CN113773327B - Preparation method of pyrazolopyrimidinyltriazole ring compound - Google Patents
Preparation method of pyrazolopyrimidinyltriazole ring compound Download PDFInfo
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- CN113773327B CN113773327B CN202111067102.1A CN202111067102A CN113773327B CN 113773327 B CN113773327 B CN 113773327B CN 202111067102 A CN202111067102 A CN 202111067102A CN 113773327 B CN113773327 B CN 113773327B
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- 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
- C07D487/12—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 three hetero rings
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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
Abstract
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of a pyrazolopyrimidinyltriazole ring compound. The invention provides a preparation method of a pyrazolopyrimidinyltriazole ring compound, which comprises the following steps: mixing 2-amino-4, 6-dichloropyrimidine-5-formaldehyde with a hydrazine compound for condensation reaction to obtain pyrimidopyrazole; mixing the pyrimidopyrazole and the acylhydrazine for substitution reaction to obtain 4-hydrazide pyrimidopyrazole; and mixing the 4-hydrazidyl pyrimido-pyrazole and a condensing agent for condensation rearrangement reaction to obtain the pyrazolopyrimidino-triazole cyclic compound. The preparation method provided by the invention has the advantages of short synthetic route, easy operation and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of a pyrazolopyrimidinyltriazole ring compound.
Background
In recent years, the incidence and the fatality rate of central nervous system diseases are on the rise, the life quality of patients is seriously influenced, and great burden is brought to the patients and the society. Adenosine is of the formula C10H13N5O4Present in every cell, it regulates a wide range of physiological functions by interacting with specific cell surface receptors, which are classified as a1, a2A、A2BAnd A3The adenosine receptor subtype. Wherein A is2AThe receptor plays an important role in treating central nervous system diseases such as Alzheimer disease, Parkinson disease, Huntington disease and the like, including the regulation of glial inflammatory response, neuronal plasticity, barrier permeability and the like, so that high-selectivity A is developed2AOf importance are receptor antagonists, of which the pyrazolopyrimidinotriazole ring is the more widely used A2AA receptor antagonist.
The existing pathway for the synthesis of pyrazolopyrimidotriazole rings is as follows (Pier Giovanni Baraldi et al, Pyrazolo [4,3-e ] -1,2,4-triazolo [1,5-c ] pyrimidine Derivatives: Power and Selective A2A Adenosine inhibitors, J.Med.chem.1996,39, 1164-Amphio 1171):
in the synthesis of N1On the basis of-alkyl-4-cyano-5-aminopyrazole 9, amino and triethyl orthoformate are condensed to obtain ethoxyimine 12, the ethoxyimine and furoyl hydrazine 13 are condensed to form a ring to obtain 14, a dihydropyrimidine ring in the 14 is hydrolyzed and returns to an aminopyrazole ring to obtain 15, and finally triazole N in the 15 attacks cyanamide to further perform intramolecular condensation ring formation with the pyrazole ring to obtain a product 6.
The existing preparation steps for synthesizing the pyrazolopyrimidintriazole ring are complicated and are not easy to realize industrial production.
Disclosure of Invention
In view of the above, the present invention provides a preparation method of pyrazolopyrimidinyltriazole ring compounds. The preparation method provided by the invention has simple steps and is easy for industrial production.
In order to solve the technical problems, the invention provides a preparation method of pyrazolopyrimidinyltriazole ring compounds, which comprises the following steps:
mixing 2-amino-4, 6-dichloropyrimidine-5-formaldehyde and a hydrazine compound with a structure shown in a formula I for condensation reaction to obtain pyrimidine pyrazole with a structure shown in a formula II;
mixing the pyrimidine pyrazole with the structure shown in the formula II with acyl hydrazine with the structure shown in the formula III for substitution reaction to obtain 4-hydrazide pyrimidine pyrazole with the structure shown in the formula IV;
mixing the 4-hydrazidyl pyrimidine pyrazole with the structure shown in the formula IV with a condensing agent for condensation rearrangement reaction to obtain a pyrazolopyrimidino-triazole ring compound with the structure shown in the formula V;
R1-NHNH2the compound of the formula I is shown in the specification,
in the formulae I to V, R1Is butyl, isoamyl, phenethyl, methylOr phenyl, R2Is furyl, phenyl or pyridyl.
Preferably, the molar ratio of the 2-amino-4, 6-dichloropyrimidine-5-formaldehyde to the hydrazine compound with the structure shown in the formula I is 1 (1-3).
