CN115785101B - Phenylpiperazine structure-containing nafil compound and preparation method thereof - Google Patents
Phenylpiperazine structure-containing nafil compound and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of biological medicines, and particularly discloses a nafil compound containing a phenylpiperazine structure, wherein the structure of the nafil compound containing the phenylpiperazine structure is shown as a formula (I). The invention also discloses a preparation method of the compound, which specifically comprises the steps of taking p-hydroxybenzoic acid or 3-aldehyde-4-hydroxybenzoic acid as a raw material, obtaining a phenylpiperazine intermediate through reaction, and obtaining the nafil compound through acylation or condensation and dehydration reaction with 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-formamide. The preparation method has the advantages of wide and easily available raw materials, mild reaction conditions, simple operation, and cheap and easily available selected reagents.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to a nafil compound containing a phenylpiperazine structure and a preparation method thereof.
Background
Phosphodiesterase-5 (PDE-5) inhibitors are a class of drugs that inhibit phosphodiesterase activity and are widely used in the treatment of diseases such as male Erectile Dysfunction (ED). PDE-5 type inhibitors can reduce the breakdown of cyclic guanosine monophosphate (cGMP) by inhibiting PDE-5 activity. Thus, when the patient takes a PDE-5 inhibitor, upon receiving a sexual stimulus, the PDE-5 inhibitor inhibits PDE-5 activity, increases cGMP levels in the corpora cavernosa, relaxes smooth muscle, and allows blood to flow into the cavernosa, thereby increasing the number and duration of erections in male erectile dysfunction patients.
The main representative drugs of PDE-5 inhibitors are sildenafil, vardenafil, tadalafil, atorvastatin, etc. Among them, compounds containing a pyrazolopyrimidinone skeleton structure represented by sildenafil and vardenafil have excellent inhibitory activity against PDE. The development of PDE-5 inhibitors based on pyrazolopyrimidinone backbone structures has been the focus of attention. Currently, the main representative drugs of PDE-5 inhibitors are sildenafil, vardenafil, tadalafil, and avanafil. Among them, compounds containing a pyrazolopyrimidinone skeleton structure represented by sildenafil and vardenafil have excellent inhibitory activity against PDE. The development of PDE-5 inhibitors based on pyrazolopyrimidinone backbone has been the focus of attention, however, such molecules with specific structures, in addition to their use as effective therapies for ED, have limited widespread use due to several significant side effects such as headache, nausea, skin flushing, visual impairment, and various sequelae due to the non-selective and non-targeted activity of the molecule itself. Therefore, the development of novel PDE-5 inhibitors with high selectivity and low side effects is one of the current directions of development in this field.
Currently, few reports exist on the synthesis of such compounds, which limit the further research thereof by the person skilled in the art; and the yields and process routes of the synthesis in the prior art are to be optimized, providing more of those compounds containing phenylpiperazine structures, and providing more economical and efficient synthetic routes is a concern in the art.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a nafil compound containing a phenylpiperazine structure, the structure of the nafil compound is shown as a formula (I),
preferably, said R 1 、R 2 The radicals being independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alicyclic or substituted alicyclic, and R being excluded simultaneously 1 Is H, R 2 Is propyl;
the number of carbon atoms of the alkyl is in the range of 1-8;
the number of carbon atoms of the alkylene or alkynyl ranges from 2 to 8;
the substituent of the substituted alkyl, substituted alkylene, substituted aryl, substituted heteroaryl or substituted lipoheteroaryl contains at least one oxygen, nitrogen or sulfur atom.
Furthermore, the invention also provides a preparation method of the phenylpiperazine structural nafil compound, which comprises the following steps:
step one, carrying out aldehyde formation on p-hydroxybenzoic acid (compound 1) to obtain a compound 2, reacting the compound 2 with an acylating agent to obtain a compound 3, and reacting the compound 3 with a phenylpiperazine compound to obtain a compound 4; x in the structural formula of the compound 3 1 Is Cl or Br;
step two, reacting the compound 4 with a halide to obtain a compound 5;
step three, oxidizing the compound 5 to obtain a compound 6;
step four, compound 7 is obtained after the reaction of compound 6 and an acylating agent, and compound 8 is obtained after the reaction of compound 7 and 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide; x in the structural formula of the compound 7 2 Is Cl or Br;
step five, ring-closing the compound 8 in the presence of an alkaline agent to obtain a nafil compound 9 with a phenylpiperazine structure
Preferably, the acylating reagent in the first step and the fourth step is thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride; the halogenide in the second step is a bromide or a chloride; the bromide is 1-bromopropane, 2-bromopropane, 1-bromobutane, 2-bromobutane or 2-bromo-2-methylpropane; the chloro is 1-chloropropane, 2-chloropropane, 1-chlorobutane, 2-chloro-2-methylpropane or benzyl chloride; the structure of the phenylpiperazine compound in the first step is shown as a formula (II),
preferably, the specific step of the first step includes:
dissolving the compound 2 in the solvent of the first step, adding the acylating reagent of the first step and the alkaline agent of the first step, and reacting under reflux;
the solvent in the first step is dichloromethane, trichloromethane, 1, 2-dichloroethane or 1, 3-dichloropropane; the alkaline agent in the first step is triethylamine, tripropylamine, pyridine or 4-dimethylaminopyridine; the molar ratio of the compound 2, the acylating agent of the step one and the alkaline agent of the step one is 1:5:0.01-1:20:0.05.
