Name: 139756-21-1|5-(2-Ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one|95%
Brand: Ambeed
SKU: A122141
Price: 11.0 USD
Availability: InStock
Rating: 91 (40 reviews)

1
[ 139756-03-9 ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With aluminum oxide for 0.0166667h; microwave irradiation;
95.4%	With sodium hydroxide In <i>tert</i>-butyl alcohol at 80 - 90℃; for 35h;	2-10 Example 2 Preparation of Compound II Add 50.0g of Compound I, 300ml of tert-butanol to a 1L reaction flask,7.2g NaOH. Warm up to 80-90.CAfter the system was kept at 80-90C for 35h, the temperature was reduced to 0-10C.Use hydrochloric acid solution to adjust the system pH to 6-7. Precipitation of solids,0 ~ 10 crystallization 1 ~ 2h. Filter and wash the filter cake with purified water.Blow dry at 45 for 12-15h. White solid powder was obtained,Compound II was obtained (44.7g, yield 95.40%, purity 99.78%).
93.3%	With sodium hydroxide In ethanol for 3h; Reflux;	1-7 50 g of the compound II was added to the reaction flask, 400 ml of dichloromethane was added thereto, and the mixture was stirred at room temperature, and 2 equivalents of the acid-binding agent triethylamine was added thereto, and the compound I was added thereto, and the mixture was stirred at room temperature for 1 hour, and the dichloromethane was distilled off under reduced pressure, and 250 ml of ethanol was added thereto. 3 equivalents of sodium hydroxide, the temperature was raised to reflux reaction for 3 hours, the reaction was cooled to room temperature, about half of the solvent was distilled off under reduced pressure, 400 ml of purified water was added, and hydrochloric acid was added to adjust pH = 8-9, stirring was continued for 1 hour, suction filtration and drying were obtained. Product 80g, yield 93.3%, HPLC purity 99.72%

85%	With dihydrogen peroxide; sodium hydroxide In ethanol at 200℃; for 0.166667h; Microwave irradiation;	4.3 1-methyl-3-propyl-5 - (2-ethoxy phenyl) - 1,6-dihydro -7H-pyrazolo-[ 4,3-d] pyrimidin-7-one preparation: heating the prepared 6mmol compound 1-methyl-3-propyl-4 - (2-ethoxy methyl amido) pyrazole-5-carboxamide dissolved in 60 ml of ethanol in a mixture with hydrogen peroxide, wherein the volume ratio of ethanol and hydrogen peroxide (20-80): 1, by adding 13mmol naoh, stirring to dissolve, microwave heating 200 °C reaction 10 minutes, after the reaction of the organic solvent is removed by reduced pressure distillation, the residue is distilled water washes, ethyl acetate extraction, organic subtraction-pressure distillation to remove the solvent, and drying to obtain the kind of white 1-methyl-3-propyl-5 - (2-ethoxy phenyl) - 1,6-dihydro -7H-pyrazolo-[ 4,3-d] pyrimidin-7-one, to yield 85%;
72%	With hydrogenchloride; sodium hydroxide; dihydrogen peroxide In methanol; ethanol; dichloromethane; water	7 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one EXAMPLE 7 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid was treated with 2N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1700 ml, 3200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3*400 ml) and brine (300 ml), then dried (Na2 SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (1000 g), using a methanol in dichloromethane elution gradient (0-1%), followed by trituration of the crude product with ether (300 ml), gave the title compound as a colourless solid (152.2 g, 72%), m.p. 143°-146° C. Found: C,65.56; H,6.44; N,18.14. C17 H20 N4 O2 requires C,65.36; H,6.45; N,17.94%.
72%	With hydrogenchloride; sodium hydroxide; dihydrogen peroxide In methanol; ethanol; dichloromethane; water	7 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one PREPARATION 7 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one 4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid was treated with 2N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1700 ml, 3200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3*400 ml) and brine (300 ml), then dried (Na2 SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (1000 g), using a methanol in dichloromethane elution gradient (0-1% methanol), followed by trituration of the crude product with ether (300 ml), gave the title compound as a colourless solid (152.2 g, 72%), m.p. 143°-146° C. Found C,65,56; H,6.44; N,18.14. C17 H20 N4 O2 requires C,65.36; H,6.45; N,17.94%
72%	With hydrogenchloride; sodium hydroxide; dihydrogen peroxide In methanol; ethanol; dichloromethane; water	101 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one EXAMPLE 101 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid was treated with 2N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1700 ml, 3200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3*400 ml) and brine (300 ml), then dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (1000 g), using a methanol in dichloromethane elution gradient (0-1), followed by trituration of the crude product with ether (300 ml), gave the title compound as a colourless solid (152.2 g, 72%), m.p. 143-146° C. Found: C,65.56; H,6.44; N,18.14. C17H20N4O2 requires C,65.36; H,6.45; N,17.94%.
72%	With hydrogenchloride; sodium hydroxide; dihydrogen peroxide In methanol; ethanol; dichloromethane; water	17 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one PREPARATION 17 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid was treated with 2N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1700 ml; 3200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3*400 ml) and brine (300 ml), then dried (Na2SO4) and evaporated under vacuum. Chromatography of the residue on silica gel (1000 g), using a methanol in dichloromethane elution gradient (0-1% methanol), followed by trituration of the crude product with ether (300 ml), gave the title compound as a colourless solid (152.2 g, 72%), m.p. 143-146° C. Found: C,65.56; H,6.44; N,18.14. C17H20N4O2 requires C,65.36; H,6.45; N,17.94%.
72%	With sodium hydroxide; dihydrogen peroxide In ethanol at 90℃; for 2.5h;
	With sodium hydroxide In ethanol; water
	With sodium hydroxide In ethanol
	With sodium ethanolate In ethanol at 120℃; for 0.166667h; Microwave irradiation;	5-(2-ethoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one. (NEU-024, 6) General procedure: To the solution of the pyrazole 4b (30 mg, 1 equiv.)1 and PyBrOP (67 mg, 1.1 equiv.) in DCE (1.5 mL), was added 2-ethoxybenzoic acid (23 mg, 1.05 equiv.) and Et3N (37 µL, 2 equiv.). The reaction was heated in the microwave at 120 oC for 20 min. After cooling down, the reaction mixture was filtered to remove the solid followed by evaporation of the solvent. To the residue was added EtOAc and sat. NH4Cl, and the organic layer was separated, dried under sodium sulfate and evaporated to give ethyl 4-(2-ethoxybenzamido)-3-phenyl-1H-pyrazole-5-carboxylate S1 which was not further characterized. A portion of this material (45 mg, 1 equiv.) was dissolved in dioxane (1 mL) and conc. NH4OH (2 mL) was added. The reaction mixture was stirred for three days. The solvent was then concentrated to give 4-(2-ethoxybenzamido)-3-phenyl-1H-pyrazole-5-carboxamide S2, which was taken to the next step without further purification. To the solution of NaOEt (60 µL, 21% wt, 4 equiv.) in EtOH (1.5 mL) was added S2 (26 mg, 1 equiv.) after which the reaction was heated in the microwave at 120 oC for 10 min. The reaction was neutralized by 1 M HCl to pH ~7, then concentrated to remove most of the ethanol. The residue was filtered, rinsed by H2O and subsequently EtOAc to give 5-(2-ethoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (6) as a pale yellow solid.
228 g	With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 80℃; for 2h;	1.2 Step 2: Synthesis of intermediate M2 In a 2L reaction flask, put 250g intermediate M1 and 1.25L tert-butanol in sequence, stir and disperse, and then add 100g potassium tert-butoxide in batches while stirring, stir and disperse, turn on the heating, and the system will change when the reaction temperature reaches about 80°C. Clear, and continue to react for 2h. After the reaction is completed, the temperature is lowered to 10°C, 2.5L H2O is added, and the pH is adjusted to 7-8 with appropriate 3N hydrochloric acid. Stir and crystallize at 10°C for 1 h. Filter, wash the solid with H2O, drain, collect the solid, and dry the solid at 60°C under reduced pressure. 228 g of white solid was obtained.