Preferably, the time of the condensation reaction is 12-24 h.
Preferably, the molar ratio of the pyrimidine pyrazole with the structure shown in the formula II to the acyl hydrazine with the structure shown in the formula III is 1 (1-5).
Preferably, the temperature of the substitution reaction is 60-100 ℃, and the time is 12-20 h.
Preferably, the dosage ratio of the 4-hydrazinopyrimidine pyrazole with the structure shown in the formula IV to the condensing agent is 1g (5-15) mL.
Preferably, the temperature of the condensation rearrangement reaction is 80-140 ℃ and the time is 8-24 h.
Preferably, the condensing agent comprises N, N-carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate or O-benzotriazol-tetramethyluronium hexafluorophosphate.
Preferably, in said formulae I to V, R1Is butyl, isopentyl or phenethyl, R2Is furyl, pyridyl or phenyl.
Preferably, the hydrazine compound with the structure shown in the formula I is prepared by performing substitution reaction on hydrazine hydrate and halogenated hydrocarbon.
The invention provides a preparation method of a pyrazolopyrimidinyltriazole ring compound, which comprises the following steps: mixing 2-amino-4, 6-dichloropyrimidine-5-formaldehyde and a hydrazine compound with a structure shown in a formula I for condensation reaction to obtain pyrimidine pyrazole with a structure shown in a formula II; mixing the pyrimidine pyrazole with the structure shown in the formula II and the acyl hydrazine with the structure shown in the formula III for substitution reaction to obtain 4-hydrazide pyrimidine pyrazole with the structure shown in the formula IV; and (2) mixing the 4-hydrazinopyrimidine pyrazole with the structure shown in the formula IV with a condensing agent to perform condensation rearrangement reaction to obtain the pyrazolopyrimidinyltriazole ring compound with the structure shown in the formula V. The preparation method provided by the invention has the advantages of short synthetic route, easiness in operation and suitability for industrial production.
Drawings
FIG. 1 is a NMR spectrum of 5-amino-2-furyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine prepared in example 1;
FIG. 2 is a NMR carbon spectrum of 5-amino-2-furyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine prepared in example 1.
Detailed Description
The invention provides a preparation method of a pyrazolopyrimidinyltriazole ring compound, which comprises the following steps:
mixing 2-amino-4, 6-dichloropyrimidine-5-formaldehyde and a hydrazine compound with a structure shown in a formula I for condensation reaction to obtain pyrimidine pyrazole with a structure shown in a formula II;
mixing the pyrimidine pyrazole with the structure shown in the formula II and the acyl hydrazine with the structure shown in the formula III for substitution reaction to obtain 4-hydrazide pyrimidine pyrazole with the structure shown in the formula IV;
mixing the 4-hydrazidyl pyrimidine pyrazole with the structure shown in the formula IV with a condensing agent for condensation rearrangement reaction to obtain a pyrazolopyrimidino-triazole ring compound with the structure shown in the formula V;
R1-NHNH2the compound of the formula I is shown in the specification,
in the formulae I to V, R1Is butyl, isopentyl, phenethyl, methyl or phenyl, R2Is furyl, phenyl or pyridyl.
In the present invention, unless otherwise specified, all the raw materials used are commercially available in the art.
The invention mixes 2-amino-4, 6-dichloropyrimidine-5-formaldehyde and a hydrazine compound with a structure shown in a formula I for condensation reaction to obtain the pyrimidine pyrazole with a structure shown in a formula II.
In the invention, in the formula I, R1Preferably a phenethyl group.
In the invention, the molar ratio of the 2-amino-4, 6-dichloropyrimidine-5-formaldehyde to the hydrazine compound with the structure shown in the formula I is preferably 1 (1-3).
In the invention, the condensation reaction temperature is preferably 20-30 ℃, and more preferably 23-28 ℃; the time of the condensation reaction is preferably 12-24 h, and more preferably 16-20 h.
In the present invention, the condensation reaction is preferably carried out in an organic solvent, preferably tetrahydrofuran.
In the invention, the condensation reaction is preferably carried out in the presence of triethylamine, and the mass-to-volume ratio of the 2-amino-4, 6-dichloro-pyrimidine-5-carbaldehyde to the triethylamine is preferably 1g (3-7) mL.
In the invention, the volume ratio of the triethylamine to the organic solvent is preferably 1 (5-7), and more preferably 1: 6.
