrazolo [1,5-a]A pyrimidine;
3) 5.0mmol of 5, 7-dichloro-pyrazolo [1,5-a ]]Pyrimidine and 50mL of 2-propanol solution containing 10mmol of N, N-dimethyl-1, 3-propane diamine are mixed and stirred, heated for 15 hours at 353K and then cooled to room temperature; extracting the obtained reaction product with ethyl acetate, collecting organic phase, washing the organic phase with water and sodium chloride aqueous solution, and adding anhydrous Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography to obtain compound NCPS.
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Citations (4)
| 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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Patent Citations (4)
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and antifungal properties of certain 7-alkylaminopyrazolo[1,5-a]pyrimidines;Thomas Novinson et al.;《Journal of Medicinal Chemistry》;19771231;第20卷(第2期);第296-299页 * |
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