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Structure of 139756-22-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
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 76percent.
76%
for 12 h; 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 76percent.
75.9%
at -10 - 25℃; for 3 h;
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 75.9percent.
75%
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 75percent. ‘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
at -10 - 25℃; for 3 h;
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 (50g, 160mmo) into 100ml chlorosulfonic acid, keeping the reaction solution at temperature no greaterthan 25°C 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 25°C; and then stirring under roomtemperature for 1 hour, filtering and drying, 50g white solid ZTH-4 is obtained, wherein the yield is 75.9percent.
2.0 g
at 20℃; for 2 h; 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
at 20℃; for 2 h; 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.
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 9, p. 2807 - 2815
[2] Angewandte Chemie - International Edition, 2017, vol. 56, # 1, p. 221 - 224[3] Angew. Chem., 2017, vol. 129, # 1, p. 227 - 230,4
[4] Chemical Communications, 2016, vol. 52, # 67, p. 10245 - 10248
[5] Patent: EP2666776, 2013, A1, . Location in patent: Paragraph 0022; 0023
[6] Patent: US2014/18351, 2014, A1, . Location in patent: Paragraph 0044; 0045
[7] Patent: US2013/116265, 2013, A1, . Location in patent: Paragraph 0030; 0031
[8] Patent: WO2015/114647, 2015, A1, . Location in patent: Page/Page column 48
[9] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 1, p. 84 - 88
[10] Journal of the Indian Chemical Society, 2008, vol. 85, # 10, p. 1045 - 1049
[11] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
[12] Patent: EP2589601, 2013, A1, . Location in patent: Paragraph 0019; 0030; 0031
[13] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 82
[14] Patent: WO2016/20307, 2016, A1, . Location in patent: Page/Page column 51
General procedure: 56.1 g of N-methylpiperazine was added to a 2 L three-necked flask, and 800 ml of purified water was added.Stir well, add 100 g of the compound of the formula (I), using mechanical stirring.The temperature was raised to 50 C, and the reaction was carried out for 1 to 3 hours. After the reaction of the raw materials was monitored,Stop the reaction, reduce to room temperature, add 0.2 eq 10% sodium hydroxide solution, stir for 10 min, suction filtration, filter cake with purified waterWashing to the eluent pH=7-8, the filtered cake after rinsing is dried at 105 C to a constant weight to obtain 108.3 g of product, the yield is 93.7%; pureThe degree is 99.99%.After the reaction is completed, a small amount of alkali solution is added to adjust the pH of the solution, which is mainly used to remove acidic impurities in the system.Further improving the purity of the product, the lye may be a sodium hydroxide solution, a sodium carbonate solution or a potassium carbonate solution.
91%
With triethylamine; In methanol; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
86.1 - 95.5%
With triethylamine; In isopropyl alcohol; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
76.5%
With sodium hydroxide; In water; ethyl acetate; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
75.7%
With sodium hydroxide; In water; toluene; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
73%
With triethylamine; In acetonitrile; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
72%
With triethylamine; In butanone; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
70%
With sodium hydroxide; In methanol; water; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
67.1%
With triethylamine; In ethanol; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
62.3 - 72.7%
With triethylamine; In acetone; at 20℃; for 0.75h;Product distribution / selectivity;
Using the procedure described in Example 1, the reaction solvent and proton scavenger were varied.
57.5 - 91%
With sodium hydroxide; In water; acetone; at 20 - 22℃; for 0.75 - 1h;Product distribution / selectivity;
In a 3-necked flask, benzene sulfonyl chloride-3- (4, 7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo (4,3-d) pyrimidin-5-yl) -4-ethoxyphenyl) (5 g, 12.2 mmol) was mixed with acetone (100 ml) at room temperature, then aqueous NaOH 47% (0. 487g, 10 mmol) was added. N-methyl piperazine (1.34 g, 11 mmol) was added dropwise. The reaction mixture was stirred for 45 min, then cooled to 0C and filtered. The precipitate was washed with water twice and dried at 50C under 10 mm Hg to give sildenafil in a 88. 8% yield.; In a 3-necked flask, benzene sulfonyl chloride-3- (4, 7-dihydro-l-methyl-7-oxo- 3-propyl-lH-pyrazolo (4,3-d) pyrimidin-5-yl)-4-ethoxyphenyl) (100 g, 0.24 mol) was mixed with acetone (1000 ml) at room temperature and NaOH (9.74 g, 47%). N- methyl piperazine (26.8 g, 0.27 mol) was added dropwise. The reaction mixture was stirred for 45 min, cooled to 0C, and filtered. The collected precipitate was washed with water twice and dried at 50C under 10 mm Hg to yield pure sildenafil in 85% yield.; In a 3-necked flask, N-methyl piperazine (1.34 g, 13.4 mol) and NaOH (47%, 0.49 g) were mixed at room temperature. Benzene sulfonyl chloride-3- (4, 7-dihydro- 1-methyl-7-oxo-3-propyl-IH-pyrazolo (4,3-d) pyrimidin-5-yl) -4-ethoxyphenyl) (5 g, 12.2 mmol) was suspended in acetone (50 ml) and the suspension was added to the mixture of bases to form a reaction mixture. The reaction mixture was stirred for 45 min, cooled to 0C, and filtered. The collected precipitate was washed with water twice and dried at 50C under 10 mm Hg to yield pure sildenafil in 87% yield.; In a 3-necked flask, N-methyl piperazine (1.34 g, 13.4 mmol) and benzene sulfonyl chloride-3- (4, 7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo (4,3-d) pyrimidin-5-yl) -4-ethoxyphenyl) (5 g) were suspended in acetone (50 ml) at room temperature. NaOH (0.49 g, 47%) was added dropwise. The reaction mixture was stirred for 45 min, cooled to 0C, and filtered. The collected precipitate was washed with water twice and dried at 50C under 10 mm Hg to give pure sildenafil in 86. 