In the present invention, the mixing of the 2-amino-4, 6-dichloropyrimidine-5-carbaldehyde, the triethylamine and the organic solvent having the structure represented by formula I preferably comprises the steps of:
dissolving the 2-amino-4, 6-dichloropyrimidine-5-formaldehyde in a part of organic solvent to obtain a first solution;
mixing the first solution with triethylamine to obtain a second solution;
dissolving a hydrazine compound with a structure shown in the formula I in the residual organic solvent to obtain a hydrazine compound solution;
and dropwise adding the hydrazine compound solution into the second solution to obtain a reaction solution.
In the invention, the volume percentage of the part of the organic solvent in the organic solvent is preferably 80-85%, and more preferably 83-84%. In the invention, the dissolving temperature is preferably 1-9 ℃, and more preferably 3-7 ℃.
In the invention, the dripping speed is preferably 2-5 drops/min, and more preferably 2-4 drops/min. In the present embodiment, the dropwise addition is preferably completed within 15 min.
In the present invention, after the completion of the condensation reaction, it is preferable to further perform rotary evaporation and chromatographic separation on the obtained condensation reaction product in sequence.
The present invention does not specifically limit the temperature and time of the rotary evaporation, and the solvent in the system after the condensation reaction can be removed.
In the invention, the solvent for chromatographic separation is preferably a mixture of petroleum ether and ethyl acetate, and the mass ratio of the petroleum ether to the ethyl acetate is preferably 1.8-5.2: 1, more preferably 5: 1.
in the present invention, taking phenethyl hydrazine as an example, the principle of the condensation reaction is shown in formula a:
in the invention, the hydrazine compound with the structure shown in the formula I is preferably prepared by performing substitution reaction on hydrazine hydrate and halogenated hydrocarbon. The present invention is not particularly limited to specific conditions for the hydrazine hydrate, the halogenated hydrocarbon and the substitution reaction, and commercially available products known to those skilled in the art may be used. In particular embodiments of the present invention, the halogenated hydrocarbon preferably comprises a halobutane, a haloisopentane, a halomethane, or a haloalkylbenzene, and the halobutane preferably comprises a bromobutane or a chlorobutane, more preferably a bromobutane; the halogenated isopentane preferably comprises bromoisopentane or chloroisopentane, more preferably bromoisopentane; the methyl halide preferably comprises methyl bromide or methyl chloride, more preferably methyl bromide; the haloalkylbenzenes preferably comprise bromomethylbenzene, chloromethylbenzene, 2-chloroethylbenzene or 2-bromoethylbenzene, more preferably 2-bromoethylbenzene.
In the invention, the molar ratio of the hydrazine hydrate to the halogenated hydrocarbon is preferably 1 (1-3).
In the present invention, the substitution reaction is preferably carried out in ethanol.
In the invention, the volume ratio of hydrazine hydrate to ethanol is preferably (12.3-13.5): 100, and more preferably (12.6-13.1): 100.
In the present invention, the mixing of hydrazine hydrate, halogenated hydrocarbon and ethanol preferably comprises the steps of:
dissolving hydrazine hydrate in ethanol to obtain a hydrazine hydrate ethanol solution;
adding a halogenated hydrocarbon to the hydrazine hydrate ethanol solution.
In the invention, hydrazine hydrate is dissolved in ethanol to obtain hydrazine hydrate ethanol solution. The dissolution is not particularly limited in the present invention.
After obtaining the hydrazine hydrate ethanol solution, the invention adds the halogenated hydrocarbon into the hydrazine hydrate ethanol solution. In the present invention, the addition is preferably performed under reflux.
In the invention, the substitution reaction is preferably carried out under the reflux condition, and the temperature of the substitution reaction is preferably 58-62 ℃, and more preferably 60 ℃; the time of the substitution reaction is preferably 1-2 h, and more preferably 1.5-1.8 h.
In the present invention, the substitution reaction preferably further comprises: and sequentially carrying out rotary evaporation, extraction and solvent removal on the obtained product after the substitution reaction to obtain the hydrazine compound with the structure shown in the formula I.
The present invention is not particularly limited with respect to the temperature and time of the rotary evaporation.
In the invention, the extraction solvent for extraction is preferably ethyl acetate, and the number of times of extraction is preferably 2-4 times, and more preferably 3 times.