Preferably, the specific steps of the second step include:
dissolving the compound 4 in the solvent of the second step, adding the alkaline agent of the second step, stirring for 20-50 minutes at room temperature, then adding the halogenated compound of the second step into the reaction solution, and reacting under the protection of nitrogen and reflux;
the solvent of the second step is acetone, acetonitrile, propanol, isopropanol, butanol, tertiary butanol, N '-dimethylformamide, N' -dimethylacetamide or tetrahydrofuran; the alkaline agent in the second step is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate or sodium ethoxide; the molar ratio of the compound 4 to the alkaline agent in the second step to the halide in the second step is 1:3:1.1-1:10:2.
Preferably, the specific steps of the third step include:
dissolving the compound 5 in tetrahydrofuran, adding a sodium dihydrogen phosphate aqueous solution, stirring for 5-15 minutes, and then dropwise adding a mixed aqueous solution of sodium chlorite and hydrogen peroxide, wherein the molar ratio of the compound 5 to the sodium dihydrogen phosphate to the sodium chlorite to the hydrogen peroxide is 1:0.5:3:2-1:1:5:5.
Preferably, the specific steps of the fourth step include:
dissolving the compound 6 in a solvent of the fourth step, adding an acylating reagent of the fourth step and an alkaline agent of the fourth step for reaction under reflux, after the reaction is finished, evaporating the redundant acylating reagent of the fourth step and the solvent of the fourth step under reduced pressure to obtain a crude product of the compound 7, directly dissolving the crude product of the compound 7 by using a dry solvent to prepare a compound 7 solution, and adding the compound 7 solution into the solution of the 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide and the alkaline agent (or alkaline agent composition) of the fourth step for reaction;
the solvent in the fourth step is dichloromethane, trichloromethane, 1, 2-dichloroethane or 1, 3-dichloropropane; the alkaline agent in the fourth step comprises one or more of triethylamine, tripropylamine, pyridine or 4-dimethylaminopyridine; the molar ratio of the compound 2 to the acylating agent in the fourth step to the alkaline agent in the fourth step is 1:5:0.01-1:20:0.05; the molar ratio of the compound 7, the 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide and the alkaline agent (or the alkaline agent composition) in the step four is 1:1:0.01-1:1.2:0.1.
Preferably, the specific steps of the fifth step include:
dissolving the compound 8 in an alcohol solvent, adding the alkaline agent in the fifth step, and reacting under a reflux condition;
the alcohol solvent is methanol, ethanol, propanol, isopropanol, butanol or tertiary butanol; the alkaline agent in the fifth step is sodium hydroxide, potassium hydroxide, sodium ethoxide or potassium tert-butoxide; the molar ratio of the compound 8 to the alkaline agent in the step five is 1:1-1:2.
Furthermore, the invention also provides a preparation method of the phenylpiperazine structural nafil compound, which comprises the following steps:
step one, reacting 3-aldehyde-4-hydroxybenzoic acid (compound 2), a condensing agent, a catalyst and phenylpiperazine compounds to obtain a compound 4;
step two, reacting the compound 4 with a halide to obtain a compound 5;
step three, reacting the compound 5 and an acid catalyst with 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide to obtain a compound 9;
step four, the compound 4 and an acid catalyst react with 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-formamide to obtain a compound 10
Preferably, the acid catalyst in the third and fourth steps comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, heteropolyacids, molecular sieves and solid superacids; the solid super acid is SO 4 2- /TiO 2 、SO 4 2- /TiO 2 -La 2 O 3 Or SO 4 2- /ZrO 2 -TiO 2 The method comprises the steps of carrying out a first treatment on the surface of the The halogenide in the second step is a bromide or a chloride; the bromide is 1-bromopropane, 2-bromopropane,1-bromobutane, 2-bromobutane or 2-bromo-2-methylpropane; the chloro is 1-chloropropane, 2-chloropropane, 1-chlorobutane, 2-chloro-2-methylpropane or benzyl chloride.
Preferably, the specific step of the first step includes:
dissolving the compound 2 in an aprotic organic solvent, adding the condensing agent of the first step, the phenylpiperazine compound of the first step and the catalyst of the first step at the temperature of 0 ℃, and reacting at room temperature;
the aprotic organic solvent is dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1, 3-dichloropropane, N '-dimethylformamide, N' -dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran or acetone; the condensing agent in the first step is dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, N, N ' -carbonyldiimidazole or 2- (7-azabenzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate; the catalyst in the first step is 4-dimethylaminopyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole or N, N' -diisopropylethylamine; the molar ratio of the compound 2 to the condensing agent in the first step to the phenylpiperazine compound in the first step to the catalyst in the first step is 1:1:1:0.01-1:1.5:1.5:0.5.
Preferably, in the third step, the molar ratio of the compound 5 to the acid catalyst of the third step to the 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide is 1:0.01:0.5-1:0.05:1.5.
Preferably, in the fourth step, the molar ratio of the compound 4, the acid catalyst of the fourth step and the 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide is 1:0.01:0.5-1:0.05:1.5.
Furthermore, the invention also provides application of the phenylpiperazine structural nafil compound in preparation of phosphodiesterase-5 inhibitor medicines.