3% yield.; In a 0.25 L reactor equipped with mechanical stirrer and thermometer, 100 ml of acetone was added. The reactor was maintained at room temperature (22C). 5.35 g of N-methyl piperazine (1. 1 equivalents) followed by 4.16 g of NaOH solution (47%, 1 equivalent) were added. 20 g ofl- [ [3- (4, 7-Dihydro-l-methyl-7-oxo-3- propyl-lH-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl chloride was added portion-wise (5 g each). The reaction mixture was kept at room temperature with mixing for 1 hour. The reaction mixture was kept at 5C for 2 hours. During that period, sildenafil base precipitated. After filtration, the cake was washed with water (50 ml). 29.24 g wet sildenafil base was obtained. In a 0.5 L reactor equipped with mechanical stirrer and thermometer, 27 g wet sildenafil base and 100 ml water were added. The reaction mixture was maintained at 25C with mixing for 1 hour and filtered. 23. 5g wet sildenafil base was obtained. (Yield 91%)
a 3-necked flask, benzene sulfonyl chloride-3- (4, 7-dihydro-l-methyl-7-oxo- 3-propyl-lH-pyrazolo (4,3-d) pyrimidin-5-yl) -4-ethoxyphenyl) (10 g, 0.024 mol) was mixed with acetone (100 ml) and NaOH (0.974 g, 47%) at room temperature. N-methyl piperazine (2. 68 g, 0.027 mol) was added dropwise to the mixture. Thereafter, the reaction was stirred for 45 min, additional acetone (100 ml) was added, and then the mixture was heated to reflux. Citric acid (5 g, 0.024 mol) was added, and a white precipitate appeared immediately. The reaction was maintained at reflux for one hour and then allowed to cool to room temperature over 3 hours. The precipitate was collected by filtration, and dried at 50C under 10 mm Hg to give pure sildenafil citrate in 72% yield.
EXAMPLE 8 5-(5-Chlorosulphonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (10.0 g, 32.1 mmol) was added portionwise to chlorosulphonic acid (20 ml) at 0 C. under a nitrogen atmosphere. After being stirred overnight, the reaction solution was cautiously added to ice-water (150 ml) and the aqueous mixture extracted with a 9:1 mixture of dichloromethane and methanol (4*100 ml). The combined extracts were dried (Na2 SO4) and evaporated under vacuum to give the required sulphonyl chloride as a white solid (12.8 g, 97%), m.p. 179-181 C. Found: C,50.07; H,4.71; N, 13.29. C17 H19 ClN4 O4 S requires C,49.70; H,4.66; N, 13.64%.
97%
EXAMPLE 102 5-(5-Chlorosulphonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4 3-d]pyrimidin-7-one 5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (10.0 g, 32.1 mmol) was added portionwise to chlorosulphonic acid (20 ml) at 0 C. under a nitrogen atmosphere. After being stirred overnight, the reaction solution was cautiously added to ice-water (150 ml) and the aqueous mixture extracted with a 9:1 mixture of dichloromethane and methanol (4*100 ml). The combined extracts were dried (Na2SO4) and evaporated under vacuum to give the required sulphonyl chloride as a white solid (12.8 g, 97%), m.p. 179-181 C. Found: C,50.07; H,4.71; N,13.29. C17H19CIN4O4S requires C,49.70; H,4.66; N,13.64%.
4
[ 39546-32-2 ]
methanoldimethylformamide[ No CAS ]
[ 139756-22-2 ]
5-[2-Ethoxy-5-(4-carbamoylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
In methanol; ethanol; dichloromethane;
EXAMPLE 9 5-[2-Ethoxy-5-(4-carbamoylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 4-Carbamoylpiperidine (703 mg, 5.50 mmol) was added to a stirred suspension of 5-(5-chlorosulphonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (750 mg, 1.80 mmol) in ethanol (50 ml) at room temperature. The resulting mixture was stirred for 4 days before removing the solvent by evaporation under vacuum. The residue was dissolved in a 9:1 mixture of dichloromethane and methanol (100 ml) and the solution washed with saturated aqueous sodium carbonate solution (100 ml). The aqueous phase was further extracted with dichloromethane-methanol mixtures (3*100 ml) and all the organic fractions were combined, dried (MgSO4) and evaporated under vacuum to give a solid. Crystallisation from a mixture of methanoldimethylformamide gave the title sulphonamide as an off-white solid (446 mg, 49%), m.p. 274-276 C. Found: C,55.36; H,6.01; N,16.65. C23 H29 N6 O5 S requires C,55.08; H,5.83; N,16.75%.
With trichlorophosphate; at 70 - 80℃; for 2h;Product distribution / selectivity;
Method 4(VIII) (5 g, 0.012 mol) was added into a 50 mL flask, POCl3 (10 mL) was added slowly to prepare a solution, the reaction mixture was heated at 80 0C for 2 hours and then poured into ice-water (20 mL) . The resulting solid was collected by filtration, washed with ice water until the filtrate was neutral, and dried in vacuo to obtain (III) (X=Cl, 4.8 g, yield 92 %) as a white solid.Method 5(VIII) (5 g, 0.012 mol) was added into a 50 mL flask, POCl3 (10 mL) was added slowly to prepare a solution, the reaction mixture was heated at 70 0C for 2 hours and then poured into ice water (20 mL) . The resulting solid was collected by filtration, washed with ice water until the filtrate was neutral, <n="23"/>and dried in vacuo to obtain (III) (X=Cl, 4.8 g, yield 92 %) as a white solid.