Reference： [1]Khan, Khalid Mohammed; Maharvi, Ghulam Murtaza; Choudhary, Muhammad Iqbal; Atta-Ur-Rahman; Perveen, Shahnaz [Journal of Heterocyclic Chemistry, 2005, vol. 42, # 6, p. 1085 - 1093]
[2]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - CN111116591, 2020, A Location in patent: Paragraph 0099-0106
[3]Current Patent Assignee: CHONGQING CONQUER PHARMACEUTICAL - CN108558890, 2018, A Location in patent: Paragraph 0033-0046
[4]Current Patent Assignee: GUANGDONG PHARMACEUTICAL UNIVERSITY - CN103755709, 2016, B Location in patent: Paragraph 0063; 0083; 0093
[5]Current Patent Assignee: PFIZER INC - US5250534, 1993, A
[6]Current Patent Assignee: PFIZER INC - US5272147, 1993, A
[7]Current Patent Assignee: ASTELLAS PHARMA INC. - US6200980, 2001, B1
[8]Current Patent Assignee: ASTELLAS PHARMA INC. - US6200980, 2001, B1
[9]Flores Toque, Haroldo A.; Priviero, Fernanda B. M.; Teixeira, Cleber E.; Perissutti, Elisa; Fiorino, Ferdinando; Severino, Beatrice; Frecentese, Francesco; Lorenzetti, Raquel; Baracat, Juliana S.; Santagada, Vincenzo; Caliendo, Giuseppe; Antunes, Edson; De Nucci, Gilberto [Journal of Medicinal Chemistry, 2008, vol. 51, # 9, p. 2807 - 2815]
[10]Terrett, Nicholas K.; Bell, Andrew S.; Brown, David; Ellis, Peter [Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1819 - 1824]
[11]Haning, Helmut; Niewoehner, Ulrich; Schenke, Thomas; Lampe, Thomas; Hillisch, Alexander; Bischoff, Erwin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907]
[12]Wang, Cuihua; Ashton, Trent D.; Gustafson, Alden; Bland, Nicholas D.; Ochiana, Stefan O.; Campbell, Robert K.; Pollastri, Michael P. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 7, p. 2579 - 2581]
[13]Current Patent Assignee: SUICHENG PHARMACEUTICAL - CN112961160, 2021, A Location in patent: Paragraph 0039-0042; 0046-0047

2
4-[(2-ethoxybenz-(E)-ylidene)amino]-2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid amide [ No CAS ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol Heating;

Reference： [1]Abdel-Jalil, Raid J.; Khanfar, Monther; Abu-Safieh, Kayed; Al-Gharabli, Samer; El-Abadelah, Mustafa; Voelter, Wolfgang [Monatshefte fur Chemie, 2005, vol. 136, # 4, p. 619 - 624]

3
[ 865855-32-9 ]
[ 938-73-8 ]
[ 139756-21-1 ]
[ 139756-03-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,2005,vol. 42,p. 1085 - 1093

4
[ 613-69-4 ]
[ 139756-02-8 ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 100℃;Sealed tube; Microwave irradiation;	We intended to synthesize compounds based on 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one scaffold by using microwave assisted protocol (Scheme 1). In this direction we started the studies for optimization of synthesis of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one 3a. The optimization studies were initiated by screening of different oxidizing agents as depicted in Table1, see Supplementary data using DMSO:Water in 1:1 proportion to see the conversion in desired product. Amongst all oxidants, the best result was observed with K2S2O8, in equivalence studies for catalyst, 3eq. of catalyst has given maximum yields (Table1, see Supplementary data). Therefore, all reactions were conducted using this condition after optimization of catalyst. However, oxone has also given the product 3a with minor yields. After screening of the catalyst we started study of selectivity for solvent that could affect the formation of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one 3a. The solvent screening was carried out to find out the best conversion, the mixture of DMSO:H2O in 1:1 proportion has given the best results with excellent yields (Table2, see Supplementary data). The microwave protocols were optimized for this reaction as mentioned in Table 3, see Supplementary data; the reactions carried under different microwave Watt powers have given varied results. Wherein, entry 3(b) (Table3, see Supplementary data) was found to be the best condition for maximum conversion. A series of compounds based on 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one scaffold was synthesized using these optimized conditions, wherein, all kind of substrates with diversity around aryl ring were chosen for conversion and in all cases products obtained in good to excellent yields (Table1).
91.4%		To a 250 ml three-necked flask was added 8.15 g of <strong>[613-69-4]2-ethoxybenzaldehyde</strong>, 9.6 g of 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide and 150 ml of isopropanol, 3 hours; to the reaction system into the oxygen, add 8.56g anhydrous ferric chloride, temperature 60 C reaction 3 hours; reaction is completed, add 180ml of purified water, cooled to room temperature filtration, drying solid 15.78. Yield:
83%		Step 7: Synthesis of 5-(2-ethoxyphenyl)-1 -methyl-3-propyl-1H-pyrazolo[4,3- d]pyrimidin-7(611)-one:- 4-amino-i -methyi-3-propyi- 1 H-pyrazole-5-earboxamide (7.0gm 3.84 m.ml) and 2-ethoxybenz- aldehyde (6.0 gm 4.0 m.ml) were suspended in ethanol and the mixture was heated at 70 C for 1.5 hours after conformation of forming of imine by TLC. Added CuC12 (15.4 gm 11.5 m ml) and the reaction mixture heated at 70 C under 02 for 1.5 hours. After there action was completed, the ethanol was removed under vacuum. Then work up was carried out using ethyl acetate and water.The organic layer was separated and water layer re-extracted with 100 ml ethyl acetate. The combined organic layers are washed with brine solution, concentrated under vacuum; Yield 83%. ?H NMR (400 MHz CDC13): 10.80(s 1H), 8.46(m 1H), 7.47(m 1H), 7.14(m 1H) 7.06(m 1H) 4.38 (q, J=7.OHz 2H), 4.27(s 3H), 2.94(t, J= 7.6 Hz 2H), 1 .87(m 2H), 1 .64(t, J = 7.0Hz 3H). 1 .03(t J = 7.2Hz 3H). ppm MASS: ESI [M + H] :313.14