The beneficial technical effects of the invention are as follows:
the nafil compound containing the phenylpiperazine structure is a potential PDE-5 inhibitory activity compound, is modified and optimized on the basis of pyrazolopyrimidinone skeleton structures in sildenafil and vardenafil, abandons sulfonyl groups in the original nafil medicine molecular structure, and is a novel compound containing the phenylpiperazine structure, the physicochemical property of the compound is improved, and the foundation is laid for enhancing the patent medicine property of the compound.
The preparation method of the nafil compound containing the phenylpiperazine structure has the advantages of wide and easily available raw materials, mild reaction conditions, simplicity in operation, low price and easiness in obtaining selected reagents and the like.
Drawings
FIG. 1, HPLC chart of 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one.
(chromatographic conditions: C 18 Or a chromatographic column of comparable performance; mobile phase acetonitrile-water (85:15), isocratic elution; the column temperature is 30 ℃; the detection wavelength is 230nm; the flow rate is 1.0mL per minute; the sample volume was 10. Mu.L. )
Detailed Description
The present invention will be described in more detail by way of examples. It is also to be understood that the following examples are given solely for the purpose of illustration and are not to be construed as limitations on the scope of the invention, since various modifications and adaptations may be made by those skilled in the art in light of the teachings herein. The specific process parameters and the like described below are also merely examples of suitable ranges, i.e., one skilled in the art can make a selection within the suitable ranges by the description herein and are not intended to be limited to the specific data described below.
According to one embodiment of the invention, the structure of the nafil compound containing the phenylpiperazine structure is shown as a formula (I),
said R is 1 、R 2 The radicals independently being H atoms, alkyl radicals, substituted alkyl radicals, alkenyl radicals, substituted olefinsRadicals, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alicyclic radicals, and excluding R at the same time 1 Is H, R 2 Is propyl;
the number of carbon atoms of the alkyl is in the range of 1-8;
the number of carbon atoms of the alkylene and alkynyl ranges from 2 to 8;
the substituted alkyl, substituted alkylene, substituted aryl and substituted heteroaryl contain at least one oxygen, nitrogen or sulfur atom.
The invention provides two different routes for synthesizing target products, taking 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidine-7-ketone and 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-hydroxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidine-7-ketone as examples, and specifically comprising:
the synthesis route I is as follows:
1) Adding p-hydroxybenzoic acid into trifluoroacetic acid, protecting with nitrogen, stirring for dispersion, dissolving hexamethylenetetramine in trifluoroacetic acid, gradually adding into the reaction solution, wherein the molar ratio of p-hydroxybenzoic acid to hexamethylenetetramine is 1:1-1:2, and heating the reaction solution to reflux after the addition is completed. Cooling to room temperature after the reaction is finished, gradually adding the reaction solution into about 250mL of 15% hydrochloric acid, continuously stirring for about 2-4 hours, precipitating solid, filtering, washing a filter cake with a small amount of water for many times, and drying in a dark place to obtain the 3-aldehyde-4-hydroxybenzoic acid.
2) Dissolving 3-aldehyde-4-hydroxybenzoic acid in dry dichloromethane, adding thionyl chloride, dropwise adding 3-5 drops of triethylamine, wherein the molar ratio of 3-aldehyde-4-hydroxybenzoic acid to thionyl chloride to triethylamine is 1:5:0.01-1:20:0.05, stirring uniformly, and carrying out reflux reaction for 3-4 hours. After the reaction is finished, the redundant thionyl chloride and solvent are distilled off under reduced pressure to obtain a crude product of 3-aldehyde-4-hydroxybenzoyl chloride, and then the crude product is directly dissolved by dry dichloromethane to prepare a dichloromethane solution of the 3-aldehyde-4-hydroxybenzoyl chloride. Dissolving 1-phenylpiperazine in dry dichloromethane, stirring to dissolve, gradually dripping the dichloromethane solution of the 3-aldehyde-4-hydroxybenzoyl chloride, continuing to react until the reaction is finished, adding saturated sodium bicarbonate solution for neutralization, extracting with dichloromethane or ethyl acetate, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain 5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde.
3) Dissolving 5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde in anhydrous acetone, adding anhydrous potassium carbonate, stirring at room temperature for 20-50 minutes, and then adding a bromide or a chloride into the reaction solution, wherein the bromide is 1-bromopropane, 2-bromopropane, 1-bromobutane, 2-bromobutane or 2-bromo-2-methylpropane; the chloro compound is 1-chloropropane, 2-chloropropane, 1-chlorobutane, 2-chloro-2-methylpropane or benzyl chloride, the molar ratio of 5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde, anhydrous potassium carbonate and bromo or chloro compound is 1:3:1.1-1:10:2, the reflux reaction is carried out for 8-24 hours under the protection of nitrogen, the solvent is removed by reduced pressure after the reaction, the residual solid is dissolved in clear water, the ethyl acetate or dichloromethane is used for extraction, the organic phase is combined, the organic phase is washed by clear water and saturated saline water in sequence, then dried by anhydrous sodium sulfate, and the 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde is obtained by column chromatography separation after concentration.
