CN104804003A - Synthesis technology of 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone - Google Patents

Synthesis technology of 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone Download PDF

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CN104804003A
CN104804003A CN201510206468.0A CN201510206468A CN104804003A CN 104804003 A CN104804003 A CN 104804003A CN 201510206468 A CN201510206468 A CN 201510206468A CN 104804003 A CN104804003 A CN 104804003A
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郑庆泉
黄世福
曹徐涛
李永健
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Guangzhou Tongjuan Pharmaceutical Technology Co Ltd
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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
    • C07D487/02—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
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Abstract

The invention discloses a synthesis technology of 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone. The synthesis technology comprises the following steps: mixing substituted aryl aldehyde with 1-methyl-3-propyl-4-amino pyrazole-5-formylamine, and contracting the mixture so as to obtain bisiminophosphorane benzyl benzoate; placing the bisiminophosphorane benzyl benzoate in a solvent, and under the common action of a ring forming agent and a pro-oxygenic agent, performing cyclization oxidization so as to obtain the 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone. The synthesis technology disclosed by the invention is mild in reacting conditions, greatly higher in the conversion rate of a cyclization oxidation reaction, short in the reaction time, and less in the side reactions. The reaction can be carried out in different reactors in two steps, and can also be carried out in the same reactor. A stepwise synthesis method is favorable for the quality control of the bisiminophosphorane benzyl benzoate and the purification of products, the adoption of a one-step synthesis method simplifies the synthetizing working procedures and shortens the reaction time, and all the methods can effectively synthetize the 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone. The used reagent is basically non-toxic or low-toxic, and besides, the synthesis technology is low in cost and is low in synthesis cost.

Description

The synthesis technique of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one
Technical field
The present invention relates to a kind of synthesis technique of key intermediate of medicament, particularly the synthesis technique of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one.
Background technology
Virga (Sildenafil; trade(brand)name: Viagra); chemistry 5-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones by name.Sildenafil citrate is the medicine for the treatment of erective dysfunction and the hypertensive pulmonary vascular disease of being developed by Pfizer drugmaker and being sold.Virga is high selectivity PDE5 (PDE5) inhibitor, and PDE5 expresses at corpus cavernosum penis camber, and in other tissue, (comprising thrombocyte, blood vessel and visceral smooth muscle, skeletal muscle), expression is low.Virga, by Selective depression PDE5, strengthens nitrogen protoxide NO-cGMP approach, raises cGMP level and cause corpus cavernosum smooth muscle to relax, making patients with erectile dysfunction produce natural erectile response to sexual stimulus.This medicine in July, 2000 in Discussion on Chinese Listed.In global range, the annual sales amount of sildenafil citrate is up to 2,000,000,000 dollars, wide market.
The synthesis technique of Virga is complicated, and its key structure fragment is 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one, and the key technical problems synthesizing this compounds is pyrimidone the structure of structure fragment.
With reference to the synthetic route document of Virga and other pertinent literatures, the structure of known pyrimidone structure fragment needs condensation and cyclization two reaction occur, according to the difference of synthesis material and cyclization mode, and existing relevant routes induction and conclusion:
1, patent US5250534, synthetic route is shown in route 1:
Route 1
This route forms amide intermediate with 2-ethoxy benzoyl chloride and the condensation of 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide, and then cyclization obtains Virga key intermediate
2, patent WO0122918A2, synthetic route is shown in route 2:
Route 2
This route forms imine intermediate with 2-oxyethyl group-5-[4-methylpiperazine-1-alkylsulfonyl] phenyl aldehyde and the condensation of 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide, and then cyclization oxidation obtains Virga.
In above-mentioned two synthetic routes, cyclization oxidizing reaction uses NaHSO 3as oxygenant, need high temperature (100-180 DEG C) and reaction for a long time, production unit requires high, and cost increases.
3, patent CN1406939A synthetic route forms imine intermediate with 2-oxyethyl group-5-[4-methylpiperazine-1-alkylsulfonyl] phenyl aldehyde and the condensation of 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide equally, and then cyclization oxidation obtains Virga.