According to the invention, after extraction, the obtained organic phases are combined and then mixed with anhydrous potassium carbonate to remove water in the organic phases. In the present invention, it is preferable to further include, after water removal: filtering a system formed by mixing the obtained organic phase and anhydrous potassium carbonate; the solvent in the filtrate was pumped off with a water pump. The filtration is not particularly limited in the present invention and may be performed in a manner conventional in the art. In the invention, the temperature of the water pump for pumping out the solvent in the filtrate is preferably 78-82 ℃, and more preferably 80 ℃; the pressure is preferably 0.093-1.097 bar, and more preferably 0.095 bar.
In the invention, taking the halogenated compound as bromoethylbenzene as an example, the principle of the substitution reaction is shown as formula b:
after obtaining the pyrimidine pyrazole with the structure shown in the formula II, the pyrimidine pyrazole with the structure shown in the formula II and the acyl hydrazine with the structure shown in the formula III are mixed for substitution reaction to obtain the 4-hydrazide pyrimidine pyrazole with the structure shown in the formula IV.
In the present invention, in the formula III, R2Preferably furyl.
In the invention, the molar ratio of the pyrimidine pyrazole with the structure shown in the formula II to the acyl hydrazine with the structure shown in the formula III is preferably 1: 1-5, and more preferably 1: 1.3-2.
In the invention, the temperature of the substitution reaction is preferably 80-100 ℃, more preferably 85-95 ℃, and the time is preferably 12-20 h, more preferably 14-18 h.
In the present invention, the substitution reaction is preferably carried out in an organic solvent, and more preferably n-butanol.
The amount of the organic solvent used in the present invention is not particularly limited as long as the organic solvent can be completely dissolved. In the embodiment of the invention, the mass-to-volume ratio of the pyrimidine pyrazole with the structure shown in the formula II to the organic solvent is preferably 2.67-2.79 g:120 mL.
The present invention is not particularly limited as long as the pyrimidine pyrazole having the structure represented by formula II, the acyl hydrazine having the structure represented by formula III, and the organic solvent can be mixed uniformly.
The present invention preferably uses TCL to follow the progress of the substitution reaction.
In the present invention, the substitution reaction preferably further comprises: and carrying out rotary evaporation and chromatographic separation on the obtained substitution reaction solution in sequence.
The present invention does not specifically limit the temperature and time of the rotary evaporation, and the solvent in the system after the substitution reaction can be removed.
In the invention, the chromatographic column for chromatographic separation is preferably a silica gel column, the solvent for chromatographic separation is preferably a mixture of petroleum ether and ethyl acetate, and the mass ratio of the petroleum ether to the ethyl acetate is preferably 1-5: 1, more preferably 5: 1.
in the invention, taking 2-furoyl hydrazine as an example, the principle of the substitution reaction is shown as formula c:
after the 4-hydrazidyl pyrimidine pyrazole with the structure shown in the formula IV is obtained, the 4-hydrazidyl pyrimidine pyrazole with the structure shown in the formula IV and a condensing agent are mixed for condensation rearrangement reaction, and the pyrazolopyrimidintriazole ring compound with the structure shown in the formula V is obtained.
In the present invention, the condensing agent preferably includes N, N-Carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), or O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU).
In the invention, the dosage ratio of the 4-hydrazoylpyrimidine pyrazole to the condensing agent is preferably 1.2-1.3 g:10mL, and more preferably 1.25-1.28 g:10 mL.
In the invention, the temperature of the condensation rearrangement reaction is preferably 100-140 ℃, and more preferably 110-130 ℃; the condensation rearrangement time is preferably 8-16 h, and more preferably 10-14 h. The present invention preferably uses TCL to track the progress of the condensation rearrangement reaction.
In the present invention, the condensation rearrangement reaction preferably further comprises: and sequentially carrying out rotary evaporation, chromatographic separation and recrystallization on the obtained condensation rearrangement reaction solution.
In the present invention, the temperature and time of the rotary evaporation are not particularly limited, and the excessive condensing agent may be removed.
In the invention, the solvent for chromatographic separation is preferably a mixture of petroleum ether and ethyl acetate, and the mass ratio of the petroleum ether to the ethyl acetate is preferably 1-10: 1, more preferably 10: 1.
in the present invention, the recrystallization is preferably carried out by mixing the resulting chromatographically separated product with an ethyl acetate-petroleum ether mixed solvent.
In the present invention, taking furan-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide as an example, the principle of the condensation rearrangement reaction is shown in formula d:
the reaction principle for preparing the pyrazolopyrimidinyltriazole ring compound is shown as a formula e:
the preparation method provided by the invention has the advantages of easily available raw materials, short synthetic route and easy industrial production.