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 80,p. 201 - 208
[2]Patent: CN104804003,2017,B .Location in patent: Paragraph 0067; 0068; 0069; 0070
[3]Heterocycles,2005,vol. 65,p. 1821 - 1827
[4]Patent: WO2015/114647,2015,A1 .Location in patent: Page/Page column 48

5
5-propyl-4<i>H</i>-pyrazole-3-carboxylic acid ethyl ester [ No CAS ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: NaOH 2: HNO₃; H₂SO₄ 3: NH₃ 4: SnCl₂ 5: NEt₃; DMAP / CH₂Cl₂ 6: NaOH / ethanol

Reference： [1]Haning, Helmut; Niewoehner, Ulrich; Schenke, Thomas; Lampe, Thomas; Hillisch, Alexander; Bischoff, Erwin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907]

6
[ 139756-01-7 ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: SnCl₂ 2: NEt₃; DMAP / CH₂Cl₂ 3: NaOH / ethanol
	Multi-step reaction with 3 steps 1: palladium on activated charcoal; hydrogen / methanol / 30 °C / 2585.81 Torr 2: triethylamine / dichloromethane / 20 °C 3: sodium hydroxide; dihydrogen peroxide / ethanol; water / 100 °C
	Multi-step reaction with 2 steps 1.1: iron; ammonium chloride / ethanol; water / 4.5 h / 80 °C 2.1: ethanol / 1.5 h / 70 °C 2.2: 1.5 h / 70 °C

Multi-step reaction with 3 steps 1: palladium on activated charcoal; hydrogen / methanol / 30 °C / 2585.81 Torr 2: triethylamine / dichloromethane / 20 °C 3: sodium hydroxide; dihydrogen peroxide / water; ethanol / 100 °C

Reference： [1]Haning, Helmut; Niewoehner, Ulrich; Schenke, Thomas; Lampe, Thomas; Hillisch, Alexander; Bischoff, Erwin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907]
[2]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2014/131855, 2014, A1
[3]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2015/114647, 2015, A1
[4]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2016/20307, 2016, A1

7
[ 42926-52-3 ]
[ 139756-21-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 3900 - 3907
[2]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 1819 - 1824
[3]Patent: CN103755709,2016,B

8
[ 36983-31-0 ]
[ 139756-21-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 3900 - 3907
[2]Patent: WO2014/131855,2014,A1
[3]Patent: WO2016/20307,2016,A1

9
[ 139755-99-0 ]
[ 139756-21-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 3900 - 3907
[2]Patent: WO2014/131855,2014,A1
[3]Patent: WO2015/114647,2015,A1
[4]Patent: WO2016/20307,2016,A1

10
[ 133261-07-1 ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: NaOH 2: HNO₃; H₂SO₄ 3: NH₃ 4: SnCl₂ 5: NEt₃; DMAP / CH₂Cl₂ 6: NaOH / ethanol
	Multi-step reaction with 7 steps 1: hydrogenchloride / water / 100 °C 2: nitric acid; sulfuric acid / 50 °C 3: thionyl chloride / Reflux 4: ammonium hydroxide / tetrahydrofuran / 2 h / Cooling with ice 5: palladium on activated charcoal; hydrogen / methanol / 30 °C / 2585.81 Torr 6: triethylamine / dichloromethane / 20 °C 7: sodium hydroxide; dihydrogen peroxide / ethanol; water / 100 °C
	Multi-step reaction with 5 steps 1.1: sodium hydroxide / 3 h / 75 °C 2.1: sulfuric acid; nitric acid / 8 h / 50 °C 3.1: thionyl chloride / 5 h / Reflux 4.1: iron; ammonium chloride / ethanol; water / 4.5 h / 80 °C 5.1: ethanol / 1.5 h / 70 °C 5.2: 1.5 h / 70 °C

Multi-step reaction with 7 steps 1: hydrogenchloride; water / 100 °C 2: sulfuric acid; nitric acid / 50 °C 3: thionyl chloride / Reflux 4: ammonium hydroxide / tetrahydrofuran / 2 h / Cooling with ice 5: palladium on activated charcoal; hydrogen / methanol / 30 °C / 2585.81 Torr 6: triethylamine / dichloromethane / 20 °C 7: sodium hydroxide; dihydrogen peroxide / water; ethanol / 100 °C

Reference： [1]Haning, Helmut; Niewoehner, Ulrich; Schenke, Thomas; Lampe, Thomas; Hillisch, Alexander; Bischoff, Erwin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907]
[2]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2014/131855, 2014, A1
[3]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2015/114647, 2015, A1
[4]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2016/20307, 2016, A1

11
[ 139756-02-8 ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NEt₃; DMAP / CH₂Cl₂ 2: NaOH / ethanol
	Multi-step reaction with 2 steps 1: 93 percent / ethanol / 1 h / Heating 2: 85 percent / tBuOK / 2-methyl-propan-2-ol / Heating
	Multi-step reaction with 2 steps 1: Et₃N, DMAP / CH₂Cl₂ 2: NaOH / ethanol; H₂O

	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 °C 2: sodium hydroxide; dihydrogen peroxide / ethanol; water / 100 °C
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 °C 2: sodium hydroxide; dihydrogen peroxide / water; ethanol / 100 °C
	Multi-step reaction with 2 steps 1: ethanol / 1.5 h / 70 °C 2: copper dichloride; oxygen / ethanol / 1.5 h / 70 °C
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1.5 h / 20 °C 2: sodium hydroxide / <i>tert</i>-butyl alcohol / 35 h / 80 - 90 °C
	Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / ethyl acetate / 1 h / 40 °C 1.2: 36 h / Reflux 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 2 h / 80 °C