Cyclization oxidizing reaction is used alone FERRIC CHLORIDE ANHYDROUS, and need high temperature and reaction for a long time, yield is low.
4, document N M, B K, Ismail, et al.InCl3-catalysed synthesis of 2-aryl quinazolin-4 (3H)-onesand 5-aryl pyrazolo [4, 3-d] pyrimidin-7 (6H)-ones and their evaluation as potential anticanceragents. [J] .Bioorganic & Medicinal Chemistry Letters, 2012, 22 (15): 5063 – 5066. report 5-aryl-1H-pyrazolo [4, 3-d] synthetic method of pyrimidine-7 (6H)-one, synthetic route is shown in route 3:
Route 3
This route using substituted aroma aldehyde and 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide as raw material, with Lewis acid InCl in acetonitrile 3as catalyzer, " one kettle way " condensation, cyclization oxidation form 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one compounds.
InCl 3expensive cost is high, have heavy-metal residual to endanger, be not suitable for amplifying and produce.
Summary of the invention
The object of the present invention is to provide a kind of synthesis technique of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one.
The technical solution used in the present invention is:
The synthesis technique of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one, comprises the steps:
1) mixed with 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide by the substituted aryl aldehyde shown in formula III, condensation obtains the imine intermediate shown in formula V;
2) by imine intermediate in solvent under the acting in conjunction becoming ring agent and pro-oxygenic agent, cyclization oxidation obtains 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one;
Wherein, become ring agent to be the Lewis acid with oxidation activity, the general structure of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one is such as formula shown in I;
In formula I, III and V, R1, R2 are independently selected from H, halogen, trifluoromethyl, OH, methoxyl group, oxyethyl group, propoxy-, 2-hydroxyl-oxethyl, are positioned at 2 ~ No. 5 positions of ring, are H when R1, R2 are different; X is selected from C or N.
Further, in formula I, III and V, R 1, R 2in one be H, another is halogen, trifluoromethyl, OH, methoxyl group, oxyethyl group, propoxy-or 2-hydroxyl-oxethyl.As 4-fluorine, 2-fluorine, 4-trifluoromethyl, 2-trifluoromethyl, 4-bromine, 2-bromine, 4-chlorine, 3-chlorine, 2-chlorine, 4-methyl, 4-hydroxyl, 2-hydroxyl, 4-methoxyl group, 3-methoxyl group, 2-methoxyl group, 2,4-dimethoxy, 2,5-dimethoxy, 2-(2-hydroxyl-oxethyl), 4-oxyethyl group, 2-oxyethyl group, 2-propoxy-.
Further, in formula I, III and V, one in R1, R2 is H, another 2-oxyethyl group, and X is C.
Preferably, in above-mentioned synthesis technique, as one or more in the solvent selected from methanol used in cyclization oxidation, ethanol, Virahol, acetonitrile, methylene dichloride, ethyl acetate, the best is Virahol.
Preferably, in above-mentioned synthesis technique, ring agent is become to be selected from FERRIC CHLORIDE ANHYDROUS, Iron trichloride hexahydrate, anhydrous chlorides of rase ferrous iron, iron protochloride hydrate, anhydrous cupric chloride, cupric chloride hydrate.Because water carries out unfavorable to reaction, therefore, become ring agent preferably without crystal water.FERRIC CHLORIDE ANHYDROUS is both anhydrous, has again suitable oxidisability, is one of selection of the best.
Preferably, in above-mentioned synthesis technique, the molar ratio becoming ring agent and imine intermediate is (0.05 ~ 5): 1, is further (0.5 ~ 3): 1, (0.8 ~ 1.5): 1, (0.9 ~ 1.1): 1.
Preferably, in above-mentioned synthesis technique, pro-oxygenic agent is oxygen, comprises oxygen and other do not have the gas mixture of oxidation activity gas, as air, or the mixed gas of artificial allotment.The best is pure oxygen.