4) Dissolving 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde in tetrahydrofuran, adding a sodium dihydrogen phosphate aqueous solution, stirring for about 10 minutes, then dropwise adding a mixed aqueous solution of sodium chlorite and 30% hydrogen peroxide, wherein the molar ratio of the 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde to the sodium dihydrogen phosphate is 1:0.5:3:2-1:1:5:5, stirring at room temperature for about 3 hours, after the reaction is finished, evaporating the solvent under reduced pressure, dissolving the residual solid in clear water, extracting with ethyl acetate, merging the organic phases, washing the organic phases with clear water, extracting the reaction product in the organic phases with 2M sodium hydroxide, merging the aqueous phases, adjusting the pH value to 5-6 with concentrated hydrochloric acid, standing, precipitating solids, filtering, and drying to obtain the 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoic acid.
5) Dissolving 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoic acid in dry dichloromethane, adding thionyl chloride, dropwise adding 3-5 drops of triethylamine, wherein the molar ratio of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoic acid to thionyl chloride to triethylamine is 1:5:0.01-1:20:0.05, stirring uniformly, and carrying out reflux reaction for 3-4 hours. After the reaction is finished, the redundant thionyl chloride and solvent are distilled off under reduced pressure to obtain a crude product of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoyl chloride, and then the crude product is dissolved with dry dichloromethane without separation to prepare a dichloromethane solution of the 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoyl chloride. Then sequentially placing 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-formamide, triethylamine and 4-dimethylaminopyridine in dry dichloromethane, continuously reacting until the reaction is finished, sequentially extracting with dichloromethane or ethyl acetate, washing an organic phase with saturated saline water, drying with anhydrous sodium sulfate, concentrating, and then separating by column chromatography to obtain the dichloromethane solution of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoyl chloride and 1-methyl-4- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoyl amide, wherein the molar ratio of the triethylamine to the 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-formamide to the 4-n-propyl-1H-pyrazole-5-carboxamide is 1:1.01:0.01-1:1.2:0.1:0.1.
6) Dissolving 1-methyl-4- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzamide) -3-propyl-1H-pyrazole-5-carboxamide in an alcohol solvent, wherein the alcohol solvent is methanol, ethanol, propanol, isopropanol, butanol, tertiary butanol and the like, stirring and dissolving, adding an alkaline agent, wherein the alkaline agent is sodium hydroxide, potassium hydroxide, sodium ethoxide, tertiary potassium butoxide and the like, the molar ratio of the 1-methyl-4- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzamide) -3-propyl-1H-pyrazole-5-carboxamide to the alkaline agent is 1:1-1:2, protecting with nitrogen, refluxing and heating for about 6-8 hours, and cooling to room temperature after the reaction is finished. Adding ice water into the reaction solution, regulating the pH value of the solution to be neutral by using concentrated hydrochloric acid, continuously stirring for about 1-2 hours at the temperature of 0-10 ℃, precipitating solid, carrying out suction filtration, washing a filter cake with ice water for a plurality of times, and drying to obtain 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidine-7-ketone.
The synthesis route II is as follows:
1) Dissolving 3-aldehyde-4-hydroxybenzoic acid in dry dichloromethane, carrying out ice water bath to 0 ℃, stirring for 5 minutes, sequentially adding dichloromethane solution dissolved with dicyclohexylcarbodiimide, dichloromethane solution dissolved with 1-phenylpiperazine, finally adding dichloromethane solution dissolved with 4-dimethylaminopyridine, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography to separate 5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde, wherein the molar ratio of 3-aldehyde-4-hydroxybenzoic acid, dicyclohexylcarbodiimide, 1-phenylpiperazine and 4-dimethylaminopyridine is 1:1:0.01-1:1.5:1.5:0.5:0.5, heating to room temperature for 2-4 hours, removing the solvent by reduced pressure rotary evaporation after the reaction is finished, adding 20mL of ethyl acetate, carrying out suction filtration, washing filter cakes with a small amount of ethyl acetate for many times, collecting an organic phase, washing the organic phase with clear water and saturated saline, and carrying out column chromatography separation after the concentration.
2) Dissolving 5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde in anhydrous acetone, adding anhydrous potassium carbonate, stirring at room temperature for 30 minutes, sequentially adding 1-bromopropane, 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde, anhydrous potassium carbonate and 1-bromopropane in a molar ratio of 1:3:1.1-1:5:2 into the reaction solution, protecting with nitrogen, carrying out reflux reaction for 8-24 hours, evaporating the solvent under reduced pressure after the reaction is finished, dissolving the residual solid in clear water, extracting with ethyl acetate or dichloromethane, merging organic phases, sequentially washing the organic phases with clear water and saturated saline, drying with anhydrous sodium sulfate, concentrating, and carrying out column chromatography separation to obtain 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde.
3) Dissolving 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde in glacial acetic acid, sequentially adding p-toluenesulfonic acid, 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide, 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde, p-toluenesulfonic acid and 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide in a molar ratio of 1:0.01:0.5-1:0.05:1.5, protecting with nitrogen, heating and refluxing for 5-8 hours, cooling to room temperature after the reaction is finished, adding clear water, precipitating solid, filtering, drying and recrystallizing to obtain 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidine-7-ketone.
4) Dissolving 5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde in glacial acetic acid, sequentially adding p-toluenesulfonic acid, 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide, 5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde, p-toluenesulfonic acid and 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide in a molar ratio of 1:0.01:0.5-1:0.05:1.5, heating and refluxing for 5-8 hours, cooling to room temperature after the reaction is finished, adding clear water, precipitating solid, carrying out suction filtration, drying and recrystallizing to obtain 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-hydroxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidine-7-ketone.
