CN113583006B - Method for preparing medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative - Google Patents
Method for preparing medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative Download PDFInfo
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the field of pharmaceutical chemicals, and particularly discloses a method for preparing a pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative, which comprises the steps of taking aromatic aldehyde and a 5-amino-4-cyanopyrazole derivative as reaction raw materials, adding a catalyst into an acetonitrile solvent, uniformly mixing, and carrying out heating reflux reaction to obtain the 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative, wherein the catalyst is a nano material containing an alkaline ionic liquid. According to the method for preparing the medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative, the aromatic aldehyde and the 5-amino-4-cyanopyrazole derivative are used as reaction raw materials, the nano material containing the alkaline ionic liquid is selected as the catalyst, and the catalyst is used for catalyzing and preparing the 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative, so that the efficiency and the selectivity are high, the reaction efficiency can be effectively improved, and the generation of byproducts is inhibited.
Description
Technical Field
The invention relates to a preparation method of a medical intermediate, in particular to a method for preparing a medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -ketone derivative, and belongs to the field of pharmaceutical chemicals.
Background
The pyrazolopyrimidine derivative is very similar to purine in structure and has wide biological activity and pharmacological activity as an important nitrogen-containing fused heterocyclic compound. Has antibacterial, antiinflammatory, anticancer, antidiabetic, cardiovascular disease treating, gout treating and antiviral effects. In addition, the literature reports that the compound has good chemotherapeutic effect on cytotoxin, can selectively inhibit phosphodiesterase, and is likely to be developed into cardiotonics, antidepressants and the like. Therefore, the preparation of pyrazolopyrimidine derivatives has attracted a great deal of attention from drug synthesizers.
As one of pyrazolopyrimidine derivatives, there are currently mainly two methods for preparing 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivatives. The first mode is that the o-amino pyrazole amide is used as raw material to carry out acylation and cyclization reaction with acyl chloride, carboxylic ester, carbonyl compound and the like; the second mode is prepared by directly reacting o-amino pyrazole nitrile as a raw material with carboxylic acid. However, both of the above methods have many disadvantages, such as low yield and purity of the product, use of a large amount of volatile organic solvent as the reaction solvent and inability to recycle, complicated purification process of the product, and serious environmental pollution. Based on the above, in order to simplify the reaction path, improve the yield of the product and reduce the pollution to the environment, the Sunzoqi of Beijing technology university and the like can effectively catalyze 5-amino-4-cyanopyrazole derivatives and aromatic aldehyde to prepare a series of 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivatives by a one-pot method by using water as a reaction medium and sodium hydroxide as a catalyst. The method has the advantages of easily obtained raw materials, simple operation, environmental protection and the like (the 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative in an aqueous medium is quickly and efficiently synthesized into [ J ], organic chemistry, DOI: 10.6023/cjoc 202104043).
However, the preparation method still has many disadvantages in the industrial large-scale application process, for example, the catalyst and the reaction solvent cannot be recycled, the production cost is high, and a large amount of waste liquid generated pollutes the environment; the preparation process is relatively complex in operation, long in time consumption and large in energy consumption; the purification of the product needs recrystallization operation, which is time-consuming, labor-consuming, expensive and poor in environmental protection; the utilization rate of reaction raw materials is low, and the atom economy is poor; the reaction solution has strong corrosivity, great damage to production equipment and high replacement frequency of equipment.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for preparing a medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative.