Reference： [1]Haning, Helmut; Niewoehner, Ulrich; Schenke, Thomas; Lampe, Thomas; Hillisch, Alexander; Bischoff, Erwin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907]
[2]Abdel-Jalil, Raid J.; Khanfar, Monther; Abu-Safieh, Kayed; Al-Gharabli, Samer; El-Abadelah, Mustafa; Voelter, Wolfgang [Monatshefte fur Chemie, 2005, vol. 136, # 4, p. 619 - 624]
[3]Terrett, Nicholas K.; Bell, Andrew S.; Brown, David; Ellis, Peter [Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1819 - 1824]
[4]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2014/131855, 2014, A1
[5]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2016/20307, 2016, A1
[6]Reddy, G. Lakshma; Dar, Mohd. Ishaq; Hudwekar, Abhinandan D.; Mahajan, Priya; Nargotra, Amit; Baba, Adil Manzoor; Nandi, Utpal; Wazir, Priya; Singh, Gurdarshan; Vishwakarma, Ram A.; Syed, Sajad Hussain; Sawant, Sanghapal D. [Bioorganic Chemistry, 2019, vol. 89]
[7]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - CN111116591, 2020, A
[8]Current Patent Assignee: SUICHENG PHARMACEUTICAL - CN112961160, 2021, A

12
[ 139756-00-6 ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: NH₃ 2: SnCl₂ 3: NEt₃; DMAP / CH₂Cl₂ 4: NaOH / ethanol
	Multi-step reaction with 5 steps 1: thionyl chloride / Reflux 2: ammonium hydroxide / tetrahydrofuran / 2 h / Cooling with ice 3: palladium on activated charcoal; hydrogen / methanol / 30 °C / 2585.81 Torr 4: triethylamine / dichloromethane / 20 °C 5: sodium hydroxide; dihydrogen peroxide / ethanol; water / 100 °C
	Multi-step reaction with 3 steps 1.1: thionyl chloride / 5 h / Reflux 2.1: iron; ammonium chloride / ethanol; water / 4.5 h / 80 °C 3.1: ethanol / 1.5 h / 70 °C 3.2: 1.5 h / 70 °C

Multi-step reaction with 5 steps 1: thionyl chloride / Reflux 2: ammonium hydroxide / tetrahydrofuran / 2 h / Cooling with ice 3: palladium on activated charcoal; hydrogen / methanol / 30 °C / 2585.81 Torr 4: triethylamine / dichloromethane / 20 °C 5: sodium hydroxide; dihydrogen peroxide / water; ethanol / 100 °C

Reference： [1]Haning, Helmut; Niewoehner, Ulrich; Schenke, Thomas; Lampe, Thomas; Hillisch, Alexander; Bischoff, Erwin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907]
[2]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2014/131855, 2014, A1
[3]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2015/114647, 2015, A1
[4]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2016/20307, 2016, A1

13
[ 613-69-4 ]
[ 139756-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 93 percent / ethanol / 1 h / Heating 2: 85 percent / tBuOK / 2-methyl-propan-2-ol / Heating
	Multi-step reaction with 2 steps 1: ethanol / 1.5 h / 70 °C 2: copper dichloride; oxygen / ethanol / 1.5 h / 70 °C

Reference： [1]Abdel-Jalil, Raid J.; Khanfar, Monther; Abu-Safieh, Kayed; Al-Gharabli, Samer; El-Abadelah, Mustafa; Voelter, Wolfgang [Monatshefte fur Chemie, 2005, vol. 136, # 4, p. 619 - 624]
[2]Reddy, G. Lakshma; Dar, Mohd. Ishaq; Hudwekar, Abhinandan D.; Mahajan, Priya; Nargotra, Amit; Baba, Adil Manzoor; Nandi, Utpal; Wazir, Priya; Singh, Gurdarshan; Vishwakarma, Ram A.; Syed, Sajad Hussain; Sawant, Sanghapal D. [Bioorganic Chemistry, 2019, vol. 89]

14
[ 139756-21-1 ]
[ 147676-70-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With Oxone; potassium bromide In water; acetone at 23℃; for 2h;
80%	With bromine In acetic acid at 20℃;
79.7%	With bromine In acetic acid at 20℃;	Preparation of intermediate I-i 2a: 5-(5-Bromo-2-ethoxyrhenyl)-1 -methyl-3-rroryl-1 H-ryrazolo[4,3-dlryrimidin-7(6H)-one To a solution of intermediate I-09a (2 g, 6.41 mmol) in AcOH (30 mL) was added Br2 (1 .25 g, 7.69 mmol) slowly, the reaction mixture was stirred at room temperature overnight, then Na2SO3 (0.0189 g, 3 mmol) and water was added into the reaction mixture, stirred at r.t for 2 hours. Then the reaction mixturewas concentrated under vacuo and extracted by EA and washed with water and dried by Na2SO4, then concentrated under vacuo to give I-i 2a (2 g, 79.7%). ESI-MS (Mi-i): 391 calc. for C17H19BrN4O2: 390.2.

79.7%	With bromine; acetic acid at 20℃;	Preparation of intermediate 1-12a: 5-(5-Bromo-2-ethoxyphenyl)-1 -methyl-3- propyl-1 H-pyrazolo[4,3-dlpyrimidin-7(6H)-one Preparation of intermediate 1-12a: 5-(5-Bromo-2-ethoxyphenyl)-1 -methyl-3- propyl-1 H-pyrazolo[4,3-dlpyrimidin-7(6H)-one To a solution of intermediate l-09a (2 g, 6.41 mmol) in AcOH (30 ml_) was added Br2 (1 .25 g, 7.69 mmol) slowly, the reaction mixture was stirred at room temperature overnight, then Na2SO3 (0.0189 g, 3 mmol) and water was added into the reaction mixture, stirred at r.t. for 2 hours. Then the reaction mixture was concentrated under vacuo and extracted by EA and washed with water and dried by Na2SO4, then concentrated under vacuo to give 1-12a (2 g, 79.7%). ESI-MS (M+1 ): 391 calc. for Ci7H19BrN4O2: 390.2.
45%	With bromine In methanol; dichloromethane; acetic acid	21 5-(5-Bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one EXAMPLE 21 5-(5-Bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one Bromine (0.93 g, 0.0058 mol) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Preparation 7, 1.1 g, 0.00352 mol) in glacial acetic acid (20 ml). The mixture was stirred at 100° C. for 6.5 hours and the solvent was then removed by evaporation under vacuum. The residue was dissolved in a 9:1 mixture of methanol in dichloromethane (50 ml), and the solution washed with saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml) and saturated brine (50 ml), then dried (MgSO4) and evaported under vacuum. The residue was chromatographed in silica gel (15 g) eluding with a mixture of methanol and dichloromethane (1:99) to give, after crystallisation from acetonitrile, the title compound (0.62 g, 45%), m.p. 157°-159° C. Found C,52,41; H,5.25; N,14.01. C17 H19 BrN4 O2 requires C,52.18; H,4.89; N,14.32%.