Synthetic route one example:
example 1) Synthesis of 3-formyl-4-hydroxybenzoic acid (Compound 2)
Parahydroxybenzoic acid (compound 1, 10.00g,72.4 mmol) was weighed into a 250mL round bottom flask containing 30mL of trifluoroacetic acid, nitrogen protected, stirred for dispersion, hexamethylenetetramine (11.16 g,79.6 mmol) was dissolved in 35mL of trifluoroacetic acid and gradually added to the reaction solution, after the addition was completed, the reaction solution was warmed to reflux, monitored by TLC (CH 2 Cl 2 Meoh=10:1) until the starting p-hydroxybenzoic acid disappeared. Cooling to room temperature after the reaction is finished, gradually adding the reaction solution into about 250mL of 15% hydrochloric acid, continuously stirring for about 2-4 hours, filtering out precipitated solid, washing a filter cake with a small amount of water for multiple times, and drying in a dark place to obtain 4.49g of light yellow solid with the yield of 37.3%.
Example 2) Synthesis of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde (Compound 4)
3-aldehyde-4-hydroxybenzoic acid (Compound 2,1.00g,6.02 mmol) was dissolved in 10mL of dried dichloromethane, thionyl chloride (7.16 g,60.2 mmol) was added, 3 drops of triethylamine were added dropwise, and after stirring well, the reaction was refluxed for 3-4 hours. To be treatedAfter the reaction, the redundant thionyl chloride and solvent are distilled off under reduced pressure to obtain a crude product of 3-aldehyde-4-hydroxybenzoyl chloride (compound 3), and then the crude product is dissolved with dry dichloromethane without separation to prepare about 10mL of dichloromethane solution of 3-aldehyde-4-hydroxybenzoyl chloride. Then 1-phenylpiperazine (0.98 g,6.02 mmol) is placed in 10mL of dry dichloromethane, stirred and dissolved, the dichloromethane solution of the 3-aldehyde-4-hydroxybenzoyl chloride is gradually dripped, the reaction is continued until the reaction is finished after dripping, and saturated NaHCO is added 3 The solution was neutralized, then extracted with dichloromethane (3X 50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 1.12g (3.62 mmol) of a white solid in 60.1% yield.
Example 3) Synthesis of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde (Compound 5)
5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde (compound 4,1.00g,3.22 mmol) was dissolved in 50mL of anhydrous acetone, anhydrous potassium carbonate (1.34 g,9.66 mmol) was added, stirred at room temperature for 30 minutes, 1-bromopropane (0.59 g,4.83 mmol) was then added to the reaction solution, respectively, and the reaction was refluxed for 8 to 24 hours, after the completion of the reaction, the solvent was distilled off under reduced pressure, the residual solid was dissolved in clear water, and extracted with ethyl acetate or dichloromethane (3X 50 mL), the organic phases were combined, washed with clear water (2X 50 mL) and saturated brine (2X 50 mL) in this order, then dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to separate 0.92g (2.62 mmol) of pale yellow product, yield 81.2%.
Example 4) Synthesis of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoic acid (Compound 6)
5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde (Compound 5,1.00g,2.84 mmol) was dissolved in 5mL of tetrahydrofuran, 2mL of an aqueous solution of sodium dihydrogen phosphate (0.23 g,1.70 mmol) was added, stirring was carried out for about 10 minutes, then 2mL of a mixed aqueous solution of sodium chlorite (0.85 g,9.37 mmol) and 30% hydrogen peroxide (0.65 mL,6.25 mmol) was added dropwise, stirring was carried out at room temperature for about 3 hours, after the completion of the reaction, the solvent was distilled off under reduced pressure, the residual solid was dissolved in clear water, and extracted with ethyl acetate (3X 15 mL), the organic phases were combined, the reaction product in the organic phases was washed with clear water (3X 5 mL), then extracted with 2M sodium hydroxide (5X 5 mL), the aqueous phases were combined, the pH was adjusted to 5-6 with concentrated hydrochloric acid, the solid was precipitated by standing, and dried to obtain a pale yellow product (0.89 g,2.42 mmol) with a yield of 85.1%.
Example 5) Synthesis of 1-methyl-4- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzamide) -3-propyl-1H-pyrazole-5-carboxamide (Compound 8)
5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoic acid (Compound 6,1.00g,2.71 mmol) was dissolved in 10mL of dried dichloromethane, thionyl chloride (3.22 g,27.1 mmol) was added, 3 drops of triethylamine were added dropwise, and after stirring well, the reaction was refluxed for 3-4 hours. After the reaction is finished, the redundant thionyl chloride and solvent are distilled off under reduced pressure to obtain a crude product of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoyl chloride (compound 7), and then about 10mL of a dichloromethane solution of the 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoyl chloride is prepared by dissolving with dry dichloromethane without separation. Then, 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (0.98 g,2.71 mmol), triethylamine (0.027 g, 0.271mmol) and 4-dimethylaminopyridine (0.033 g, 0.271mmol) were sequentially placed in 10mL of dry dichloromethane, stirred and dissolved, a dichloromethane solution of the above 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzoyl chloride was gradually dropped, the reaction was continued until the reaction was completed after the dropping, a proper amount of ice water was added, dichloromethane was sequentially used for extraction (3X 20 mL), the organic phase was washed with clear water (2X 10 mL) and saturated brine (2X 10 mL), then dried over anhydrous sodium sulfate, and concentrated and then subjected to column chromatography separation to obtain 1.26g (2.62 mmol) of pale yellow product, the yield was 83.2%.