92%
With trichlorophosphate; at 80℃; for 2h;Product distribution / selectivity;
The compound of formula (VIII) (5 g, 0.012 mol) was added into a 50 mL flask, and POCl3 (10 mL) was added slowly to prepare a solution. After heated at 80 C. for 2 hours, the reaction mixture was then poured into ice-water (20 mL). The resulting white solid was collected by filtration, washed with ice-water until the dropwise filtrate was neutral, and dried under vacuum to obtain the compound of formula (III) (4.8 g, yield 92%) as a white solid.
67%
With phosphorus pentachloride; In benzene; at 0 - 90℃; for 2.5h;Product distribution / selectivity;
Method 6(VIII) (5 g, 0.012 mol) was dissolved in benzene (40 inL) . PCl5 was added into the solution in an ice bath. 30 minutes later, the ice bath was removed, the reaction mixture was heated at 90 0C for 2 hours and then poured into ice water (20 inL) . The resulting solid was collected by filtration, washed with ice water until the filtrate was neutral, and dried in vacuo to obtain (III) (X=Cl, 3.5 g, yield 67 %) as a white solid.
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%.
In ethanol; at 100℃; for 1h;Microwave irradiation;
To a solution of I-lOa (0.41 g, 1 mmol) in ethanol (273 ml) was addedpiperazine (R-06a, 0.256 g, 2 mmol) and the mixture was stirred at 10000under microwave (MW) for 1 hour. The reaction mixture was concentratedunder vacuo to give 1-1 1 a (0.4 g, 86.8% yield). ESI-MS (Mi-i): 461 calc. for 021H28N604S: 460.2.
86.8%
In ethanol; at 100℃; for 1h;Microwave irradiation;
Preparation of intermediate 1-1 1 a: /V-([3-(6,7-dihvdro-1 -methyl-7-oxo-3-propyl- 1 /-/-pyrazolo[4,3-c lpyrimidin-5-yl)-4-ethoxy1benzene-1 -sulfonyl)piperazine To a solution of 1-10a (0.41 g, 1 mmol) in ethanol (273 ml_) was added piperazine (R-06a, 0.256 g, 2 mmol) and the mixture was stirred at 100 C under microwave (MW) for 1 hour. The reaction mixture was concentrated under vacuo to give 1-1 1 a (0.4 g, 86.8% yield). ESI-MS (M+1 ): 461 calc. for
With triethylamine; In ethanol; at 0 - 10℃; for 1h;Inert atmosphere;
A mixture, at ambient temperature and in a nitrogen atmosphere, of <strong>[139756-22-2]4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride</strong> (1.0 g, 2.4 mmol) in ethanol (10 mL)is slowly added to a mixture of 1,4-diazepane (0.25 g, 2.4 mmol) and triethylamine (0.37 g, 3.64 mmol) in ethanol (10 mL). After one hour, eliminate the solvent, dissolve the product in dichloromethane and wash with brine. Dry the organic phase and eliminate the solvent to obtain compound 1 with a 36.25% yield.; The product was analyzed giving the following results: white solid; m.p. 156-159C. IR numax (cm-1): 3299, 2932, 1698, 1601, 1534, 1487, 1467, 1330, 1246, 1155, 1027, 813, 759 ( Figure 1 ). RMN 1H (200 MHz, CDCl3) delta (ppm): 1.02 (t, 3H, J= 7.0 Hz); 1.65 (t, 3H, J= 7.0 Hz); 1.86 (m, 4H); 2.93 (m, 6H); 3.45 (m, 4H); 4.25 (s, 3H); 4.35 (c, 2H, J= 7.0 Hz); 7.14 (d, 1H, Jo = 8.8 Hz); 7.88 (dd, 1H, Jm = 2.6 Hz, Jo = 8.8 Hz); 8.85 (d, 1H, Jm = 2.6 Hz); 10.91 (a, 1H), ( Figure 2 ). ESI/EM: [M+1]+ 475 m/z ( Figure 3 ).; Examples 2 to 6 were obtained under the experimental conditions described for example 1, using different stoichiometric ratios between the substrates, as well as the experimental modifications specified in Table 2. Table 2. Conditions for optimizing the compound 1.
With triethylamine; In ethanol; at 20℃; for 1h;Inert atmosphere;
A mixture, at ambient temperature and in a nitrogen atmosphere, of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (1.0 g, 2.4 mmol) in ethanol (10 mL)is slowly added to a mixture of 1,4-diazepane (0.25 g, 2.4 mmol) and triethylamine (0.37 g, 3.64 mmol) in ethanol (10 mL). After one hour, eliminate the solvent, dissolve the product in dichloromethane and wash with brine. Dry the organic phase and eliminate the solvent to obtain compound 1 with a 36.25% yield.; The product was analyzed giving the following results: white solid; m.p. 156-159C. IR numax (cm-1): 3299, 2932, 1698, 1601, 1534, 1487, 1467, 1330, 1246, 1155, 1027, 813, 759 ( Figure 1 ). RMN 1H (200 MHz, CDCl3) delta (ppm): 1.02 (t, 3H, J= 7.0 Hz); 1.65 (t, 3H, J= 7.0 Hz); 1.86 (m, 4H); 2.93 (m, 6H); 3.45 (m, 4H); 4.25 (s, 3H); 4.35 (c, 2H, J= 7.0 Hz); 7.14 (d, 1H, Jo = 8.8 Hz); 7.88 (dd, 1H, Jm = 2.6 Hz, Jo = 8.8 Hz); 8.85 (d, 1H, Jm = 2.6 Hz); 10.91 (a, 1H), ( Figure 2 ). ESI/EM: [M+1]+ 475 m/z ( Figure 3 ).; Examples 8 to 11 were performed under the experimental conditions described in example 1, changing only the stoichiometric ratio to 1:1.1 for the chlorosulfonyl derivate and the suitable derivates of 1,4-diazepane, respectively (Table 3).