Reference： [1]Shavnya, Andrei; Coffey, Steven B.; Smith, Aaron C.; Mascitti, Vincent [Organic Letters, 2013, vol. 15, # 24, p. 6226 - 6229]
[2]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; De Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso De Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004]
[3]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2014/131855, 2014, A1 Location in patent: Page/Page column 82
[4]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2016/20307, 2016, A1 Location in patent: Page/Page column 52
[5]Current Patent Assignee: PFIZER INC - US5272147, 1993, A

15
[ 139756-21-1 ]
5-(2-Ethoxy-5-nitrophenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sulfuric acid; potassium nitrate at 0℃; for 0.333333h;
95%	With sulfuric acid; potassium nitrate at 0℃;
85%	With sulfuric acid; nitric acid at -10℃;	4.4 4) 1-methyl-3-propyl-5 - (2-ethoxy-5-nitrophenyl) - 1,6-dihydro -7H-pyrazolo-[ 4,3-d] pyrimidin-7-one preparation : - 10 °C conditions, preparing volume ratio (1-5): 1 with concentrated nitric acid mixed solution of concentrated sulfuric acid of 10 ml, under stirring, by adding 4.5mmol1-methyl-3-propyl-5 - (2-ethoxy phenyl) - 1,6-dihydro -7H-pyrazolo-[ 4,3-d] pyrimidin-7-one, after stirring to dissolve, -10 ° C reaction 10h rear, directly the reaction liquid after the reaction is poured into the ice water and stirring the precipitate generating completely, is filtered and dried to obtain 1-methyl-3-propyl-5 - (2-ethoxy-5-nitrophenyl) - 1,6-dihydro -7H-pyrazolo-[ 4,3-d] pyrimidin-7-one, to yield 85%;

61%	With nitric acid In dichloromethane; sulfuric acid; water	17 5-(2-Ethoxy-5-nitrophenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one PREPARATION 17 5-(2-Ethoxy-5-nitrophenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one Concentrated nitric acid (0.5 ml) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (2.0 g, 0.0064 mol) in concentrated sulphuric acid (10 ml) at 0° C., an the resulting orange solution was stirred at room temperature for 18 hours. The reaction solution was then added dropwise to stirred ice and water (200 g) and the solid precipitate collected by filtration. This solid was then dissolved in dichloromethane (50 ml) and the solution washed successively with brine (2*30 ml) and water (30 ml), dried (Na2 SO4) and evaporated under vacuum to give a yellow solid. Crystallisation from acetronitrile gave the title compound as yellow needles (1.40 g, 61%), m.p. 214°-216° C. Found: C,57.36; H,5.21; N,19.49. C17 H19 N5 O4 requires C,57.13; H,5.36; N,19.60%.
61%	With nitric acid In dichloromethane; sulfuric acid; water	27 5-(2-Ethoxy-5-nitrophenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one PREPARATION 27 5-(2-Ethoxy-5-nitrophenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one Concentrated nitric acid (0.5 ml) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2.0 g, 0.0064 mol) in concentrated sulphuric acid (10 ml) at 0° C., and the resulting orange solution was stirred at room temperature for 18 hours. The reaction solution was then added dropwise to stirred ice and water (200 g) and the solid precipitate collected by filtration. This solid was then dissolved in dichloromethane (50 ml) and the solution washed successively with brine (2*30 ml) and water (30 ml), dried (Na2SO4) and evaporated under vacuum to give a yellow solid. Crystallisation from acetonitrile gave the title compound as yellow needles (1.40 g, 61%), m.p. 214-216° C. Found: C,57.35; H,5.21; N,19.49. C17H19N5O4 requires C,57.13; H,5.36; N,19.60%.
	With sulfuric acid; potassium nitrate at 0℃; for 0.333333h;	Preparation of intermediate I-98a: 5-(2-ethoxy-5-nitro-rhenyl)-1 -methyl-3- roryl-6H-ryrazolo[4 ,3-d1yrim id in-7-one To a solution of intermediate I-09a (1 .0 g, 3.21 mmol) in concentrated sulfuricacid (5 mL) was added KNO3 (324 mg, 3.21 mmol) in portions at 0°C, thenthe reaction mixture was stirred at 0°C for 20 mm until LC-MS showed thestarting material was consumed completely, then the mixture was poured into ice water and extracted with EtOAc three times, the organic layer was washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, concentrated to give the crude intermediate I-98a (1.10 g, 95.65%) as a white solid. ESIMS (Mi-i): 358 calc. for Cl 7H1 9N504: 357.1.

Reference： [1]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; De Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso De Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004]
[2]Bremerich, Maximilian; Conrads, Christian M.; Langletz, Tim; Bolm, Carsten [Angewandte Chemie - International Edition, 2019, vol. 58, # 52, p. 19014 - 19020][Angew. Chem., 2019, vol. 131, p. 19190 - 19196,7]
[3]Current Patent Assignee: GUANGDONG PHARMACEUTICAL UNIVERSITY - CN103755709, 2016, B Location in patent: Paragraph 0064; 0084; 0094
[4]Current Patent Assignee: PFIZER INC - US5272147, 1993, A
[5]Current Patent Assignee: ASTELLAS PHARMA INC. - US6200980, 2001, B1
[6]Current Patent Assignee: FUNDACION PARA LA INVESTIGACION MEDICA APLICADA - WO2014/131855, 2014, A1 Location in patent: Page/Page column 99; 100

16
[ 598-21-0 ]
[ 139756-21-1 ]
5-(5-Bromoacetyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	In dichloromethane; water	8 5-(5-Bromoacetyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one PREPARATION 8 5-(5-Bromoacetyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one Aluminium trichloride (12.8 g, 0.096 mol) was added portionwise over 1 hour to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (10.0 g, 0.032 mol) and bromoacetyl bromide (5.6 ml, 0.064 mol) in dichloromethane (150 ml) at 0° C. After 18 hours at room temperature, the reaction mixture was poured into ice an water (400 g) and the resulting mixture stirred vigorously. The organic phase was separated and the aqueous phase further extracted with dichloromethane (2*100 ml). The organic solutions were combined, dried (Na2 SO4) and evaporated under vacuum to give an off-white solid, trituration of which from ether gave the title compound as a white solid (10.87 g, 78%), m.p. 159°-160° C. Found C,52,54; H,4.88; N,12.78. C19 H21 BrN4 O3 requires C,52.67; H,4,88; N,12.93%
78%	With aluminium trichloride In dichloromethane; water	18 5-(5-Bromoacetyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one PREPARATION 18 5-(5-Bromoacetyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one Aluminum trichloride (12.8 g, 0.096 mol) was added portionwise over 1 hour to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (10.0 g, 0.032 mol) and bromoacetyl bromide (5.6 ml, 0.064 mol) in dichloromethane (150 ml) at 0° C. After 18 hours at room temperature, the reaction mixture was poured into ice and water (400 g) and the resulting mixture stirred vigorously. The organic phase was separated and the aqueous phase further extracted with dichloromethane (2*100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum to give an off-white solid, trituration of which from ether gave the title compound as a white solid (10.87 g, 78%), m.p. 159-160° C. Found: C,52.54; H,4.88; N,12.78. C19H21BrN4O3 requires C,52.67; H,4.88; N,12.93%.
25%	With aluminum (III) chloride In dichloromethane at 0 - 15℃; for 16h;