Example 6) Synthesis of 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (Compound 9)
1-methyl-4- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzamide) -3-propyl-1H-pyrazole-5-carboxamide (Compound 8,1.00g,1.88 mmol) was dissolved in 10mL of t-butanol, stirred and dissolved, then fresh potassium t-butoxide (0.25 g,2.26 mmol) was added thereto, and the mixture was heated under reflux under nitrogen for about 6-8 hours, and the reaction was cooled to room temperature. About 10mL of ice water is added into the reaction solution, the pH value of the solution is regulated to be neutral by using concentrated hydrochloric acid, stirring is continued for about 1-2 hours at the temperature of 0-10 ℃, solid precipitation and suction filtration are carried out, the filter cake is washed for a plurality of times by using a small amount of ice water, and the filter cake is dried to obtain 0.63g (1.22 mmol) of white solid powder, and the yield is 65.2%. The physical and chemical properties are as follows: m.p.76-77 ℃; the infrared spectrum is: IR (KBr): 3285.5 (. Nu) N-H )，3065.0(ν C-H )，1602.9、1497.0(ν C＝C )，2955.8、2871.5(ν CH3 )，2930.9、2857.7(ν -CH2- )，1712.2(ν C＝O )，1646.8(ν C＝O )，1228.4、1002.2(ν C-O-C )cm -1 The method comprises the steps of carrying out a first treatment on the surface of the The nuclear magnetic resonance hydrogen spectrum is: 1 H NMR(800MHz，CDCl 3 )：δ＝0.99(t,J＝7.4Hz,3H,-CH 3 )，1.20(t,J＝7.4Hz,3H,-CH 3 )，1.84(m,2H,-CH 2 -)，2.06(m,2H,-CH 2 -)，2.92(t,J＝7.7Hz,2H-CH 2 -)，3.22(br,2H,-CH 2 -)，3.33(br,2H,-CH 2 -)，3.75(br,2H,-CH 2 -)，4.01(br,2H,-CH 2 -)，4.24(t,J＝6.4Hz,2H,-OCH 2 -)，4.30(s,3H,-NCH 3 )，6.98(t,J＝7.2Hz,1H,ArH)，7.00(d,J＝7.5Hz,2H,ArH)，7.14(d,J＝8.5Hz,1H,ArH)，7.34(t,J＝7.8Hz,2H,ArH)，7.64(dd,J＝8.5Hz,2.1Hz,1H,ArH)，8.62(d,J＝2.1Hz,1H,ArH)，11.20(s,1H,NH)。 13 C NMR(201MHz，CDCl 3 )：10.79，14.12，22.22，22.50，27.61，38.24，42.15，47.80，49.52，49.79，71.08，112.54，116.71，119.55，120.74 124.17, 128.09, 129.24, 130.44, 131.84, 138.16, 146.51, 147.35, 150.65, 153.72, 157.46, 169.20; the mass spectrum is as follows: HR-ESI-MS (m/z): 515.27686[ M+H ]] + (Positive mode), 513.26151 [ M-H ]] + (negative mode). Purity 99.8% (HPLC), and chromatogram is shown in figure 1.
Synthetic route two examples:
example 7) Synthesis of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde (Compound 4)
3-aldehyde-4-hydroxybenzoic acid (Compound 2,1.00g,6.02 mmol) was dissolved in 10mL of dried dichloromethane, ice-water bath was carried out to 0℃and stirred, then 2mL of a dichloromethane solution in which dicyclohexylcarbodiimide (DCC, 1.49g,7.22 mmol) was dissolved was sequentially added, 5mL of a dichloromethane solution in which 1-phenylpiperazine (0.98 g,6.02 mmol) was dissolved was finally added, 2mL of a dichloromethane solution in which 4-dimethylaminopyridine (0.033 g,0.602 mmol) was dissolved was finally added, the reaction was warmed to room temperature for 2 to 4 hours, after the completion of the reaction, the solvent was removed by spin-evaporation under reduced pressure, then 20mL of ethyl acetate was added, suction filtration was carried out, and the filter cake was washed a small number of times with ethyl acetate, the organic phase was sequentially washed with clear water (2X 20 mL), saturated brine (2X 20 mL) and dried over anhydrous sodium sulfate, and concentrated to obtain 1.41g (4.54 mmol) of a white solid in 75.3% yield.
Example 8) Synthesis of 5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde (Compound 5)
5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde (compound 4,1.00g,3.22 mmol) was dissolved in 50mL of anhydrous acetone, anhydrous potassium carbonate (1.34 g,9.66 mmol) was added, stirred at room temperature for 30 minutes, then 1-bromopropane (0.59 g,4.83 mmol) was added sequentially to the reaction solution, nitrogen was used for protection, reflux reaction was carried out for 8-24 hours, after the reaction was completed, the solvent was distilled off under reduced pressure, the residual solid was dissolved in clear water, and extracted with ethyl acetate or dichloromethane (3X 50 mL), the organic phases were combined, washed sequentially with clear water (2X 50 mL), saturated brine (2X 50 mL), and then dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography separation to obtain 1.02g (2.89 mmol) of pale yellow product, yield 90.2%.