With triethylamine; In ethanol; at 20℃; for 1h;Inert atmosphere;
A mixture, at ambient temperature and in a nitrogen atmosphere, of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (1.0 g, 2.4 mmol) in ethanol (10 mL)is slowly added to a mixture of 1,4-diazepane (0.25 g, 2.4 mmol) and triethylamine (0.37 g, 3.64 mmol) in ethanol (10 mL). After one hour, eliminate the solvent, dissolve the product in dichloromethane and wash with brine. Dry the organic phase and eliminate the solvent to obtain compound 1 with a 36.25% yield.; The product was analyzed giving the following results: white solid; m.p. 156-159C. IR numax (cm-1): 3299, 2932, 1698, 1601, 1534, 1487, 1467, 1330, 1246, 1155, 1027, 813, 759 ( Figure 1 ). RMN 1H (200 MHz, CDCl3) delta (ppm): 1.02 (t, 3H, J= 7.0 Hz); 1.65 (t, 3H, J= 7.0 Hz); 1.86 (m, 4H); 2.93 (m, 6H); 3.45 (m, 4H); 4.25 (s, 3H); 4.35 (c, 2H, J= 7.0 Hz); 7.14 (d, 1H, Jo = 8.8 Hz); 7.88 (dd, 1H, Jm = 2.6 Hz, Jo = 8.8 Hz); 8.85 (d, 1H, Jm = 2.6 Hz); 10.91 (a, 1H), ( Figure 2 ). ESI/EM: [M+1]+ 475 m/z ( Figure 3 ).; Examples 8 to 11 were performed under the experimental conditions described in example 1, changing only the stoichiometric ratio to 1:1.1 for the chlorosulfonyl derivate and the suitable derivates of 1,4-diazepane, respectively (Table 3).; Examples 12 to 15 were performed under the experimental conditions described in example 9, with the modifications described in Table 4.
92.2%
With N-ethyl-N,N-diisopropylamine; In chloroform; for 12h;pH 9.0;Cooling with ice;
Example 2 Preparation of 5-[2-ethoxy-5-(4-methyl-1-homopiperazinylsulfonyl)]-phenyl-1-methyl-3-n-pro pyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one 5-(2-ethoxy-5-chlorosulfonyl)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-py razolo[4,3-d]pyrimidine-7-one (20.5g (0.05mol)), dried chloroform (205ml)were added into a 500ml three-neck flask with a stirrer, stirred in an ice bath, and N-methylhomopiperazine (5.65g)was further added, pH value was regulated to approximate 9 with diisopropyl ethylamine, and the reaction was performed for 12 hours. It was concentrated, ethyl acetate (200ml)was added, washed with water, dried, and then a white solid (22.5g)was obtained with a yield of 92.2%.
92.2%
With N-ethyl-N,N-diisopropylamine; In chloroform; for 12h;pH 9.0;Cooling with ice;
5-(2-ethoxy-5-chlorosulfonyl)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (20.5 g (0.05 mol)), dried chloroform (205 ml) were added into a 500 ml three-neck flask with a stirrer, stirred in an ice bath, and N-methylhomopiperazine (5.65g) was further added, pH value was regulated to approximate 9 with diisopropyl ethylamine, and the reaction was performed for 12 hours. It was concentrated, ethyl acetate (200 ml) was added, washed with water, dried, and then a white solid (22.5 g) was obtained with a yield of 92.2%
Add ZTH-4 (36g, 10mmol, 1eq), ZTH-3 (17.6g, 10mmol, 1eq), and triethylamine (60.6g, 60mmol, 6eq) into 500ml tetrahydrofuran, stirring under room temperature for overnight; evaporating the solvent; adding 200ml water and 200ml methylene chloride, separating, and rinsing the methylene chloride layer with saturated sodium bicarbonate water solution and saturated brine solution in turn, and then drying and condensing, the residue obtains 32g white crystal ZTH- 5 with recrystallizing 10 times amount of ethanol, and then obtains 16.5g white crystal ZTH-5 with recrystallizing another 50 times amount of ethanol, wherein the yield is 37%.