Preferably, in above-mentioned synthesis technique, the temperature of reaction of cyclization oxidation is 0 ~ 100 DEG C, is 20 ~ 80 DEG C further, is more preferred from 25 ~ 60 DEG C.
The invention has the beneficial effects as follows:
Synthesis technique reaction conditions of the present invention is gentle, the generation substantially increasing the transformation efficiency of cyclization oxidizing reaction, shorten the reaction times, decrease side reaction.
Reaction both can be carried out in two steps respectively in different reactors, also can carry out in same reactor.Step synthesis is conducive to the quality control of intermediate and the purifying of product, one-step synthesis simplifies synthesis procedure and shortens the reaction times, two schemes all effectively can synthesize 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one, respectively has superiority.
The reagent used is nontoxic or low toxicity substantially, simultaneously cheap, effectively can reduce the synthesis cost of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one.
Embodiment
The synthesis technique of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one, comprises the steps:
1) mixed with 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide by the substituted aryl aldehyde shown in formula III, condensation obtains the imine intermediate shown in formula V;
2) by imine intermediate in solvent under the acting in conjunction becoming ring agent and pro-oxygenic agent, cyclization oxidation obtains 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one;
Wherein, become ring agent to be the Lewis acid with oxidation activity, the general structure of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one is such as formula shown in I;
In formula I, III and V, R1, R2 are independently selected from H, halogen, trifluoromethyl, OH, methoxyl group, oxyethyl group, propoxy-, 2-hydroxyl-oxethyl, are positioned at 2 ~ No. 5 positions of ring, are H when R1, R2 are different; X is selected from C or N.
The Lewis acid with oxidation activity not only comprises the Lewis acid itself with certain oxidation activity, is also included within the Lewis acid that can be converted in reaction process and have oxidation activity.
Further, in formula I, III and V, R 1, R 2in one be H, another is halogen, trifluoromethyl, OH, methoxyl group, oxyethyl group, propoxy-or 2-hydroxyl-oxethyl.As 4-fluorine, 2-fluorine, 4-trifluoromethyl, 2-trifluoromethyl, 4-bromine, 2-bromine, 4-chlorine, 3-chlorine, 2-chlorine, 4-methyl, 4-hydroxyl, 2-hydroxyl, 4-methoxyl group, 3-methoxyl group, 2-methoxyl group, 2,4-dimethoxy, 2,5-dimethoxy, 2-(2-hydroxyl-oxethyl), 4-oxyethyl group, 2-oxyethyl group, 2-propoxy-.
Further, in formula I, III and V, one in R1, R2 is H, another 2-oxyethyl group, and X is C.
Preferably, in above-mentioned synthesis technique, as one or more in the solvent selected from methanol used in cyclization oxidation, ethanol, Virahol, acetonitrile, methylene dichloride, ethyl acetate, the best is Virahol.
Preferably, in above-mentioned synthesis technique, ring agent is become to be selected from FERRIC CHLORIDE ANHYDROUS, Iron trichloride hexahydrate, anhydrous chlorides of rase ferrous iron, iron protochloride hydrate, anhydrous cupric chloride, cupric chloride hydrate.Because water carries out unfavorable to reaction, therefore, become ring agent preferably without crystal water.FERRIC CHLORIDE ANHYDROUS is both anhydrous, has again suitable oxidisability, is one of selection of the best.
Preferably, in above-mentioned synthesis technique, the molar ratio becoming ring agent and imine intermediate is (0.05 ~ 5): 1, is further (0.5 ~ 3): 1, (0.8 ~ 1.5): 1, (0.9 ~ 1.1): 1.
Preferably, in above-mentioned synthesis technique, pro-oxygenic agent is oxygen, comprises oxygen and other do not have the gas mixture of oxidation activity gas, as air, or the mixed gas of artificial allotment.The best is pure oxygen.
Preferably, in above-mentioned synthesis technique, the temperature of reaction of cyclization oxidation is 0 ~ 100 DEG C, is 20 ~ 80 DEG C further, is more preferred from 25 ~ 60 DEG C.