In order to further illustrate the present invention, the following embodiments are described in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
In this example R1Is phenethyl, R2Is furyl;
dissolving 12.3mL of hydrazine hydrate with the purity of 98% in 100mL of ethanol to obtain a hydrazine hydrate ethanol solution;
under the condition of reflux, 8.8g of 2-bromoethylbenzene is dripped (the dripping is completed in 15 min) into a hydrazine hydrate ethanol solution, and a first substitution reaction is carried out for 1h at 60 ℃ under the condition of reflux; rotationally evaporating the solution after the first substitution reaction; mixing the solid obtained by rotary evaporation with 100mL of ethyl acetate for extraction, collecting an organic phase, repeatedly extracting for 3 times, mixing the collected organic phases, mixing with anhydrous potassium carbonate, filtering, and removing the solvent in the filtrate by using a water pump (the temperature is 80 ℃, and the pressure is 0.095bar) to obtain phenethyl hydrazine; the phenethyl hydrazine is colorless oily liquid with aromatic odor, and the yield is 97%;
dissolving 6.2g of 2-amino-4, 6-dichloro-pyrimidine-5-carbaldehyde in 100mL of tetrahydrofuran at 1 ℃ to obtain a first solution; mixing the first solution with 20mL of triethylamine to obtain a second solution; dissolving 6.2g of phenelzine in 20mL of tetrahydrofuran to obtain a phenelzine solution; dripping the phenethyl hydrazine solution into the second solution within 15min, and carrying out condensation reaction for 24h at 25 ℃; carrying out rotary evaporation on the system after the condensation reaction and then carrying out chromatographic separation to obtain 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine; the chromatographic column for chromatographic separation is a silica gel column, and the solvent for chromatographic separation is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1; the 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine is a pale yellow powdery solid with a yield of 83%;
2.67g (10mmol) of 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine, 1.83g of 2-furoyl hydrazine and 120mL of n-butanol were mixed and subjected to substitution reaction at 80 ℃ for 12 hours. TCL (trichloromethyl pyrrolidone) tracing reaction, after the reaction is finished, carrying out rotary evaporation, and then carrying out chromatography on a silica gel column (eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1) to obtain furan-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide; furan-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidin-yl) -4-hydrazide is a pale yellow foamy solid in 83% yield;
mixing 1.23g furan-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide and 10mL CDI (condensing agent), carrying out condensation rearrangement reaction at 100 ℃ for 8H, carrying out TCL tracking reaction, carrying out rotary evaporation, carrying out chromatographic separation (a chromatographic column is a silica gel column, and an eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 10: 1), mixing the product after the chromatographic separation and an ethyl acetate/petroleum ether mixed solvent, and then carrying out recrystallization to obtain 5-amino-2-furyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine; the 5-amino-2-furyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine is a white powdery solid with a yield of 92%.
Example 2
In this example R1Is butyl, R2Is furyl;
dissolving 12.6mL of hydrazine hydrate with the purity of 98% in 100mL of ethanol to obtain a hydrazine hydrate ethanol solution;
dropwise adding 9g of bromobutane (dropwise adding is completed within 15 min) into a hydrazine hydrate ethanol solution under the reflux condition, and carrying out substitution reaction for 1.5h at 58 ℃ under the reflux condition; carrying out rotary evaporation on the solution after the substitution reaction; mixing the solid obtained by rotary evaporation with 100mL of ethyl acetate for extraction, collecting an organic phase, repeatedly extracting for 3 times, mixing the collected organic phase with anhydrous potassium carbonate for filtration, and pumping out the solvent in the filtrate by using a water pump (the temperature is 80 ℃, and the pressure is 0.095bar) to obtain the butyl hydrazine; butylhydrazine, yield 90%;
dissolving 6.26g of 2-amino-4, 6-dichloro-pyrimidine-5-carbaldehyde in 100mL of tetrahydrofuran at 3 ℃ to obtain a first solution; mixing the first solution with 20mL of triethylamine to obtain a second solution; dissolving 6.26g of butylhydrazine in 20mL of tetrahydrofuran to obtain a butylhydrazine solution; dropwise adding the butylhydrazine solution into the second solution within 15min, and carrying out condensation reaction for 24h at 23 ℃; performing chromatographic separation after the system after the condensation reaction is subjected to rotary evaporation to obtain 4-chloro-6-amino-1-butylpyrazolo [3,4-d ] pyrimidine; the chromatographic column for chromatographic separation is a silica gel column, and the solvent for chromatographic separation is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1; the yield of the 4-chloro-6-amino-1-butylpyrazolo [3,4-d ] pyrimidine is 94%;
mixing 2.7g (10mmol) of 4-chloro-6-amino-1-butylpyrazolo [3,4-d ] pyrimidine, 1.86g of 2-furoyl hydrazine and 120mL of N-butanol, carrying out substitution reaction at 85 ℃ for 14H, carrying out TCL tracking reaction, finishing the reaction, carrying out rotary evaporation, and then carrying out chromatography on a silica gel column (eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1) to obtain furan-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide; the yield of the furan-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidin-yl) -4-hydrazide is 86%;
mixing 1.25g furan-2-carboxylic acid N' - (6-amino-1-butyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide and 10mL EDCI (condensing agent), carrying out condensation rearrangement reaction at 110 ℃ for 10H, carrying out TCL tracking reaction, carrying out rotary evaporation, carrying out chromatographic separation (a chromatographic column is a silica gel column, and an eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 10: 1), mixing the product after the chromatographic separation and an ethyl acetate/petroleum ether mixed solvent, and then carrying out recrystallization to obtain 5-amino-2-furyl-7-butyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine; the yield of the 5-amino-2-furyl-7-butyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine is 89%.