Example 9) Synthesis of 1-methyl-5- (5- (4-phenylpiperazine-1-carbonyl) -2-propoxyphenyl) -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (Compound 9)
5- (4-phenylpiperazine-1-carbonyl) -2-propoxybenzaldehyde (Compound 5,1.00g,2.84 mmol) was dissolved in 10mL of glacial acetic acid, p-toluenesulfonic acid (0.01 g,0.058 mmol), 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (0.52 g,2.84 mmol) was added sequentially, nitrogen protection, the reaction was carried out at reflux for 5-8 hours at elevated temperature, after completion of the reaction, cooled to room temperature, 30mL of clear water was added, and the solid was precipitated, filtered off, dried, and recrystallized to give 0.76g (1.48 mmol) of a white solid powder in 52.1% yield.
5- (4-phenylpiperazine-1-carbonyl) -2-hydroxybenzaldehyde (Compound 4,1.00g,3.22 mmol) was dissolved in 10mL of glacial acetic acid, p-toluenesulfonic acid (0.01 g,0.058 mmol), 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (0.59 g,3.22 mmol) was added sequentially, nitrogen protection, the reaction was carried out under reflux at elevated temperature for 5-8 hours, cooled to room temperature after completion of the reaction, 30mL of clear water was added, a solid was precipitated, suction filtered, dried, and recrystallized to give 0.54g (1.14 mmol) of a white solid powder in 35.5% yield.
The present invention may be summarized in other specific forms without departing from the spirit or essential characteristics thereof. The above embodiments of the present invention should be considered as illustrative and not restrictive, and thus any minor modifications, equivalent changes, and modifications to the above examples, which are made in accordance with the essential techniques of the present invention, are intended to fall within the scope of the present invention.
Claims (5)
1. The preparation method of the nafil compound containing the phenylpiperazine structure is characterized by comprising the following steps of:
step one, carrying out aldehyde formation on p-hydroxybenzoic acid (compound 1) to obtain a compound 2, reacting the compound 2 with an acylating agent to obtain a compound 3, and reacting the compound 3 with a phenylpiperazine compound to obtain a compound 4; x in the structural formula of the compound 3 1 Is Cl or Br;
the preparation method of the compound 2 comprises the following steps:
adding p-hydroxybenzoic acid into trifluoroacetic acid, protecting with nitrogen, stirring for dispersion, dissolving hexamethylenetetramine in trifluoroacetic acid, gradually adding into the reaction solution, wherein the molar ratio of the p-hydroxybenzoic acid to the hexamethylenetetramine is 1:1-1:2, heating the reaction solution to reflux after the addition is finished, cooling to room temperature after the reaction is finished, gradually adding the reaction solution into about 250mL of 15% hydrochloric acid, continuously stirring for about 2-4h, precipitating solid, filtering, washing a filter cake with a small amount of water for many times, and drying in a dark place to obtain a compound 2;
the preparation method of the compound 3 comprises the following steps:
dissolving a compound 2 in a solvent, adding an acylating agent and an alkaline agent, and reacting under a reflux condition to obtain a compound 3, wherein the solvent is dichloromethane, trichloromethane, 1, 2-dichloroethane or 1, 3-dichloropropane, the alkaline agent is triethylamine, tripropylamine, pyridine or 4-dimethylaminopyridine, the acylating agent is thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride, and the molar ratio of the compound 2 to the acylating agent to the alkaline agent is 1:5:0.01-1:20:0.05;
the structure of the phenylpiperazine compound is shown as a formula (II),
（Ⅱ）；
；
step two, reacting the compound 4 with a halide to obtain a compound 5; the halogeno compound is bromo compound or chloro compound; the bromide is 1-bromopropane or 2-bromopropane; the chloro is 1-chloropropane or 2-chloropropane;
；
step three, oxidizing the compound 5 to obtain a compound 6;
；
step four, compound 7 is obtained after the reaction of compound 6 and an acylating agent, and compound 8 is obtained after the reaction of compound 7 and 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide; x in the structural formula of the compound 7 2 Is Cl or Br; the acylating reagent is thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride;
；
step five, ring closure of the compound 8 is carried out in the presence of an alkaline agent to obtain a nafil compound 9 with a phenylpiperazine structure;
；
r in the structure of the above-mentioned compound 1 All are H, R 2 All are propyl groups.
2. The method for preparing a phenylpiperazine structure-containing nafil compound according to claim 1, wherein the specific steps of the second step comprise:
dissolving the compound 4 in a solvent, adding an alkaline agent, stirring at room temperature for 20-50 minutes, adding a halide into the reaction solution, and reacting under the protection of nitrogen and reflux;
the solvent is acetone, acetonitrile, propanol, isopropanol, butanol, tertiary butanol, N '-dimethylformamide, N' -dimethylacetamide or tetrahydrofuran; the alkaline agent is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate or sodium ethoxide; the molar ratio of the compound 4 to the alkaline agent to the halogenide is 1:3:1.1-1:10:2.