The purpose of the invention can be realized by the following technical scheme:
a method for preparing a medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative comprises the steps of taking aromatic aldehyde and a 5-amino-4-cyanopyrazole derivative as reaction raw materials, adding a catalyst into acetonitrile solvent, uniformly mixing, and carrying out heating reflux reaction to obtain the 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative, wherein the catalyst is a nano material containing alkaline ionic liquid and has a structural formula as follows:
the chemical reaction formula is as follows:
wherein:
is polystyrene;
R1is hydrogen atom, 2-chlorine, 2-methoxy, 2-ethoxy, 4-methyl, 3-methyl, 4-ethyl, 3-bromine, 4-chlorine, 4-bromine, 4-nitro;
R2hydrogen atom and methyl;
R3is methyl or phenyl;
the ratio of the amounts of the aromatic aldehyde and the 5-amino-4-cyanopyrazole derivative is (1-1.2): 1.
optionally, the method comprises the steps of:
the method comprises the following steps: adding acetonitrile into a single-mouth bottle with a magnetic stirrer and a spherical condenser tube, then adding aromatic aldehyde and a 5-amino-4-cyanopyrazole derivative, stirring at room temperature, uniformly mixing, and finally adding a nano-material catalyst;
step two: uniformly heating until the reaction solution flows back, keeping the temperature until the raw material point disappears, stopping magnetic stirring after the reaction is finished, and stopping heating;
step three: immediately realizing the separation of the catalyst and a reaction system by first suction filtration;
step four: cooling the residual reaction liquid with the catalyst separated out to room temperature, grinding the separated solid, standing for 12h, and carrying out secondary suction filtration;
step five: washing the filter residue obtained in the second suction filtration with distilled water for 3 times, and vacuum drying at 85 ℃ for 24H to obtain a 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative;
step six: and (3) putting the catalyst subjected to the first pumping filtration into the filtrate subjected to the second pumping filtration, adding the reaction raw materials of aromatic aldehyde and 5-amino-4-cyanopyrazole derivative, and carrying out the next reaction according to the steps.
Optionally, the nanomaterial catalyst has a mass in grams that is 8 to 12% of the amount of aromatic aldehyde used in millimoles.
Optionally, the volume amount of acetonitrile solvent in milliliters is 6 to 10 times of the molar amount of aromatic aldehyde in millimoles.
Optionally, the aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, o-methoxybenzaldehyde, o-ethoxybenzaldehyde, p-methylbenzaldehyde, m-methylbenzaldehyde, p-ethylbenzaldehyde, m-bromobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde and p-nitrobenzaldehyde.
Alternatively, the 5-amino-4-cyanopyrazole derivative is 1-methyl-5-amino-4-cyanopyrazole or 1-phenyl-3-methyl-5-amino-4-cyanopyrazole.
Optionally, the reflux reaction time in the second step is 73-137 min.
The 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivatives prepared include:
the invention has the beneficial effects that:
(1) according to the method for preparing the medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative, the aromatic aldehyde and the 5-amino-4-cyanopyrazole derivative are used as reaction raw materials, the catalyst is selected from a nano material containing alkaline ionic liquid, and the catalyst is high in efficiency and selectivity for preparing the 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative under catalysis, so that the reaction efficiency can be effectively improved, the generation of byproducts is inhibited, the yield and the purity of the obtained 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative are ensured, and the reaction time is favorably shortened.
(2) According to the method for preparing the medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative, a catalytic system consisting of a nano material catalyst and acetonitrile can be reused without any treatment, so that the utilization rate of reaction raw materials is improved, and economic and environmental benefits are high.
(3) The method for preparing the medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative adopts acetonitrile as a solvent, and optimizes the dosage of a catalyst and a reaction solvent, so that the occurrence of side reactions can be further reduced, and the catalytic activity of the catalyst can be best exerted. Simultaneously, the acetonitrile of this application not only is as reaction solvent, still has the effect of recrystallization solvent concurrently for reaction process and recrystallization purification process unite two into one, make the purification process of product very simple, need not set up the purification process alone.
Drawings
In order to facilitate understanding for those skilled in the art, the present invention will be further described with reference to the accompanying drawings.
FIG. 1 is a table comparing the effect of the number of times the catalytic system was used on product yield and purity in example 1.