Example 3
In this example R1Is isoamyl, R2Is furyl;
dissolving 12.9mL of hydrazine hydrate with the purity of 98% in 100mL of ethanol to obtain a hydrazine hydrate ethanol solution;
dripping 9.2g of isoamyl bromide (dripping is completed within 15 min) into a hydrazine hydrate ethanol solution under the reflux condition, and carrying out substitution reaction for 2h at 62 ℃ under the reflux condition; carrying out rotary evaporation on the solution after the substitution reaction; mixing the solid obtained by rotary evaporation with 100mL of ethyl acetate for extraction, collecting an organic phase, repeatedly extracting for 3 times, mixing the collected organic phases, mixing with anhydrous potassium carbonate, filtering, and pumping out the solvent in the filtrate by using a water pump (the temperature is 80 ℃, and the pressure is 0.095bar) to obtain isoamylhydrazine; the yield of isoamyl hydrazine is 94%;
dissolving 6.32g of 2-amino-4, 6-dichloro-pyrimidine-5-carbaldehyde in 100mL of tetrahydrofuran at 5 ℃ to obtain a first solution; mixing the first solution with 20mL of triethylamine to obtain a second solution; dissolving 6.32g of isoamylhydrazine in 20mL of tetrahydrofuran to obtain an isoamylhydrazine solution; dropwise adding the isoamyl hydrazine solution into the second solution within 15min, and carrying out condensation reaction for 22h at 24 ℃; carrying out rotary evaporation on the system after the condensation reaction and then carrying out chromatographic separation to obtain 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine; the chromatographic column for chromatographic separation is a silica gel column, and the solvent for chromatographic separation is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1; the yield of the 4-chloro-6-amino-1-isoamyl pyrazolo [3,4-d ] pyrimidine is 89%;
mixing 2.73g (10mmol) of 4-chloro-6-amino-1-isoamylpyrazolo [3,4-d ] pyrimidine, 1.89g of 2-furoyl hydrazine and 120mL of N-butanol, carrying out substitution reaction at 90 ℃ for 16H, carrying out TCL tracking reaction, finishing the reaction, carrying out rotary evaporation, and then carrying out chromatography on a silica gel column (eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1) to obtain furan-2-carboxylic acid N' - (6-amino-1-isoamyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide; the yield of the furan-2-carboxylic acid N' - (6-amino-1-isoamyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide is 97%;
mixing 1.27g furan-2-carboxylic acid N' - (6-amino-1-isoamyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide and 10mL TATU (condensing agent), then carrying out condensation rearrangement reaction at 120 ℃ for 12H, carrying out TCL tracking reaction, carrying out chromatography separation after the reaction is finished, carrying out rotary evaporation (a chromatography column is a silica gel column, and an eluent is a mixture of petroleum ether and ethyl acetate with the mass ratio of 10: 1), mixing the product after chromatography separation and an ethyl acetate/petroleum ether mixed solvent, and then carrying out recrystallization to obtain 5-amino-2-furyl-7-isoamyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine; the yield of the 5-amino-2-furyl-7-isoamyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine is 87%.