37%
With triethylamine; In tetrahydrofuran; at 20℃;
5. Preparation of 5-[2-ethoxyphenyl-5-(3,4,5-trimethyl piperazinyl)-sulfonyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-ketone (ZTH-5): [0033] Add ZTH-4 (36 g, 10 mmol, 1 eq), ZTH-3 (17.6 g, 10 mmol, 1 eq), and triethylamine (60.6 g, 60 mmol, 6 eq) into 500 ml tetrahydrofuran, stirring under room temperature for overnight; evaporating the solvent; adding 200 ml water and 200 ml methylene chloride, separating, and rinsing the methylene chloride layer with saturated sodium bicarbonate water solution and saturated brine solution in turn, and then drying and condensing, the residue obtains 32 g white crystal ZTH-5 with recrystallizing 10 times amount of ethanol, and then obtains 16.5 g white crystal ZTH-5 with recrystallizing another 50 times amount of ethanol, wherein the yield is 37%.
ethyl 2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.5%
With triethylamine; In ethanol; at 100℃; for 2h;Microwave irradiation;
To a solution of I-i Oa (0.41 g, 1 mmol) in ethanol (273 mL) was added ethyl2-(piperazin-1 -yl)pyrimidine-5-carboxylate (R-09a, 0.236 g, 2 mmol), Et3N(303 mg, 3 mmol). The mixture was stirred at 10000 under MW for 2 hours. The reaction mixture was concentrated under vacuo to give I-i 5a (0.4 g, 65.5% yield). ESI-MS (Mi-i): 611 calc. for 028H34N8065: 610.2.
65.5%
With triethylamine; In ethanol; at 100℃; for 2h;Microwave irradiation;
Preparation of intermediate 1-15a: Ethyl 2-(4-[3-(6,7-dihvdro-1 -methyl-7-oxo- 3-propyl-1 /-/-pyrazolo[4,3-c lpyrimidin-5-yl)-4-ethoxyphenylsulfonyllpiperazin- 1 -yl)pyrimidine-5-carboxylate To a solution of 1-10a (0.41 g, 1 mmol) in ethanol (273 ml_) was added ethyl 2-(piperazin-1 -yl)pyrimidine-5-carboxylate (R-09a, 0.236 g, 2 mmol), Et3N (303 mg, 3 mmol). The mixture was stirred at 100 C under MW for 2 hours. The reaction mixture was concentrated under vacuo to give 1-15a (0.4 g, 65.5% yield). ESI-MS (M+1 ): 61 1 calc. for C28H34N8O6S: 610.2.
2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)pyrimidine-5-carboxylic acid[ No CAS ]
2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)pyrimidine-5-carboxamide[ No CAS ]
2-(4-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenylsulfonyl]piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide trifluoroacetic acid salt[ No CAS ]
5-(2-ethoxy-5-((4-oxopiperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Step 9: Synthesis of compound Aa (5-(2-ethoxy-5-((4-oxopiperidin-1- yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo 14,3-dlpyrimidin-7(6H)-one) :-Piperidin-4-one (1 eq) was dissolved in dry DCM and added DIPEA (3 eq), stirred the reaction mixture for 10 minutes at 15 C, added 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene- 1 -sulfonyl chloride (1 eq) and stirred the reaction for 6 hours at 25 C. After completion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum Yield 90%. ?H NMR (400 MHz CDC13): oe; 10.78(s, 111), 8.87(d, J=2.4Hz, 1H),7.88(dd, J = 8.8,2.4Hz, 1H), 7.17(d, J = 8.8Hz, 1H), 4.38(q, J =6.8Hz,2H),4.27(s, 3H), 3.48 (t, J= 6.2Hz, 4H), 2.92(t, J= 7.6 Hz, 2H), 2.57(t, J= 6.2Hz, 4H),1.87(m, 2H), 1.65(t, J= 6.8Hz, 3H). l.02(t, J= 7.2Hz, 3H). MASS: ESI [M + Na] :496.00
90%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃; for 6h;
Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((4-hydroxypiperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Synthesis of Ab; Step 9: Dissolve 4-Hydroxypiperidine (1 eq) dry DCM and added DIPEA (3 eq) stirred the reaction mixture for 10 minutes at 15 C, added 4-ethoxy-3-(1-methyl-7-oxo-3 -propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5-yl)benzene- 1-sulfonyl chloride (1 eq) and stirred the reaction for 4 hours at 25 C. After completion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ab as a white solid; yield 88%.?H NMR (500 MHz CDC13): 6; 10.84(s 1H),8.83(d, J=2.4Hz 1H),7.84(ddJ= 8.8,2.4Hz 1H), 7.17(d J = 8.8Hz 1H), 4.34(q J =6.8Hz 2H),4.27(s, 3H), 3.8 (bs 1H), 3.61(t J =7.6Hz 2H) 2.97-2.90 (m 4H),l.96(m 2H), l.87(m 2H),l.69-l.63(m, 5H) l.02(t J =7.2Hz 3H). MASS: ESI [M + Na] : 498.00. Elemental anal. calcd. for C22H29N505S; C, 55.56; H, 6.15; N, 14.73; 0, 16.82; S, 6.74; found C, 55.46; H, 6.25; N, 14.63; 0, 16.87; S, 6.79.
85%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((3-oxopiperazin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
Synthesis of Ac; Step 9: Dissolve 2-Oxopiperazine (1 eq) dry CHC13 and added TEA (3 eq), stirred the reaction mixture for 10 minutes at 10C, added 4-ethoxy-3-(1-methyl- 7-oxo-3 -propyl-6,7-dihydro- 1 H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene- 1 -sulfonyl chloride (1 eq) and stirred the reaction for 6 hours at 25 C. After completion of thereaction, added 30 ml CHC13, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml CHC13 and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ac as a white solid; yield 95%.1H NMR (400 MHz, CDC13) 6 10.88 (s, 1H), 8.82 (d, J= 2.4 Hz, 1H), 7.88 (dd,J= 8.8,2.4 Hz, 1H), 7.19 (d, J= 8.8 Hz, 1H), 6.43 (s, 1H), 4.39 (q, J= 6.9 Hz, 2H), 4.28 (s,3H), 3.74 (s, 2H),3.54 -3.44 (m, 2H), 3.43 -3.34 (m, 2H), 2.94 (t, J= 7.5 Hz, 2H),1.86 (m, 2H), 1.65 (t, J= 7.0 Hz, 3H), 1.03 (t, J= 7.4 Hz, 3H). MASS: ESI {M + Na] ÷:497.00. Elemental anal. calcd. for C21H26N605S; C, 53.15; H, 5.52; N, 17.71; 0, 16.86;5, 6.76; found C, 53.10; H, 5.58; N, 17.76; 0, 16.86; 5, 6.70.