The suitable reaction times can be selected by the progress of monitoring reaction.
Below in conjunction with embodiment, further illustrate technical scheme of the present invention.
Embodiment 1,2,3:
1, the synthesis of imine intermediate (1):
Reference European Journal of Medicinal Chemistry, 2014 (80), 201-208 report method synthesizing imine intermediates 1.
2, the synthesis of 5-(2-ethoxyl phenenyl)-1-methyl-3-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (2):
In four-hole bottle, add 30g imine intermediate (1), 300ml Virahol, start stirring, not blowing air, oxygen and pass into air or oxygen, add 15.6g FERRIC CHLORIDE ANHYDROUS, be incubated 55 ~ 65 DEG C of reactions.Thin-layer chromatography is followed the tracks of.After completion of the reaction, steam 200ml, add 450ml purified water, be cooled to suction filtration after room temperature, dry solid.
The qualification result of product is:
1H NMR(500MHz,d 6-DMSO)：δ11.97(s,1H)，7.63(d,J＝7.5Hz,1H)，7.48-7.45(m,1H)，7.13(d,J＝7.5Hz,1H)，7.06-7.03(t,J＝7.5Hz,1H)，4.14(s,3H)，4.10(q,2H)，2.76(t,J＝7.5Hz,2H)，1.75-1.71(m,2H)，1.32(t,J＝7.25Hz,3H)，0.93(t,J＝7.25Hz,3H)；
ESI-MS：313.1，[M+H] +。
Three kinds of different ventilatory conditions results are as following table:
Embodiment Ventilatory conditions React completely the time Yield Purity (HPLC) Solid color
1 Stuffiness 16h, can not be complete
2 Blowing air 8h 86.7％ 96.5％ Yellow
3 Logical oxygen 3h 93.5％ 98.8％ Light yellow
Embodiment 4:
The synthesis of 5-(2-ethoxyl phenenyl)-1-methyl-3-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (2):
2-ethoxy-benzaldehyde 8.15g, 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide 9.6g and Virahol 150ml is added, stirred at ambient temperature 3 hours in 250ml there-necked flask; Pass into oxygen toward reaction system, add 8.56g FERRIC CHLORIDE ANHYDROUS, heat up 60 DEG C of reactions 3 hours; After completion of the reaction, add 180ml purified water, be cooled to room temperature suction filtration, dry solid 15.7g.Yield: 91.4%, purity (HPLC) 98.3%.
Embodiment 5:
The synthesis of 5-(4-aminomethyl phenyl)-1-methyl-3-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (3):
2-ethoxy-benzaldehyde 6.52g, 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide 9.6g and Virahol 150ml is added, stirred at ambient temperature 3 hours in 250ml there-necked flask; Pass into oxygen toward reaction system, add 8.56g FERRIC CHLORIDE ANHYDROUS, heat up 60 DEG C of reactions 3 hours; Steam Virahol and be about 100ml, add 180ml purified water, suction filtration, dry solid 14.2g.Yield: 95.50%.
The qualification result of product is:
1H NMR(400MHz,CDCl 3)：11.1(br s,1H)，7.5(d,2H,J＝11.5Hz)，7.2(d,2H,J＝11.34Hz)，7.2(d,2H,J＝11.34Hz)，2.7(t,2H),2.3(s,3H)，1.7(m,2H),0.98(t,3H)。 13C NMR(CDCl 3,100Hz)：155.1，148.3，145.9，138.7，129.9，124.6，123.3，113.0，55.3，37.8，27.2，22.1，13.8；
ESI-MS：282.6[M+H] +。
Embodiment 6:
The synthesis of 5-(4-chloro-phenyl-)-1-methyl-3-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (4):
2-ethoxy-benzaldehyde 7.63g, 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide 9.6g and Virahol 150ml is added, stirred at ambient temperature 3 hours in 250ml there-necked flask; Add 8.56g FERRIC CHLORIDE ANHYDROUS, stir lower past reaction system and pass into oxygen, heat up 60 DEG C of reactions 3 hours; Steam Virahol and be about 100ml, add 180ml purified water, suction filtration, dry solid 14.8g.Yield: 92.8%.