Example 4
In this example R1Is phenethyl, R2Is phenyl;
dissolving 13.1mL of hydrazine hydrate with the purity of 98% in 100mL of ethanol to obtain a hydrazine hydrate ethanol solution;
adding 9.4g of 2-bromoethylbenzene dropwise (after 15min dropwise addition) into a hydrazine hydrate ethanol solution under the reflux condition, and carrying out substitution reaction for 2h at 60 ℃ under the reflux condition; carrying out rotary evaporation on the solution after the substitution reaction; mixing the solid obtained by rotary evaporation with 100mL of ethyl acetate for extraction, collecting an organic phase, repeatedly extracting for 3 times, mixing the collected organic phases, mixing with anhydrous potassium carbonate, filtering, and removing the solvent in the filtrate by using a water pump (the temperature is 80 ℃, and the pressure is 0.095bar) to obtain phenethyl hydrazine; the phenethyl hydrazine is colorless oily liquid with aromatic odor, and the yield is 92%;
dissolving 6.38g of 2-amino-4, 6-dichloro-pyrimidine-5-carbaldehyde in 100mL of tetrahydrofuran at 7 ℃ to obtain a first solution; mixing the first solution with 20mL of triethylamine to obtain a second solution; dissolving 6.38g of phenelzine in 20mL of tetrahydrofuran to obtain a phenelzine solution; dropwise adding the phenelzine solution into the second solution within 15min, and carrying out condensation reaction for 24h at 25 ℃; carrying out rotary evaporation on the system after the condensation reaction and then carrying out chromatographic separation to obtain 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine; the chromatographic column for chromatographic separation is a silica gel column, and the solvent for chromatographic separation is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1; the 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine is a pale yellow powdery solid with a yield of 87%;
mixing 2.77g (10mmol) of 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine, 1.91g of benzoyl hydrazine and 120mL of N-butanol, carrying out substitution reaction at 95 ℃ for 18H, carrying out TCL tracking reaction, carrying out rotary evaporation, and then carrying out chromatography on a silica gel column (eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1) to obtain benzene-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide; the benzene-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidin-yl) -4-hydrazide yield was 85%;
mixing 1.28g of benzene-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide and 10mL of TBTU (condensing agent), then carrying out condensation rearrangement reaction at 130 ℃ for 14H, carrying out TCL tracking reaction, after the reaction is finished, carrying out chromatography separation after rotary evaporation (a chromatographic column is a silica gel column, and an eluent is a mixture of petroleum ether and ethyl acetate with the mass ratio of 10: 1), mixing the product after chromatography separation with an ethyl acetate/petroleum ether mixed solvent, and then carrying out recrystallization to obtain 5-amino-2-phenyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine; the yield of the 5-amino-2-phenyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine was 85%.
Example 5
In this example R1Is phenethyl, R2Is a pyridyl group;
dissolving 13.5mL of hydrazine hydrate with the purity of 98% in 100mL of ethanol to obtain a hydrazine hydrate ethanol solution;
adding 9.6g of 2-bromoethylbenzene dropwise (after 15min dropwise addition) into a hydrazine hydrate ethanol solution under the reflux condition, and carrying out substitution reaction for 2h at 60 ℃ under the reflux condition; carrying out rotary evaporation on the solution after the substitution reaction; mixing the solid obtained by rotary evaporation with 100mL of ethyl acetate for extraction, collecting an organic phase, repeatedly extracting for 3 times, mixing the collected organic phase with anhydrous potassium carbonate for filtration, and pumping out the solvent in the filtrate by using a water pump (the temperature is 80 ℃, and the pressure is 0.095bar) to obtain phenethyl hydrazine; the phenethyl hydrazine is colorless oily liquid with aromatic odor, and the yield is 90%;
dissolving 6.44g of 2-amino-4, 6-dichloro-pyrimidine-5-carbaldehyde in 100mL of tetrahydrofuran at 9 ℃ to obtain a first solution; mixing the first solution with 20mL of triethylamine to obtain a second solution; dissolving 6.44g of phenelzine in 20mL of tetrahydrofuran to obtain a phenelzine solution; dropwise adding the phenelzine solution into the second solution within 15min, and carrying out condensation reaction for 20h at 25 ℃; performing chromatographic separation after the system after the condensation reaction is subjected to rotary evaporation to obtain 4-chloro-6-amino-1-phenethyl pyrazolo [3,4-d ] pyrimidine; the chromatographic column for chromatographic separation is a silica gel column, and the solvent for chromatographic separation is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1; the 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine is a pale yellow powdery solid with a yield of 90%;
mixing 2.79g (10mmol) of 4-chloro-6-amino-1-phenethylpyrazolo [3,4-d ] pyrimidine, 1.95g of 4-pyridine formhydrazide and 120mL of N-butyl alcohol, carrying out substitution reaction at 100 ℃ for 20H, carrying out TCL tracking reaction, carrying out rotary evaporation, and carrying out chromatography on a silica gel column (eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 5: 1) to obtain pyridine-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidin-yl) -4-hydrazide; the pyridine-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidin-yl) -4-hydrazide yield is 83%;
mixing 1.29g pyridine-2-carboxylic acid N' - (6-amino-1-phenethyl-1H-pyrazolo [3,4-d ] pyrimidine-yl) -4-hydrazide and 10ml of ATU (condensing agent), then carrying out condensation rearrangement reaction at 140 ℃ for 16H, carrying out TCL tracking reaction, carrying out rotary evaporation, then carrying out chromatographic separation (a chromatographic column is a silica gel column, and an eluent is a mixture of petroleum ether and ethyl acetate in a mass ratio of 10: 1), mixing the product after the chromatographic separation and an ethyl acetate/petroleum ether mixed solvent, and then carrying out recrystallization to obtain 5-amino-4-pyridyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine; the yield of the 5-amino-4-pyridyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine was 93%.