FIG. 2 is a table comparing the effect of the number of times the catalytic system was used on product yield and purity in example 10.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1-2, a method for preparing a pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative is provided, in which an aromatic aldehyde and a 5-amino-4-cyanopyrazole derivative are used as reaction raw materials, a catalyst is added into an acetonitrile solvent to be uniformly mixed, and then the mixture is heated and refluxed to obtain the 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative, wherein the catalyst is a nanomaterial containing an alkaline ionic liquid, and has a structural formula:
the chemical reaction formula is as follows:
wherein:
is polystyrene;
R1is hydrogen atom, 2-chlorine, 2-methoxy, 2-ethoxy, 4-methyl, 3-methyl, 4-ethyl, 3-bromine, 4-chlorine, 4-bromine, 4-nitro;
R2hydrogen atom and methyl;
R3is methyl or phenyl;
the ratio of the amounts of the aromatic aldehyde and the 5-amino-4-cyanopyrazole derivative is (1-1.2): 1.
as a technical optimization scheme of the invention, the method comprises the following steps:
the method comprises the following steps: adding acetonitrile into a single-mouth bottle with a magnetic stirrer and a spherical condenser tube, then adding aromatic aldehyde and a 5-amino-4-cyanopyrazole derivative, stirring at room temperature, uniformly mixing, and finally adding a nano-material catalyst;
step two: uniformly heating until the reaction solution flows back, keeping the temperature until the raw material point disappears, stopping magnetic stirring after the reaction is finished, and stopping heating;
step three: immediately realizing the separation of the catalyst and a reaction system through first suction filtration;
step four: cooling the residual reaction liquid with the catalyst separated to room temperature, grinding the precipitated solid, standing for 12h, and performing secondary suction filtration;
step five: washing the filter residue obtained in the second suction filtration with distilled water for 3 times, and vacuum drying at 85 ℃ for 24H to obtain a 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative; the purity of the product can be ensured by using distilled water for washing, and impurities are removed.
Step six: and (3) putting the catalyst subjected to the first pumping filtration into the filtrate subjected to the second pumping filtration, adding the reaction raw materials of aromatic aldehyde and 5-amino-4-cyanopyrazole derivative, and carrying out the next reaction according to the steps. The solvent and the catalyst can be recycled, the residual byproducts in the catalyst are less, and the catalyst can be recycled without adding other impurity removal steps. After 6 times of recycling, the prepared product can still keep higher purity and higher yield.
As a technical optimization scheme of the invention, the mass of the nano material catalyst in grams is 8-12% of the amount of the aromatic aldehyde in millimoles.
As a technical optimization scheme of the invention, the volume of acetonitrile serving as a solvent is 6-10 times of the molar amount of aromatic aldehyde in millimole.
As a technical optimization scheme of the invention, the aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, o-methoxybenzaldehyde, o-ethoxybenzaldehyde, p-methylbenzaldehyde, m-methylbenzaldehyde, p-ethylbenzaldehyde, m-bromobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde and p-nitrobenzaldehyde.
As a technical optimization scheme of the invention, the 5-amino-4-cyanopyrazole derivative is 1-methyl-5-amino-4-cyanopyrazole or 1-phenyl-3-methyl-5-amino-4-cyanopyrazole.
As a technical optimization scheme of the invention, the reflux reaction time in the second step is 73-137 min.
Example 1
Adding 1.0mmol of benzaldehyde and 1.0mmol of 1-methyl-5-amino-4-cyanopyrazole into a 50ml single-neck bottle with a spherical condenser tube and a stirrer, containing 6ml of acetonitrile, stirring at room temperature, uniformly mixing, and adding 0.09g of nano material catalyst. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 81min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.20g of product 6-phenyl-1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one is obtained, the purity is 98.7 percent by high performance liquid chromatography, and the calculated yield is 86 percent. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding benzaldehyde and 1-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product 6-phenyl-1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a white solid; m.p.244-246 ℃; ir (kbr) v: 3196, 1697cm-1；1H NMR(400MHz，DMSO-d6)：δ＝3.95(s，3H)，7.33～7.78(m，3H)，8.04(s，1H)，8.19(d，J＝7.2Hz，2H)，12.32(s，1H)。
Comparative example 1
Adding 1.0mmol of benzaldehyde and 1.0mmol of 1-methyl-5-amino-4-cyanopyrazole into a 50ml single-neck bottle with a spherical condenser tube and a stirrer, containing 6ml of acetonitrile, stirring at room temperature, uniformly mixing, and adding 0.09g of nano material catalyst. Heating in oil bath, uniformly heating to 50 deg.C, maintaining the temperature for 81min, and detecting by TLC (thin plate chromatography) until the raw material point is not completely disappeared. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed for 3 times by distilled water, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.14g of product 6-phenyl-1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone is obtained, the purity is 95.2 percent by high performance liquid chromatography, and the calculated yield is 61 percent.