The qualification result of product is:
1H NMR(400MHz,CDCl 3)：11.12(brs,1H)，8.06(d,J＝8.6Hz,2H)，7.42(d,J＝8.56Hz,2H)，4.13(s,3H)，2.84(t,J＝7.56Hz,2H)，1.76(q,J＝7.34,14.8Hz,2H)，1.01(t,J＝7.34Hz,3H)； 13C NMR(CDCl 3,100Hz)：155.2，148.0，146.2，139.0，137.1，130.7，128.7，128.4，128.1，124.0，37.9，29.2，27.3，21.9，14.1；
ESI-MS：302.9[M+H] +。
Embodiment 7:
The synthesis of 5-(2-oxyethyl group-3-pyridyl)-1-methyl-3-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (5):
2-oxyethyl group-3-pyridylaldehyde 8.20g, 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide 9.6g and Virahol 150ml is added, stirred at ambient temperature 3 hours in 250ml there-necked flask; Add 8.56g FERRIC CHLORIDE ANHYDROUS, stir lower past reaction system and pass into oxygen, 60 DEG C are reacted 3 hours; Steam Virahol and be about 100ml, add 180ml purified water, suction filtration, dry solid 15.7g.Yield heats up: 95.1%.
The qualification result of product is:
1H NMR(400MHz CDCl 3)：11.08(brs.,1H)，8.83(dd,J＝7.6Hz,J＝1.9Hz,1H)，8.29(dd,J＝4.8Hz,J＝1.9Hz,1H)，7.12(dd,J＝7.6Hz,J＝4.8Hz,1H)，4.67(q,J＝7.0Hz,2H)，4.28(s,3H)，2.93(t,J＝7.6Hz,2H)，1.87(sxt,J＝7.6Hz,2H)，1.57(t,J＝7.0Hz,3H)，1.03(t,J＝7.6Hz,3H)； 13C NMR(100MHz,CDCl 3)：159.8，153.7，149.3，146.6，146.5，139.9，138.5，124.5，118.1，114.8，63.4，38.2，27.8，22.4，14.6，14.1；
ESI-MS：314.2[M+H] +。
Above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although by referring to the preferred embodiments of the present invention, invention has been described, but those of ordinary skill in the art is to be understood that, various change can be made to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.

Claims (10)

  1. The synthesis technique of 1.5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one, comprises the steps:
    1) mixed with 1-methyl-3-propyl group-4-amino-pyrazol-5-methane amide by the substituted aryl aldehyde shown in formula III, condensation obtains the imine intermediate shown in formula V;
    2) by imine intermediate in solvent under the acting in conjunction becoming ring agent and pro-oxygenic agent, cyclization oxidation obtains 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one;
    Wherein, become ring agent to be the Lewis acid with oxidation activity, the general structure of 5-aryl-1H-pyrazolo [4,3-d] pyrimidine-7 (6H)-one is such as formula shown in I;
    (formula I), (formula III), (formula V)
    In formula I, III and V, R 1, R 2independently be selected from H, halogen, trifluoromethyl, OH, methoxyl group, oxyethyl group, propoxy-, 2-hydroxyl-oxethyl, be positioned at 2 ~ No. 5 positions of ring, R 1, R 2be asynchronously H; X is selected from C or N.
  2. 2. synthesis technique according to claim 1, is characterized in that: R 1, R 2in one be H, another is halogen, trifluoromethyl, OH, methoxyl group, oxyethyl group, propoxy-or 2-hydroxyl-oxethyl.
  3. 3. synthesis technique according to claim 1, is characterized in that: the solvent selected from methanol used in cyclization oxidation, ethanol, Virahol, acetonitrile, methylene dichloride, one or more in ethyl acetate.