70%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((4-methoxypiperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Synthesis of Ad; Step 9: Dissolve 4-methoxypiperidine (1 eq) dry acetone and added K2C03 (3 eq) stirred the reaction mixture for 10 minutes at 20 C, added 4-ethoxy-3 -(1- methyl-7-oxo-3 -propyl-6,7-dihydro- 1 H-pyrazolo [4,3 -d]pyrimidin-5-yl)benzene- 1-sulfonyl chloride (1 eq) and stirred the reaction for 5 hours at 35 C. After completionof the reaction remove the acetone under vacuum added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ad as a white solid; yield 90%. ?H NMR (400 MHz, CDC13) 6 10.84 (s, 1H), 8.83 (d, J= 2.4 Hz, 1H), 7.84 (dd, J 8.7,2.4 Hz, 1H), 7.15 (d, J= 8.7 Hz, 1H), 4.38 (q, J= 7.0 Hz, 2H), 4.28 (s, 3H), 3.34 - 3.28(m, 1H), 3.26 (s, 3H), 3.18 (m 2H), 3.12 - 3.04 (m, 2H), 2.93 (t, J= 7.5 Hz, 2H), 1.95 -1.71 (m, 6H), 1.65 (t, J= 7.0 Hz, 3H), 1.03 (t, J= 7.4 Hz, 3H). MASS: ESI [M + H] :490.10. Elemental anal. calcd. for C23H31N505S; C, 56.42; H, 6.38; N, 14.30; 0, 16.34;S, 6.55; found C, 56.52; H, 6.33; N, 14.35; 0, 16.27; S, 6.52.
80%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Synthesis of Ae; Step 9: Dissolve 4-piperidinylmethanol (1 eq) dry DCM and added DMAP (3 eq) stirred the reaction mixture for 10 minutes at 20 C, added 4-ethoxy-3-(1-methyl-7-oxo-3 -propyl-6,7-dihydro- 1 H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene- 1-sulfonyl chloride (1 eq) and stirred the reaction for 3 hours at 35 C. After completion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by columnchromatography on silica the desired product Ac as a white solid; yield 85%.?H NMR (400 MHz, CDC13) 8 10.82 (s, 1H), 8.82 (d, J= 2.3 Hz, 1H), 7.85 (dd,J 8.7,2.3 Hz, 1H), 7.15 (d, J= 8.8 Hz, 1H), 4.38 (q, J=t 6.9 Hz, 2H), 4.27 (s, 3H), 3.89 (d, J=11.6 Hz, 2H), 3.49 (m, 2H), 2.93 (t, J= 7.5 Hz, 2H), 2.37 (m, 2H), 1.84 (m, 2H), 1.67 (t, J= 6.9 Hz 3H), 1.51 1.12 (m, 5H), 1.03 (t, J= 7.4 Hz, 3H). MASS: ESI [M + H] + 490.05. Elemental anal. calcd. for C23H31N505S; C, 56.42; H, 6.38; N, 14.30; 0, 16.34;5, 6.55; found C, 56.47; H, 6.33; N, 14.35; 0, 16.36; 5, 6.53.
70%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((4-(2-hydroxyethyl)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Synthesis of Af Step 9: Dissolve the amine 2-(4-piperidinly)ethanol (1 eq) dry DCE and added DIPEA (3 eq) stirred the reaction mixture for 10 minutes at 18 C, added 4- ethoxy-3 -(1 -methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (1 eq) and stirred the reaction for 4.5 hours at 35 C.After completion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Af as a white solid; yield 85%. ?H NMR (400 MHz, CDC13) oe 10.83 (s, 1H), 8.82 (d, J= 2.3 Hz, 1H), 7.84(dd, J= 8.7, 2.4 Hz, 1H), 7.15 (d, J 8.8 Hz, 1H), 4.38 (q, J= 7.0 Hz, 2H), 4.27 (s,3H), 3.83 (d,J 11.8 Hz, 2H), 3.66 (t,J= 6.3 Hz, 2H), 2.93 (t,J= 7.5 Hz, 2H), 2.35 (t,J 11.5 Hz, 2H), 1.86 (m 2H), 1.77 (d, J= 11.5 Hz, 2H), 1.65 (t, J= 7.0 Hz 3H), 1.50(m, 2H), 1.14-1.25 (m 3H) 1.03 (t, J = 7.4 Hz, 3H). MASS: ES [M + H] : 504.05.Elemental anal. calcd. for C24H33N5055; C, 57.24; H, 6.60; N, 13.91; 0, 15.88; 5, 6.37;found C, 57.34; H, 6.55; N, 13.84; 0, 15.95; S, 6.32.