Comparative example 2
Adding 1.0mmol of benzaldehyde and 1.0mmol of 1-methyl-5-amino-4-cyanopyrazole into a 50ml single-neck bottle with a spherical condenser and a stirrer, containing 6ml of acetonitrile, stirring at room temperature, uniformly mixing, and adding 0.09g of a nano material catalyst. Heating in oil bath, uniformly heating to 70 deg.C, maintaining the temperature for 81min, and detecting by TLC (thin plate chromatography) until the raw material point is not completely disappeared. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed for 3 times by distilled water, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.18g of product 6-phenyl-1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one is obtained, the purity is 96.3 percent by high performance liquid chromatography, and the calculated yield is 75 percent.
Example 2
1.0mmol of benzaldehyde and 1.0mmol of 1-phenyl-3-methyl-5-amino-4-cyanopyrazole are added into a 50ml single-neck flask with a spherical condenser tube and a stirrer, which is filled with 7ml of acetonitrile, stirred at room temperature, mixed uniformly, and then 0.08g of nano material catalyst is added. Heating in oil bath, heating uniformly until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser), maintaining reflux for 76min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃ to obtain 0.28g of product 1, 6-diphenyl-3-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone, the purity is 98.3 percent by high performance liquid chromatography, and the calculated yield is 91 percent. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding benzaldehyde and 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product 1, 6-diphenyl-3-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a white solid; m.p.>300℃；IR(KBr)ν：3071，1678cm-1；1H NMR(400MHz，DMSO-d6)：δ＝2.54(s，3H)，7.32(t，J＝7.6Hz，1H)，7.55(dt，J＝15.4，7.6Hz，5H)，8.12(d，J＝8.0Hz，2H)，8.18(d，J＝7.2Hz，2H)，12.49(s，1H)。
Comparative example 3
1.0mmol of benzaldehyde and 1.0mmol of 1-phenyl-3-methyl-5-amino-4-cyanopyrazole were added to a 50ml single-neck flask with a spherical condenser and a stirrer containing 7ml of acetonitrile, stirred at room temperature, mixed well, and then 0.08g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating to 40 deg.C, maintaining the temperature for 76min, detecting by TLC (thin-plate chromatography), and ending the reaction if the raw material point does not completely disappear. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.17g of product 1, 6-diphenyl-3-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone is obtained, the purity is 94.7 percent by high performance liquid chromatography, and the calculated yield is 52 percent.
Comparative example 4
1.0mmol of benzaldehyde and 1.0mmol of 1-phenyl-3-methyl-5-amino-4-cyanopyrazole are added into a 50ml single-neck flask with a spherical condenser tube and a stirrer, which is filled with 7ml of acetonitrile, stirred at room temperature, mixed uniformly, and then 0.08g of nano material catalyst is added. Heating in oil bath, uniformly heating to 70 deg.C, maintaining the temperature for 76min, detecting by TLC (thin-plate chromatography), and ending the reaction if the raw material point does not completely disappear. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.25g of product 1, 6-diphenyl-3-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone is obtained, the purity is 95.9 percent by high performance liquid chromatography, and the calculated yield is 79 percent.