The 5-amino-2-furyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine prepared in example 1 was subjected to nuclear magnetic detection, and the nuclear magnetic spectrum obtained was as shown in FIGS. 1 to 2. Wherein FIG. 1 is a NMR hydrogen spectrum of 5-amino-2-furyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine prepared in example 1, and FIG. 2 is a NMR carbon spectrum of 5-amino-2-furyl-7-phenethyl-7H-pyrazolo [4,3-e ] [1,2,4] triazolo [1,5-c ] pyrimidine prepared in example 1.
As can be seen from FIGS. 1 and 2, pyrazolopyrimidinyltriazole ring compounds can be prepared according to the preparation method of the present invention.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and all of the embodiments are included in the scope of the present invention.
Claims (10)
1. A preparation method of a pyrazolopyrimidintriazole ring compound is characterized by comprising the following steps:
mixing 2-amino-4, 6-dichloropyrimidine-5-formaldehyde and a hydrazine compound with a structure shown in a formula I for condensation reaction to obtain pyrimidopyrazole with a structure shown in a formula II;
mixing the pyrimidopyrazole with the structure shown in the formula II and the acyl hydrazine with the structure shown in the formula III for substitution reaction to obtain 4-hydrazidyl pyrimidopyrazole with the structure shown in the formula IV;
mixing the 4-hydrazino pyrimido pyrazole with the structure shown in the formula IV with a condensing agent to carry out condensation rearrangement reaction to obtain a pyrazolopyrimidino triazolo cyclic compound with the structure shown in the formula V;
R1-NHNH2the compound of the formula I is shown in the specification,
in the formulae I to V, R1Is butyl, isopentyl, phenethyl, methyl or phenyl, R2Is furyl, phenyl or pyridyl.
2. The preparation method according to claim 1, wherein the molar ratio of the 2-amino-4, 6-dichloropyrimidine-5-carbaldehyde to the hydrazine compound having the structure shown in the formula I is 1 (1-3).
3. The preparation method according to claim 1 or 2, wherein the condensation reaction time is 12-24 hours.
4. The preparation method according to claim 1, wherein the molar ratio of the pyrimidopyrazole having the structure represented by formula II to the acylhydrazine having the structure represented by formula III is 1 (1-5).
5. The preparation method according to claim 1 or 4, wherein the temperature of the substitution reaction is 60 to 100 ℃ and the time is 12 to 20 hours.
6. The preparation method according to claim 1, wherein the 4-hydrazoylpyrimidopyrazole with the structure shown in formula IV and the condensing agent are used in a ratio of 1g (5-15) mL.
7. The preparation method according to claim 1 or 6, wherein the temperature of the condensation rearrangement reaction is 80-140 ℃ and the time is 8-24 h.
8. The method according to claim 1 or 6, wherein the condensing agent comprises N, N-carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate or O-benzotriazol-tetramethylurea hexafluorophosphate.
9. The process according to claim 1, wherein in the formulae I to V, R1Is butyl, isopentyl or phenethyl, R2Is furyl, pyridyl or phenyl.
10. The preparation method according to claim 1, wherein the hydrazine compound having the structure shown in formula I is prepared by substitution reaction of hydrazine hydrate and halogenated hydrocarbon.
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