65%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((4-(2-hydroxyphenyl)piperazin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Synthesis of Ag; Step 9 Dissolve 2-(1-piperazinyl)phenol (1 eq) dry DCM and added Pyridine (2 eq) stirred the reaction mixture for 10 minutes at 25 C, added 4-ethoxy-3-(1 -methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -djpyrimidin-5-yl)benzene- 1-sulfonyl chloride (1 eq) and stirred the reaction for 5.5 hours at 25 C. After completion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ag as a white solid; yield 80%. ?H NMR (400 MHz CDC13): o; 10.82(s 1H),8.88(d J=2.4Hz 1H),7.89(dd, J 8.8, 2.4Hz, 1H), 7.20(d, J = 8.8Hz, 1H),7.l0(m, 2H),6.88(m, 2H) 6.60(s, 1H) 4.41 (q, J =7.0Hz,2H),4.28(s 3H), 3.25 (bs 4H), 2.99(t J = 4.8Hz 4H), 2.92(t, J 7.6 Hz, 2H), 1.85(m2H), l.67(t, J = 7.0Hz, 3H). 1.02(t, J = 7.2Hz 3H). MASS: ESI [M + H] : 553.00. Elemental anal. calcd. for C27H32N605S; C, 58.68; H, 5.84; N, 15.21; 0, 14.48; S, 5.80; found C, 58.65; H, 5.82; N, 15.26; 0, 14.52; S, 5.76
5-(5-((4-(4-acetylphenyl)piperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Synthesis of Ah; Step 9: Dissolve 1-[4-(1-piperazinyl)phenyl]ethanone (1 eq) dry aceto nitrile and added K2C03 (3 eq) stirred the reaction mixture for 10 minutes at 20 C, added 4-ethoxy-3 -(1 -methyl-7-oxo-3 -propyl-6,7-dihydro- 1 H-pyrazolo[4,3-d]pyrimidin- 5-yl)benzene-1-sulfonyl chloride (1 eq) and stirred the reaction for 5 hours at 35 C.After completion of the reaction, remove the acetonitrile under vacuum added 30 mlDCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20ml DCM and the combined organic layer are washed with brine solution, concentratedunder vacuum. The residue was purified by column chromatography on silica thedesired product Ah as a white solid; yield 90%. ?H NMR (400 MHz CDC13): 10.80(s1H),8.87(d J =2.4Hz 1H),7.88-7.81(m 3H), 7.17(d J = 8.8Hz 1H), 6.81(d J = 8.8Hz2H) 4.38 (q, J =7.0Hz, 2H),4.27(s, 3H), 3.46 (bs s, 4H), 3.23(br s 4H), 2.94(t, J = 7.6Hz, 2H), 2.50(s, 3H),1.87(m, 2H), 1.64(t, J = 7.0Hz, 3H). 1.03(t, J = 7.2Hz, 3H).MASS: ESI [M + H] : 579.00. Elemental anal. calcd. for C29H34N605S; C, 60.19; H,5.92; N, 14.52; 0, 13.82; S, 5.54; found C, 60.15; H, 5.90; N, 14.54; 0, 13.80; S, 5.56.
65%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((4-(pyridin-4-yl)piperazin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Synthesis of Ai; Step 9: Dissolve l-(4-pyridinyl)piperazine (1 eq) dry CHC13 and added TEA (3 eq) stirred the reaction mixture for 10 minutes at 10 C, added 4-ethoxy-3 -(1-methyl-7-oxo-3 -propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5-yl)benzene- 1- sulfonyl chloride (1 eq) and stirred the reaction for 6 hours at 25 C. After completion of the reaction, added 30 ml CHC13, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml CHC13 and the combined organic layer are washedwith brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ai as a white solid; yield 93%.?H NMR (400 MHz, CDC13) 10.82 (s, 1H), 8.84 (s, 1H), 8.26 (d, J= 4.8Hz, 2H), 7.85(d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6,60 (d, J = 5.0 Hz, 2H), 4.38 (q, J =6.9Hz, 2H), 4.27 (s, 3H), 3.45 (t, J= 4.8 Hz 4H), 3.20 (t, J= 4.8 Hz 4H), 2.94 (t, J= 7.5Hz, 2H), 1.88 (m, 2H), 1.64 (t, J= 6.9 Hz, 3H), 1.04 (t, J= 7.3 Hz, 3H). MASS: ES [M + H] : 538.10; Elemental anal. calcd. for C26H3,N704S; C, 58.08; H, 5.81; N, 18.24; 0,11.90; S, 5.96; found C, 58.14; H, 5.78;N, 18.21; 0,11.88; S, 5.98.