Example 3
1.2mmol of o-chlorobenzaldehyde and 1.0mmol of 1-methyl-5-amino-4-cyanopyrazole were added to a 50ml single neck flask with a spherical condenser and a stirrer containing 7ml of acetonitrile, stirred at room temperature, mixed well, and then 0.11g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 117min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the first suction filtration is immediately carried out while the solution is hot, a large amount of white solid is separated out after the filtrate is cooled to room temperature, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.19g of the product 6- (2-chlorphenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone is obtained, the purity is 98.7 percent by high performance liquid chromatography, and the calculated yield is 72 percent. And (3) putting the filter residue obtained by the first pumping filtration into the filtrate obtained by the second pumping filtration, adding o-chlorobenzaldehyde and 1-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product 6- (2-chlorophenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a white solid; m.p.>300℃；IR(KBr)ν：2957，1672cm-1；1H NMR(400MHz，DMSO-d6)：δ＝3.94(s，3H)，7.55(td，J＝7.6，1.4Hz，1H)，7.62(td，J＝8.2，1.6Hz，1H)，7.66(dd，J＝8.4，1.7Hz，1H)，7.70(dd，J＝7.7，1.4Hz，1H)，8.15(s，1H)，12.56(s，1H)。
Example 4
1.1mmol of o-chlorobenzaldehyde and 1.0mmol of 1-phenyl-3-methyl-5-amino-4-cyanopyrazole were added to a 50ml single neck flask with a spherical condenser and a stirrer containing 8ml of acetonitrile, stirred at room temperature, mixed well, and then 0.10g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 112min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.27g of the product 6- (2-chlorphenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone is obtained, the purity is 98.4 percent by high performance liquid chromatography, and the calculated yield is 79 percent. And (3) putting the filter residue obtained by the first pumping filtration into the filtrate obtained by the second pumping filtration, adding o-chlorobenzaldehyde and 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product 6- (2-chlorophenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a white solid; m.p.277-279 ℃; ir (kbr) v: 3062, 1685cm-1；1H NMR(400MHz，DMSO-d6)：δ＝2.55(s，3H)，7.31(t，J＝7.6Hz，1H)，7.46～7.52(m，3H)，7.54～7.63(m，2H)，7.65～7.79(m，1H)，8.07(d，J＝8.2Hz，2H)，12.73(s，1H)。
Example 5
To a 50ml single neck flask with a spherical condenser and stirrer containing 9ml acetonitrile were added 1.1mmol of o-ethoxybenzaldehyde and 1.0mmol of 1-methyl-5-amino-4-cyanopyrazole, stirred at room temperature, mixed well, and then 0.10g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 103min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of yellow solid is separated out, the yellow solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.22g of the product 6- (2-ethoxyphenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone is obtained, the purity is 98.9 percent by high performance liquid chromatography, and the calculated yield is 82 percent. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding o-ethoxybenzaldehyde and 1-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product 6- (2-ethoxyphenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a yellow solid; m.p.218-220 ℃; ir (kbr) v: 3319, 1671cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.38(t，J＝7.2H，3H)，3.96(s，3H)，4.20(q，J＝7.2Hz，2H)，7.14(t，J＝7.8Hz，1H)，7.25(d，J＝8.4Hz，1H)，7.41～7.59(m，1H)，7.54～7.63(m，2H)，7.86(dd，J＝7.9，1.8Hz，1H)，8.12(s，1H)，11.93(s，1H)。
Example 6
To a 50ml single neck flask containing 10ml acetonitrile with a spherical condenser and a stirrer were added 1.0mmol of o-ethoxybenzaldehyde and 1.0mmol of 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, stirred at room temperature, mixed well, and then 0.08g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 73min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of yellow solid is separated out, the yellow solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃ to obtain 0.33g of a product 6- (2-ethoxyphenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone, the purity is 98.3 percent by high performance liquid chromatography, and the calculated yield is 93 percent. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding o-ethoxybenzaldehyde and 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product 6- (2-ethoxyphenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a yellow solid; m.p.177-179 ℃; ir (kbr) v: 3272, 1596cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.36(t，J＝7.1H，3H)，2.53(s，3H)，4.15(q，J＝7.1Hz，2H)，7.08(t，J＝7.7Hz，1H)，7.17(d，J＝8.6Hz，1H)，7.31(t，J＝7.6Hz，1H)，7.50(t，J＝8.1Hz，3H)，7.78(dd，J＝7.9，2.0Hz，1H)，8.06(d，J＝8.0Hz，2H)，11.97(s，1H)。
Example 7
To a 50ml single neck flask with a spherical condenser and stirrer containing 9ml acetonitrile were added 1.2mmol of p-tolualdehyde and 1.0mmol of 1-methyl-5-amino-4-cyanopyrazole, stirred at room temperature, mixed well, and then 0.10g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the reflux for 119min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃, 0.18g of the product 6- (4-methylphenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone is obtained, the purity is 98.7 percent by high performance liquid chromatography, and the calculated yield is 73 percent. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding p-tolualdehyde and 1-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and steps.