Reference： [1]Current Patent Assignee: PFIZER INC - US5272147, 1993, A
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US6200980, 2001, B1
[3]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; De Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso De Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [ACS Chemical Neuroscience, 2019, vol. 10, # 3, p. 1765 - 1782]

17
[ 139756-21-1 ]
[ 946856-58-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	With trichlorophosphate at 0 - 80℃; for 2 - 4h;	1.3.2; 3 Method 2(X) (5 g, 0.015 mol) was added into a 50 mL three-neck bottle in an ice bath. POCl3 (20 mL) was added dropwise into the bottle to prepare a solution. The solution was heated at 80 0C for 2 hours, the mixture was poured into ice water to stop the reaction, and then the mixture was extracted with dichlo- romethane (3 x 30 mL) . The organic phase was washed with brine(2 x 10 mL) and dried over anhydrous sodium sulfate (2 g) , followed by concentration in vacuo to obtain (IV) (X=Cl, 4.4 g, yield 83 %) as a white solid.(X) (5 g, 0.016 mol) was added into a 50 mL three-neck bottle in an ice bath. POCl3 (10 mL) was added dropwise into the bottle to prepare a solution. The solution was heated for 4 hours at 50 0C, the mixture was poured onto ice to stop the reaction, and then the mixture was extracted with dichloromethane(3 x 30 mL) . The organic phase was washed with brine (2 x 10 mL) and dried over anhydrous sodium sulfate (2 g) for 30 minutes, followed by concentration to obtain (IV) (X=Cl, 4.4 g) as a white solid.
83%	With trichlorophosphate at 80℃; Cooling with ice;	1.3.2 The compound of formula (X) (5 g, 0.015 mol) was added into a 50 mL three-neck flask in an ice bath. POCl3 (20 mL) was added dropwise into the flask to prepare a solution. After heated at 80° C. for 2 hours, the mixture was poured into 20 mL of ice-water to quench the reaction, and extracted with dichloromethane (3×30 mL). The combined organic phase was washed with brine (2×10 mL) and dried over anhydrous sodium sulfate (2 g), followed by concentration in vacuo to give the compound of formula (IV) (4.4 g, yield 83%) as a white solid.
	With trichlorophosphate In tetrachloromethane for 20h; Heating;

Reference： [1]Current Patent Assignee: SHANDONG TEFAMAN PHARMACEUTICAL MATERIAL - WO2008/74512, 2008, A1 Location in patent: Page/Page column 19; 28
[2]Current Patent Assignee: SHANDONG TEFAMAN PHARMACEUTICAL MATERIAL - US2010/48897, 2010, A1 Location in patent: Page/Page column 8
[3]Kumar, Rajesh; Joshi [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2007, vol. 46, # 12, p. 2021 - 2025]

18
[ 139756-21-1 ]
[ 139756-22-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With chlorosulfonic acid; for 12h;Cooling with ice;	Example 1 Preparation of 5-(2-ethoxy-5-chlorosulfonyl)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyr azolo[4,3-d]pyrimidine-7-one Chlorosulfuric acid (50ml)was added into a 100ml three-neck flask with a stirrer, 5-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidi ne-7-one (31.2g (0.1mol)) was added in batches under stirring in an ice bath. The reaction was exothermic and was performed for 12 hrs. The reaction solution was slowly poured into icy water (100g), a white solid was separated out, filtered, dried. A white solid (30g)was obtained with a yield of 76%.
76%	With chlorosulphuric acid; for 12h;Cooling with ice;	Chlorosulfuric acid (50 ml) was added into a 100 ml three-neck flask with a stirrer, 5-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (31.2 g (0.1 mol)) was added in batches under stirring in an ice bath. The reaction was exothermic and was performed for 12 hrs. The reaction solution was slowly poured into icy water (100 g), a white solid was separated out, filtered, dried. A white solid (30 g) was obtained with a yield of 76%.
75.9%	With chlorosulfonic acid; at -10 - 25℃; for 3h;	4. Preparation of 5-(2-ethoxyphenyl-5-chlorosulphonyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-ketone (ZTH-4): [0031] At a temperature of -10 C., adding 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-ketone (50 g, 160 mmo) into 100 ml chlorosulfonic acid, keeping the reaction solution at temperature no greater than 25 C. during dropping; upon dropping completes, reacting under room temperature for 3 hours; pouring the reaction liquid into crushed ice, mechanically stirring, keeping the temperature no greater than 25 C.; and then stirring under room temperature for 1 hour, filtering and drying, 50 g white solid ZTH-4 is obtained, wherein the yield is 75.9%.

75%	With chlorosulfonic acid; at 0 - 5℃;	Step 8: Synthesis of 4-ethoxy-3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d] pyrimidin-5-yl) benzene-1-sulfonyl chloride:- To the chlorosulphonic acid (10 eq) was added 5-(2-ethoxyphenyl)- 1 -methyl-3-propyl- 1 H-pyrazolo[4,3 -d]pyrimidin-7(6H)- one (1 eq) while maintaining the temperature 0 C. Then reaction was allowed toproceed at 5 C until TLC analysis indicated the absence of starting material. After the reaction was completed then cooled CHC13 and ice in ice bath was added to the reaction mixture. Organic layer was separated. Water layer was re-extracted with 2 x 100 ml cold CHC13 and the combined organic layer are washed with brine solution, concentrated under vacuum; Yield 75%. ?H NMR (400 MHz, CDC13) 6 10.78(s 1H),8.72 (d, J= 1.4Hz, 1H), 8.04 (dd, J = 7.5, 1.4 Hz, 1H), 7.33 (d, J 7.5 Hz, 1H), 4.38(q J =6.8Hz2H),4.27(s 3H), 2.92(t J= 7.6 Hz 2H), l.87(m 2H), 1.65(t J= 6.8Hz 3H). l.02(t J=7.2Hz 3H). ESI [M + H] : 411.13
50 g	With chlorosulfonic acid; at -10 - 25℃; for 3h;	At a temperature of -10C, adding 5-(2- ethoxyphenyl)-1- methyl-3- propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-ketone (50g, 160mmo) into 100ml chlorosulfonic acid, keeping the reaction solution at temperature no greaterthan 25C during dropping; upon dropping completes, reacting under room temperature for 3 hours; pouring the reactionliquid into crushed ice, mechanically stirring, keeping the temperature no greater than 25C; and then stirring under roomtemperature for 1 hour, filtering and drying, 50g white solid ZTH-4 is obtained, wherein the yield is 75.9%.
2.0 g	With chlorosulfonic acid; at 20℃; for 2h;Cooling with ice;	I-09a (2.5 g, 8.0 mmol) was added into CISO3H (R-05, 10 mL) at ice-water and stirred at r.t. for 2 hours. The reaction mixture was quenched by adding water, and then filtrated. The filtrate cake was collected and dried under vacuo to give I-i Oa (2.0 g) ESI-MS (Mi-i): 411 calc. for C17H19C1N404S: 410.1.
2 g	With chlorosulfonic acid; at 20℃; for 2h;Cooling with ice;	Preparation of intermediate 1-10a: 4-Ethoxy-3-(6,7-dihvdro-1 -methyl-7-oxo-3- propyl-1 H-pyrazolo[4,3-c lpyrimidin-5-yl)benzene-1 -sulfonyl chloride l-09a (2.5 g, 8.0 mmol) was added into CISO3H (R-05, 10 ml_) at ice-water and stirred at r.t. for 2 hours. The reaction mixture was quenched by adding water, and then filtrated. The filtrate cake was collected and dried under vacuo to give 1-10a (2.0 g) ESI-MS (M+1 ): 41 1 calc. for d7H19CIN4O4S: 410.1.
	With chlorosulfonic acid; at 0 - 5℃;	To the chlorosulphonic acid (3.0mL, 36.58mmol) was added 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (1g, 2.4mmol) while maintaining the temperature 0C, then reaction was allowed to proceed at 0-5C until TLC analysis indicated the absence of starting material. After completion, to the reaction mixture, cold CHCl3 was added and to it ice was added in portions. Organic layer was separated and re-extracted the water layer with 2×100mL cold CHCl3 and the combined organic layer are washed with brine solution, concentrated under vacuum; Yield 75%.