70%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(5-([1,4’-bipiperidin]-1‘-ylsulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Synthesis of Al; Step 9: Dissolve 1,4-bipiperidine (1 eq) dry acetone and added K2C03 (3 eq) stirred the reaction mixture for 10 minutes at 25 C, added 4-ethoxy-3-(1 -methyl25 7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5-yl)benzene- 1 -sulfonylchloride (1 eq) and stirred the reaction for 4.5 hours at 25 C. After completion of the reaction, remove the acetone under vacuum add 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Al as a white solid; yield 90%. 1H NMR (400 MHz, CDC13) 6 10.83 (s, 1H), 8.84 (d, J= 2.2 Hz, lH), 7.87 (dd, J= 8.8, 2.2 Hz, 1H), 7.17 (d, J= 8.8 Hz, 1H), 4.40 (q, J= 7.0 Hz, 2H), 4.30 (s,3H), 3.94 (d, J= 11.5 Hz, 2H), 2.95 (t, J 7.5 Hz, 2H), 2.50 (br s, 4H), 2.35 (s, 2H),1.88 (mHz, 4H), 1.75-1.27 (m, 12H), 1.05 (t, J= 7.3 Hz, 3H). MASS: ES [M + H] :543.15. Elemental anal. calcd. for C27H38N604S; C, 59.76; H, 7.06; N, 15.49; 0, 11.79;S, 5.91; found C, 59.74; H, 7.08; N, 15.59; 0, 11.68; S, 5.90
65%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(5-((4-benzylpiperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
Synthesis of Am, Step 9: Dissolve 4-benzylpiperidine (1 eq) dry DCM and added TEA(3 eq) stirred the reaction mixture for 10 minutes at 20 C 4-ethoxy-3-(1 -methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5-yl)benzene- 1 -sulfonyl chloride (1eq) and stirred the reaction for 6 hours at 30 C. After completion of the reaction, added30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extractedwith 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Am as a white solid; yield 91%. ?H NMR (400 MHz, CDC13) 6 10.84 (s, 1H), 8.82 (d, J= 2.3 Hz, 1H), 7.84 (dd, J= 8.7, 2.3 Hz, lH), 7.26 (m, 2H)7.17 (m, 2H), 7.09 (d, J 7.1 Hz, 2H), 4.39 (q, J= 6.9 Hz, 2H), 4.29 (s, 3H), 3.85 (d, J = 11.6 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.54 (d, J = 6.6 Hz, 2H), 2.29 (t, J = 11.5 Hz, 2H), 1.86 (m, 2H), 1.76 - 1.61 (m, 4H), 1.41 (m, 2H), 1.02 (t, J= 7.4 Hz, 3H). MASS:ES [M + H] : 550.05. Elemental anal. calcd. for C29H35N504S; C, 63.37; H, 6.42; N, 12.74; 0, 11.64; S, 5.83; found C, 63.42; H, 6.40; N, 12.78; 0, 11.62; S, 5.78.
70%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
5-(2-ethoxy-5-((4-methylpiperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Synthesis of An; Step 9: Dissolve 4-methylpiperidine (1 eq) dry DCE and added DIPEA (3 eq) stirred the reaction mixture for 10 minutes at 20 C, added 4-ethoxy-3-( 1-methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo [4,3 -d]pyrimidin-5-yl)benzene- 1 -sulfonyl chloride (1 eq) and stirred the reaction for 6 hours at 30 C. After completion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brinesolution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product An as a white solid; yield 90%.?H NMR (400 MHz, CDC13) 6 10.83 (s, 1H), 8.82 (d, J= 2.4 Hz, 1H), 7.85 (dd, J= 8.8,2.4 Hz, 1H), 7.15 (d, J 8.8 Hz, 1H), 4.38 (q, J= 7.0 Hz, 2H), 4.28 (s, 3H), 3.80 (d, J=11.2 Hz, 2H), 2.93 (t, J= 7.6 Hz, 211), 2.34 (t, J= 10.5 Hz, 2H), 1.86(m, 2H), 1.65 (m511), 1.32 (m, 2H), 1.03 (t, J= 7.4 Hz, 3H), 0.92 (d, J 5.0 Hz, 3H). MASS: ESI [M + H] . 474.10; Elemental anal. calcd. for C23H3,N504S; C, 57.16; H, 6.21; N, 15.74; 0, 14.57; S, 6.31; found C, 57.14; H, 6.17; N, 15.76; 0, 14.59; S, 6.33.
80%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
tert-butyl (1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Synthesis of Ao; Step 9: Dissolve 4-(N-Boc-amino)piperidine (1 eq) dry DCM and added DIPEA (3 eq) stirred the reaction mixture for 10 minutes at 15 C, added 4- ethoxy-3 -(1 -methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5- yl)benzene- 1 -sulfonyl chloride (1 eq) and stirred the reaction for 6 hours at 30 C. Aftercompletion of the reaction, added 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ao as a white solid; yield 90%.?H NMR (400 MHz, CDC13) 6 10.85 (s, 1H), 8.82 (d, J= 1.9 Hz, 111), 7.84 (dd,J= 8.7,1.8 Hz, 111), 7.16 (d, J= 8.8 Hz, 111), 4.39 (q J= 6.9 Hz, 211), 4.28 (s, 311), 3.74 (br s,2H), 3.42 (m, 1H), 2.94 (t, J= 7.5 Hz, 211), 2.52 (br s, 2H), 2.00 (d, J 11.2 Hz, 211),1.85 (m, 211), 1.66 (t, J= 6.9 Hz, 311), 1. 53 (m, 211), 1.41 (s, 9H), 1.03 (t, J= 7.3 Hz,311). MASS: ESI [M + H] : 575.26 Elemental anal. calcd. for C27H38N606S; C, 56.43; H, 6.66; N, 14.62; 0, 16.70; S, 5.58; found C, 56.45; H, 6.56; N, 14.67; 0, 16.75; S,5.56.
75%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
N-(2-aminophenyl)-2-[4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl]-sulfonylpiperazin-1-yl]pyrimidine-5-carboxamide[ No CAS ]
(E)-ethyl 3-(4-((piperazin-1-yl)methyl)phenyl)prop-2-enoate[ No CAS ]
ethyl (E)-3-[4-[[4-[4-ethoxy-3-(3-ethyl-1-methyl-7-oxo-6Hpyrazolo[4,3-d]pyrimidin-5-yl)phenyl]sulfonylpiperazin-1-yl]-methyl]phenyl]prop-2-enoate[ No CAS ]
ethyl 2-[4-[[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6H-pyrazolo-[4,3-d]pyrimidin-5-yl)phenyl]sulfonylamino]-1-piperidyl]pyrimidine-5-carboxylate[ No CAS ]
5-(2-ethoxy-5-((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;
General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.
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