The characterization data of the product 6- (4-methylphenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a white solid; m.p.285-287 ℃; ir (kbr) v: 3082, 1667cm-1；1H NMR(400MHz，DMSO-d6)：δ＝2.41(s，3H)，3.94(s，3H)，7.30～7.38(m，2H)，8.03(s，1H)，8.05～8.12(m，2H)，12.24(s，1H)。
Example 8
To a 50ml single neck flask with a spherical condenser and stirrer containing 10ml acetonitrile were added 1.0mmol of p-tolualdehyde and 1.0mmol of 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, stirred at room temperature, mixed well, and then 0.09g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 89min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of yellow solid is separated out, the yellow solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at the temperature of 85 ℃ to obtain 0.26g of a product 6- (4-methylphenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidine-4-ketone, the purity is 98.2 percent by high performance liquid chromatography, and the calculated yield is 80 percent. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding p-tolualdehyde and 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product 6- (4-methylphenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a yellow solid; m.p.>300℃；IR(KBr)ν：2973，1687cm-1；1H NMR(400MHz，DMSO-d6)：δ＝2.38(s，3H)，2.53(s，3H)，7.35(d，J＝7.6Hz，3H)，7.54(d，J＝7.9Hz，2H)，8.06(dd，J＝17.0，7.6Hz，4H)，12.39(s，1H)。
Example 9
Adding 1.2mmol of m-bromobenzaldehyde and 1.0mmol of 1-methyl-5-amino-4-cyanopyrazole into a 50ml single-mouth bottle with a spherical condenser and a stirrer, which contains 9ml of acetonitrile, stirring at room temperature, uniformly mixing, and then adding 0.12g of a nano material catalyst. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 137min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are closed, the first suction filtration is immediately carried out while the solution is hot, the filtrate is cooled to room temperature, a large amount of white solid is separated out, the white solid is crushed and stood for 12 hours, the second suction filtration is carried out, the filter residue is washed by distilled water for 3 times, vacuum drying is carried out for 24 hours at 85 ℃ to obtain 0.21g of a product 6- (3-bromophenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one, the purity is 98.5 percent by high performance liquid chromatography, and the calculated yield is 68 percent. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding m-bromobenzaldehyde and 1-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data for the product 6- (3-bromophenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a white solid; m.p.>300℃；IR(KBr)ν：3067，1665cm-1；1H NMR(400MHz，DMSO-d6)：δ＝4.01(s，3H)，7.54(t，J＝8.0Hz，1H)，7.85(dd，J＝8.0，1.8Hz，1H)，8.13(s，1H)，8.20(dd，J＝8.0，1.8Hz，1H)，8.39(t，J＝2.0Hz，1H)，12.48(s，1H)。
Example 10
To a 50ml single neck flask with a spherical condenser and a stirrer containing 10ml acetonitrile were added 1.2mmol of m-bromobenzaldehyde and 1.0mmol of 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, stirred at room temperature, mixed well, and then 0.11g of nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 128min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. And (3) closing heating and stirring, immediately carrying out first suction filtration while the solution is hot, cooling the filtrate to room temperature, separating out a large amount of white solid, grinding, standing for 12 hours, carrying out second suction filtration, washing the filter residue with distilled water for 3 times, carrying out vacuum drying at 85 ℃ for 24 hours to obtain 0.27g of a product 6- (3-bromophenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one, wherein the purity is 98.9% by high performance liquid chromatography, and the calculated yield is 71%. And (3) putting the filter residue obtained by the first suction filtration into the filtrate obtained by the second suction filtration, adding m-bromobenzaldehyde and 1-phenyl-3-methyl-5-amino-4-cyanopyrazole, and carrying out the next reaction according to the conditions and the steps.