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 2807 - 2815
[2]Angewandte Chemie - International Edition,2017,vol. 56,p. 221 - 224
Angew. Chem.,2017,vol. 129,p. 227 - 230,4
[3]Chemical Communications,2016,vol. 52,p. 10245 - 10248
[4]Patent: EP2666776,2013,A1 .Location in patent: Paragraph 0022; 0023
[5]Patent: US2014/18351,2014,A1 .Location in patent: Paragraph 0044; 0045
[6]Patent: US2013/116265,2013,A1 .Location in patent: Paragraph 0030; 0031
[7]Patent: WO2015/114647,2015,A1 .Location in patent: Page/Page column 48
[8]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2010,vol. 49,p. 84 - 88
[9]Journal of the Indian Chemical Society,2008,vol. 85,p. 1045 - 1049
[10]Journal of Medicinal Chemistry,2016,vol. 59,p. 8967 - 9004
[11]Patent: EP2589601,2013,A1 .Location in patent: Paragraph 0019; 0030; 0031
[12]Patent: WO2014/131855,2014,A1 .Location in patent: Page/Page column 82
[13]Patent: WO2016/20307,2016,A1 .Location in patent: Page/Page column 51
[14]ACS Chemical Neuroscience,2019,vol. 10,p. 1765 - 1782
[15]Bioorganic Chemistry,2019,vol. 89
[16]Patent: CN111116591,2020,A .Location in patent: Paragraph 0107-0123

19
[ 79-04-9 ]
[ 139756-21-1 ]
[ 1058653-74-9 ]

Yield	Reaction Conditions	Operation in experiment
89.6%	Stage #1: chloroacetyl chloride With aluminum (III) chloride at 20℃; for 0.166667h; Green chemistry; Industrial scale; Stage #2: 5-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one Green chemistry; Industrial scale;	2.1 (1) Compound (B) Preparation of 5- [2-ethoxy-5- (chloromethyl-1-ylcarbonyl)] phenyl-1-methyl-3-n-propyl-1,6-dihydro -7H-pyrazolo [4,3-d] pyrimidin-7-one 180g (1.592mol) of chloroacetyl chloride was put into a dry 500ml reaction flask, and the reaction solution was cooled to below 20 ° C. 125g (0.9370mol) of anhydrous aluminum trichloride was put into batch at 20 , and the mixture was stirred for 10 minutes.After the reaction was completed, the reaction solution was cooled to below 20 ° C by ice water, 55.72g (0.1785mol) of compound (A) was put into the reaction flask in batches, and the feed rate was controlled so that the internal temperature did not exceed 20 ° C.Casting completed, the reaction was stirred at 45-50 4h.After the reaction is completed, the reaction liquid is added back to the ice-water mixture until the solid material is completely precipitated, filtered, and the solid material is collected and washed with water to a pH value of 4-5, filtered and dried to obtain 62.2g of a white solid material.Namely compound (B). Yield: 89.6% (calculated as Compound A).
78%	With aluminum (III) chloride In tetrachloromethane at 5℃; Reflux;

Reference： [1]Current Patent Assignee: Wang Jinglin; Liu Guizhen; Yu Ruimei; Zeng Qingmei; Li Yang; Wang Song - CN104650093, 2017, B Location in patent: Paragraph 0020; 0045; 0046
[2]Location in patent: experimental part Kumar, Rajesh; Joshi [Journal of the Indian Chemical Society, 2007, vol. 84, # 12, p. 1261 - 1265]

20
sildenafil citrate [ No CAS ]
[ 1357931-55-5 ]
[ 139756-21-1 ]
[ 139756-03-9 ]
Desmethylsildenafil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide In water at 80℃; for 3h;

Reference： [1]Location in patent: experimental part Kumar, A.Phani; Ganesh; Prasad, K. Hari; Hariharakrishnan; Dubey; Rao, B. Venugopala [Asian Journal of Chemistry, 2011, vol. 23, # 3, p. 1219 - 1222]

21
[ 134-11-2 ]
[ 139756-21-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2579 - 2581
[2]Patent: CN103755709,2016,B

22
[ 139756-21-1 ]
[ 1258305-28-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: chlorosulfonic acid / 3 h / -10 - 25 °C 2: triethylamine / tetrahydrofuran / 20 °C 3: methanol / 1.5 h / Reflux
	Multi-step reaction with 3 steps 1: chlorosulfonic acid / 3 h / -10 - 25 °C 2: triethylamine / tetrahydrofuran / 20 °C 3: methanol / 1.5 h / Heating

Reference： [1]Current Patent Assignee: ZHONG RONG SUZHOU MAIDIXIAN PHARMACEUTICAL TECHNOL - EP2589601, 2013, A1
[2]Current Patent Assignee: ZHONG RONG SUZHOU MAIDIXIAN PHARMACEUTICAL TECHNOL - US2013/116265, 2013, A1