3. The method for preparing a phenylpiperazine structure-containing nafil compound according to claim 1, wherein the specific steps of the third step comprise:
dissolving the compound 5 in tetrahydrofuran, adding a sodium dihydrogen phosphate aqueous solution, stirring for 5-15 minutes, and then dropwise adding a mixed aqueous solution of sodium chlorite and hydrogen peroxide, wherein the molar ratio of the compound 5 to the sodium dihydrogen phosphate to the sodium chlorite to the hydrogen peroxide is 1:0.5:3:2-1:1:5:5.
4. The method for preparing the phenylpiperazine structure-containing nafil compound according to claim 1, wherein the specific steps of the fourth step comprise:
dissolving a compound 6 in a solvent, adding an acylating agent and an alkaline agent for reaction under a reflux condition, evaporating the redundant acylating agent and the solvent under reduced pressure after the reaction is finished to obtain a crude product of the compound 7, directly dissolving the crude product of the compound 7 by using a dry solvent to prepare a compound 7 solution, and adding the compound 7 solution into the solution of 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide and the alkaline agent for reaction;
the solvent is dichloromethane, trichloromethane, 1, 2-dichloroethane or 1, 3-dichloropropane; the alkaline agent comprises one or more of triethylamine, tripropylamine, pyridine or 4-dimethylaminopyridine; the mol ratio of the compound 6 to the acylating agent to the alkaline agent is 1:5:0.01-1:20:0.05; the mol ratio of the compound 7 to the 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide to the alkaline agent is 1:1:0.01-1:1.2:0.1.
5. The method for preparing a phenylpiperazine structure-containing nafil compound according to claim 1, wherein the specific steps of the fifth step comprise:
dissolving the compound 8 in an alcohol solvent, adding an alkaline agent, and reacting under a reflux condition;
the alcohol solvent is methanol, ethanol, propanol, isopropanol, butanol or tertiary butanol; the alkaline agent is sodium hydroxide, potassium hydroxide, sodium ethoxide or potassium tert-butoxide; the molar ratio of the compound 8 to the alkaline agent is 1:1-1:2.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5874437A (en) * | 1996-11-01 | 1999-02-23 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| CN1253561A (en) * | 1997-04-25 | 2000-05-17 | 美国辉瑞有限公司 | Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3', 5'-monophosphate phosphodiesterase (cGMP PDE5) for treatment of sexual dysfunction |
| CN1742731A (en) * | 1993-06-09 | 2006-03-08 | 辉瑞爱尔兰药品公司 | Treat the Pyrazolopyrimidinonefor of female sexual disorder |
| CN101747282A (en) * | 2008-12-10 | 2010-06-23 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions and preparation methods and uses thereof |
| CN104650093A (en) * | 2015-02-02 | 2015-05-27 | 王靖林 | Synthesis method of sildenafil analog |
| CN104804003A (en) * | 2015-04-27 | 2015-07-29 | 广州同隽医药科技有限公司 | Synthesis technology of 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone |
| CN107759603A (en) * | 2016-08-18 | 2018-03-06 | 四川科伦药物研究院有限公司 | A kind of preparation method of heterocyclic compound |
| CN113372350A (en) * | 2021-03-22 | 2021-09-10 | 深圳鼎邦生物科技有限公司 | Deuterated sildenafil as well as preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009082845A1 (en) * | 2007-12-28 | 2009-07-09 | Topharman Shanghai Co., Ltd. | N-{1-[3-(2-ethoxy-5-(4-ethylpiperazinyl)benzenesulfonyl)-4,5-dihydro-5-oxo-1,2,4-triazin-6-yl]ethyl}butyramide, the preparation method and use thereof |
| US20090325964A1 (en) * | 2008-05-23 | 2009-12-31 | Wyeth | Piperazine Metabotropic Glutamate Receptor 5 (MGLUR5) Negative Allosteric Modulators For Anxiety/Depression |
-
2022
- 2022-11-23 CN CN202211470714.XA patent/CN115785101B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1742731A (en) * | 1993-06-09 | 2006-03-08 | 辉瑞爱尔兰药品公司 | Treat the Pyrazolopyrimidinonefor of female sexual disorder |
| US5874437A (en) * | 1996-11-01 | 1999-02-23 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| CN1253561A (en) * | 1997-04-25 | 2000-05-17 | 美国辉瑞有限公司 | Pyrazolopyrimidinones which inhibit type 5 cyclic guanosine 3', 5'-monophosphate phosphodiesterase (cGMP PDE5) for treatment of sexual dysfunction |
| CN101747282A (en) * | 2008-12-10 | 2010-06-23 | 上海特化医药科技有限公司 | Phenyl pyrimidone compounds, pharmaceutical compositions and preparation methods and uses thereof |
| CN104650093A (en) * | 2015-02-02 | 2015-05-27 | 王靖林 | Synthesis method of sildenafil analog |
| CN104804003A (en) * | 2015-04-27 | 2015-07-29 | 广州同隽医药科技有限公司 | Synthesis technology of 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone |
| CN107759603A (en) * | 2016-08-18 | 2018-03-06 | 四川科伦药物研究院有限公司 | A kind of preparation method of heterocyclic compound |
| CN113372350A (en) * | 2021-03-22 | 2021-09-10 | 深圳鼎邦生物科技有限公司 | Deuterated sildenafil as well as preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| CAS 2711006-61-8.《Registry》.2021,第1页. * |
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