The characterization data for the product 6- (3-bromophenyl) -3-methyl-1-phenyl-1, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one obtained in this example are as follows:
a white solid; m.p.>300℃；IR(KBr)ν：3069，1676cm-1；1H NMR(400MHz，DMSO-d6)：δ＝2.53(s，3H)，7.36(t，J＝7.6Hz，1H)，7.51(dt，J＝15.9，8.0Hz，3H)，7.78(d，J＝9.0Hz，1H)，8.04(d，J＝8.0Hz，2H)，8.12(d，J＝8.4Hz，1H)，8.31(s，1H)，12.56(s，1H)。
Example 11
The preparation is carried out by repeatedly using the catalytic systems of the embodiment 1 and the embodiment 10, the influence of the using times of the catalytic system consisting of the acetonitrile solvent and the magnetic nano material in the embodiment 1 and the embodiment 10 on the purity and the yield of the product is respectively examined, the results are respectively shown in figures 1 and 2 in the attached drawings of the specification, and the data in the figures are combined to show that the catalytic system of the invention has high efficiency of preparing the 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative, high yield and purity of the obtained product and good recycling performance.
The hydrogen nuclear magnetic resonance characterization of the reaction product 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative in the above examples adopts a nuclear magnetic resonance instrument with the model of AVANCE II 400MHz of Germany Bruker company; the high performance liquid chromatography is high performance liquid chromatography with model number Waters 2695 of Watts corporation; infrared spectrometry was carried out using an EQUINOX 55 IR spectrometer (KBr pellet) from Bruker, Germany; the melting point of the reaction product was determined by the capillary method. The 5-amino-4-cyanopyrazole derivative is prepared from benzenesulfonylhydrazone and malononitrile, and other reagents or instruments used are not indicated by the manufacturer, and are conventional products commercially available.
The preparation method of the nano material catalyst used in the invention is disclosed in the related documents:
(Polystyrene-supported basic dicationic ionic liquid as a novel，reusable，and efficient heterogeneous catalyst for the one-pot synthesis of chromene derivatives[J]，Research on Chemical Intermediates，2016，42：3829～3846)。
the preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand the invention for and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims (7)
1. A method for preparing a medical intermediate 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative is characterized in that aromatic aldehyde and a 5-amino-4-cyanopyrazole derivative are used as reaction raw materials, a catalyst is added into acetonitrile solvent to be uniformly mixed, and then the mixture is heated and refluxed to react to obtain the 1H-pyrazolo [3, 4-d ] pyrimidine-4 (5H) -ketone derivative, wherein the catalyst is a nano material containing alkaline ionic liquid, and the structural formula of the catalyst is as follows:
the chemical reaction formula is as follows:
wherein:
is polystyrene;
R1is hydrogen atom, 2-chlorine, 2-methoxy, 2-ethoxy, 4-methyl, 3-methyl, 4-ethyl, 3-bromine, 4-chlorine, 4-bromine, 4-nitro;
R2hydrogen atom and methyl;
R3is methyl or phenyl;
the ratio of the amount of the aromatic aldehyde to the amount of the 5-amino-4-cyanopyrazole derivative is (1 to 1.2): 1.