23
[ 139756-21-1 ]
[ 1257393-31-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: chlorosulfonic acid / 12 h / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / chloroform / 12 h / pH 9 / Cooling with ice
	Multi-step reaction with 2 steps 1: chlorosulphuric acid / 12 h / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / chloroform / 12 h / pH 9 / Cooling with ice
	Multi-step reaction with 2 steps 1: chlorosulfonic acid / chloroform / 0.17 h / 25 °C / Flow reactor 2: chloroform / 0.08 h / 25 °C / Flow reactor

Reference： [1]Current Patent Assignee: ZHEJIANG DADE PHARMACEUTICAL GROUP CO., LTD. - EP2666776, 2013, A1
[2]Current Patent Assignee: ZHEJIANG DADE PHARMACEUTICAL GROUP CO., LTD. - US2014/18351, 2014, A1
[3]Sthalam, Vinay Kumar; Mahajan, Bhushan; Karra, Purushotham Reddy; Singh, Ajay K.; Pabbaraja, Srihari [RSC Advances, 2021, vol. 12, # 1, p. 326 - 330]

24
[ 139756-21-1 ]
5-[2-ethoxy-5-(4-methyl-1-homopiperazinylsulfonyl)]-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one citrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: chlorosulfonic acid / 12 h / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / chloroform / 12 h / pH 9 / Cooling with ice 3: acetone / 12 h / Cooling with ice
	Multi-step reaction with 3 steps 1: chlorosulphuric acid / 12 h / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / chloroform / 12 h / pH 9 / Cooling with ice 3: acetone / 12 h / Cooling with ice

Reference： [1]Current Patent Assignee: ZHEJIANG DADE PHARMACEUTICAL GROUP CO., LTD. - EP2666776, 2013, A1
[2]Current Patent Assignee: ZHEJIANG DADE PHARMACEUTICAL GROUP CO., LTD. - US2014/18351, 2014, A1

25
[ 139756-21-1 ]
[ 479074-06-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With Lawessons reagent In toluene for 2h; Reflux;
72%	With pyridine; diphosphorus pentasulfide In toluene for 6h; Reflux;	4 Example 4 Preparation of 2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrim idine-7-thione Example 4 Preparation of 2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrim idine-7-thione [0027] [0028] 2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyri midine-7-one (50g (0.16mol)), phosphorus pentasulfide (17.8g (0.08mol)), pyridine (250ml)were added into a 500ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75ml)and ethanol 300ml were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45g)was obtained. The crude product was heated and solved into chloroform (150ml), activated carbon (5g)was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38g)was obtained with a yield of 72%
72%	With pyridine; tetraphosphorus decasulfide for 6h; Reflux;	4 Example 4 Preparation of 2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-thione 2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (50 g (0.16 mol)), phosphorus pentasulfide (17.8 g (0.08 mol)), pyridine (250 ml) were added into a 500 ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75ml) and ethanol 300ml were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45 g) was obtained. The crude product was heated and solved into chloroform (150 ml), activated carbon (5 g) was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38 g) was obtained with a yield of 72%.

Reference： [1]Zhang, Lijun; Seo, Jae Hong; Li, Huan; Nam, Ghilsoo; Yang, Hyun Ok [British Journal of Pharmacology, 2018, vol. 175, # 16, p. 3347 - 3360]
[2]Current Patent Assignee: ZHEJIANG DADE PHARMACEUTICAL GROUP CO., LTD. - EP2666776, 2013, A1 Location in patent: Paragraph 0027; 0028
[3]Current Patent Assignee: ZHEJIANG DADE PHARMACEUTICAL GROUP CO., LTD. - US2014/18351, 2014, A1 Location in patent: Paragraph 0049; 0050

26
[ 139756-21-1 ]
[ 459834-16-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium bromide; Oxone / water; acetone / 2 h / 23 °C 2.1: potassium pyrosulfite; sodium formate; palladium diacetate; triphenylphosphine; 1,10-Phenanthroline; tetraethylammonium bromide / dimethyl sulfoxide / 20 h / 70 °C / Inert atmosphere; Microwave irradiation 2.2: 20 h / 23 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: N-iodo-succinimide; iron(III) chloride / acetonitrile / 5 h / 70 °C 2.1: potassium pyrosulfite; sodium formate; palladium diacetate; triphenylphosphine; 1,10-Phenanthroline; tetraethylammonium bromide / dimethyl sulfoxide / 2 h / 70 °C / Inert atmosphere; Microwave irradiation 2.2: 20 h / 23 °C / Inert atmosphere

Reference： [1]Shavnya, Andrei; Coffey, Steven B.; Smith, Aaron C.; Mascitti, Vincent [Organic Letters, 2013, vol. 15, # 24, p. 6226 - 6229]
[2]Shavnya, Andrei; Coffey, Steven B.; Smith, Aaron C.; Mascitti, Vincent [Organic Letters, 2013, vol. 15, # 24, p. 6226 - 6229]

27
[ 139756-21-1 ]
[ 139755-83-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium bromide; Oxone / water; acetone / 2 h / 23 °C 2.1: potassium pyrosulfite; sodium formate; palladium diacetate; triphenylphosphine; 1,10-Phenanthroline; tetraethylammonium bromide / dimethyl sulfoxide / 3 h / 70 °C / Inert atmosphere; Microwave irradiation 2.2: 0.5 h / 0 - 23 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: chlorosulfonic acid / 0 - 20 °C / Sealed tube 2: tetrahydrofuran / 3 h / 20 °C / Sealed tube
	Multi-step reaction with 2 steps 1: chlorosulfonic acid / 12 h / 20 - 30 °C 2: dichloromethane / 20 - 30 °C

Multi-step reaction with 2 steps 1: chlorosulfonic acid; thionyl chloride / 0 - 20 °C / Sealed tube 2: acetone / 3 h / 20 °C / Sealed tube

Reference： [1]Shavnya, Andrei; Coffey, Steven B.; Smith, Aaron C.; Mascitti, Vincent [Organic Letters, 2013, vol. 15, # 24, p. 6226 - 6229]
[2]Laha, Joydev K.; Patel, Ketul V.; Satyanarayana Tummalapalli; Dayal, Neetu [Chemical Communications, 2016, vol. 52, # 67, p. 10245 - 10248]
[3]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - CN111116591, 2020, A
[4]Laha, Joydev K.; Gulati, Upma; Saima; Gupta, Anjali; Indurthi, Harish Kumar [New Journal of Chemistry, 2021, vol. 45, # 5, p. 2643 - 2648]

28
[ 139756-21-1 ]
[ 1491216-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium bromide; Oxone / water; acetone / 2 h / 23 °C 2.1: potassium pyrosulfite; sodium formate; palladium diacetate; triphenylphosphine; 1,10-Phenanthroline; tetraethylammonium bromide / dimethyl sulfoxide / 3.25 h / 70 °C / Inert atmosphere; Microwave irradiation 2.2: 20 h / 23 °C / Inert atmosphere