  4. 4. synthesis technique according to claim 1, is characterized in that: R 1, R 2in one be H, another 2-oxyethyl group, X is C.
  5. 5. synthesis technique according to claim 1, is characterized in that: the solvent used in cyclization oxidation is Virahol.
  6. 6. the synthesis technique according to claim 1 or 3, is characterized in that: become ring agent to be selected from FERRIC CHLORIDE ANHYDROUS, Iron trichloride hexahydrate, anhydrous chlorides of rase ferrous iron, iron protochloride hydrate, anhydrous cupric chloride, cupric chloride hydrate.
  7. 7. the synthesis technique according to claim 1 or 3, is characterized in that: pro-oxygenic agent is oxygen.
  8. 8. the synthesis technique according to claim 1 or 3, is characterized in that: the molar ratio becoming ring agent and imine intermediate is (0.05 ~ 5): 1.
  9. 9. the synthesis technique according to claim 1 or 3, is characterized in that: the temperature of reaction of cyclization oxidation is 0 ~ 100 DEG C.
  10. 10. the synthesis technique according to claim 1 or 3, is characterized in that: the temperature of reaction of cyclization oxidation is 25 ~ 60 DEG C.
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* Cited by examiner, † Cited by third party
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CN108658999A (en) * 2018-04-24 2018-10-16 温州大学 The synthetic method of 2- phenyl heterocycles simultaneously [2,3-d] pyrimidine -4 (3H) -one class compound
CN108822111A (en) * 2018-08-02 2018-11-16 温州医科大学 A kind of 5-（2- ethoxyl phenenyl）The preparation method of -1- methyl -3- propyl -1H- pyrazolo [4,3-d] pyrimidin-7-ones
CN115785101A (en) * 2022-11-23 2023-03-14 西安市食品药品检验所 Phenylpiperazine structure-containing nafil compound and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1406939A (en) * 2001-09-04 2003-04-02 广州白云山医药科技发展有限公司 Preparation of Xibo ketone
CN1454892A (en) * 2002-04-29 2003-11-12 广州白云山医药科技发展有限公司 Intermediate for preparing sildenafic and preparing method thereof
KR101127814B1 (en) * 2011-03-14 2012-03-23 에이치 엘 지노믹스(주) Novel intermediate and process for preparing sildenafil or its salt using the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1406939A (en) * 2001-09-04 2003-04-02 广州白云山医药科技发展有限公司 Preparation of Xibo ketone
CN1454892A (en) * 2002-04-29 2003-11-12 广州白云山医药科技发展有限公司 Intermediate for preparing sildenafic and preparing method thereof
KR101127814B1 (en) * 2011-03-14 2012-03-23 에이치 엘 지노믹스(주) Novel intermediate and process for preparing sildenafil or its salt using the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
G. LAKSHMA REDDY ET AL.: "Synthesis of 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs and their biological evaluation as anticancer agents: mTOR inhibitors", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
SANGHAPAL D. SAWANT ET AL.: "Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *

Cited By (5)

* Cited by examiner, † Cited by third party
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CN108658999A (en) * 2018-04-24 2018-10-16 温州大学 The synthetic method of 2- phenyl heterocycles simultaneously [2,3-d] pyrimidine -4 (3H) -one class compound
CN108658999B (en) * 2018-04-24 2021-02-05 温州大学 Synthesis method of 2-phenyl heterocyclic [2,3-d ] pyrimidine-4 (3H) -ketone compound
CN108822111A (en) * 2018-08-02 2018-11-16 温州医科大学 A kind of 5-（2- ethoxyl phenenyl）The preparation method of -1- methyl -3- propyl -1H- pyrazolo [4,3-d] pyrimidin-7-ones
CN115785101A (en) * 2022-11-23 2023-03-14 西安市食品药品检验所 Phenylpiperazine structure-containing nafil compound and preparation method thereof
CN115785101B (en) * 2022-11-23 2023-10-13 西安市食品药品检验所 Phenylpiperazine structure-containing nafil compound and preparation method thereof

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