2. a process according to claim 1 for the preparation of the pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative, which comprises the steps of:
the method comprises the following steps: adding acetonitrile into a single-mouth bottle with a magnetic stirrer and a spherical condenser tube, then adding aromatic aldehyde and a 5-amino-4-cyanopyrazole derivative, stirring at room temperature, uniformly mixing, and finally adding a nano-material catalyst;
step two: uniformly heating until the reaction solution flows back, keeping the temperature until the raw material point disappears, stopping magnetic stirring after the reaction is finished, and stopping heating;
step three: the separation of the catalyst and the reaction system is realized through the first suction filtration;
step four: cooling the residual reaction liquid with the catalyst separated out to room temperature, grinding the separated solid, standing for 12h, and carrying out secondary suction filtration;
step five: washing the filter residue obtained in the second suction filtration with distilled water for 3 times, and vacuum drying at 85 ℃ for 24H to obtain a 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative;
step six: and (3) putting the catalyst subjected to the first pumping filtration into the filtrate subjected to the second pumping filtration, adding the reaction raw materials of aromatic aldehyde and 5-amino-4-cyanopyrazole derivative, and carrying out the next reaction according to the steps.
3. The method for preparing a pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative according to claim 2, wherein the mass of the nanomaterial catalyst in grams is 8-12% of the amount of aromatic aldehyde in millimoles.
4. The process for producing a pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative according to claim 2, wherein the volume of acetonitrile as a solvent is 6 to 10 times the molar amount of the aromatic aldehyde in mmol in ml.
5. A process for preparing a pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative according to claim 2, wherein the aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, o-methoxybenzaldehyde, o-ethoxybenzaldehyde, p-methylbenzaldehyde, m-methylbenzaldehyde, p-ethylbenzaldehyde, m-bromobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde and p-nitrobenzaldehyde.
6. The process for producing a pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative according to claim 2, wherein the 5-amino-4-cyanopyrazole derivative is 1-methyl-5-amino-4-cyanopyrazole or 1-phenyl-3-methyl-5-amino-4-cyanopyrazole.
7. The method for preparing a pharmaceutical intermediate 1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one derivative according to claim 2, wherein the reflux reaction time in the second step is 73-137 min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3720674A (en) * | 1970-09-02 | 1973-03-13 | Squibb & Sons Inc | 4-amino-1h-pyrazolo(3,4-d)pyrimidine derivatives |
| CN105037372A (en) * | 2015-07-13 | 2015-11-11 | 北京理工大学 | Synthetic method for pyrazolo[3,4-d]pyrimidine-4-ketone compounds |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3720674A (en) * | 1970-09-02 | 1973-03-13 | Squibb & Sons Inc | 4-amino-1h-pyrazolo(3,4-d)pyrimidine derivatives |
| CN105037372A (en) * | 2015-07-13 | 2015-11-11 | 北京理工大学 | Synthetic method for pyrazolo[3,4-d]pyrimidine-4-ketone compounds |
Non-Patent Citations (4)
| Title |
|---|
| A catalytic method for synthesis of 6-aryl-1H-pyrazolo[3,4-d]pyrimidin-4[5H]-ones by heteropolyacids, H14[NaP5W29MoO110] and H3PMo12O40;Heravi, Majid M.，et al.;《Catalysis Communications》;20071031;第8卷(第10期);1467-1471 * |
| Base-catalyzed one-pot tandem reaction: an effective strategy for the synthesis of pyrazolo[3,4-d]pyrimidinone derivatives;Liu, Ming-xing, et al.;《Tetrahedron》;20151007;第71卷(第40期);7658-7662 * |
| Polystyrene-supported basic dicationic ionic liquid as a novel, reusable, and efficient heterogeneous catalyst for the one-pot synthesis of chromene derivatives in water;Fariba Heidarizadeh & Narges Taheri;《Research on Chemical Intermediates》;20150924;第42卷;3829-3846 * |
| Synthesis and properties of sildenafil isostere;Su, Ziqi, et al.;《Archiv der Pharmazie》;20210615;第354卷(第10期);2100145 * |
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