* 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.
Step 7 4-Amino-2-methyl-5-propyl-2H-pyrazole-3-carboxamide: To a suspension of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxamide (14.7 g, 69.3 mmol) in ethyl acetate (130 mL), was added 10percent palladium on carbon (3.3 g). The mixture was reacted at 50° C. and 4 atm hydrogen pressure overnight. The reaction mixture was cooled, and the catalyst was filtered off and washed with ethyl acetate and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (13.8 g, 98percent). 1H NMR (300 MHz, CDCl3) δ 4.12 (s, 3H), 2.84 (s, 2H), 2.55 (t, 2H, J=7.2 Hz), 1.71-1.61 (m, 2H), 0.99 (t, 3H, J=7.2 Hz); LC-MS: m/z=183 (MH)+
98.83%
With palladium on activated charcoal; hydrogen In methanol at 30℃;
To a solution of I-06a (10 g, 47.17 mmol) was dissolved in methanol (100 mL), then Pd/C (5 g) was added into the reaction mixture, and stirred at 30 °C under 50 Psi (345 kPa) at H2 atomsphere overnight. The reaction mixture was filtrated and the filtrate was concentrated under vacuo to give I-07a (8.5 g,98.83percent yield). ESI-MS (Mi-i): 183 calc. for C8H14N40: 182.1.
98.83%
With palladium on activated charcoal; hydrogen In methanol at 30℃;
Preparation of intermediate l-07a: 4-Amino-1 -methyl-3-propyl-1 /-/-pyrazole-5- carboxamide To a solution of l-06a (10 g, 47.17 mmol) was dissolved in methanol (100 ml_), then Pd/C (5 g) was added into the reaction mixture, and stirred at 30 °C under 50 Psi (345 kPa) at H2 atomsphere overnight. The reaction mixture was filtrated and the filtrate was concentrated under vacuo to give l-07a (8.5 g, 98.83percent yield). ESI-MS (M+1 ): 183 calc. for C8H14N4O: 182.1 .
93%
With ammonium chloride; zinc In water at 20℃; Ionic liquid; Green chemistry
21.2 g of 4-nitro-1-methyl-3-n-propylpyrazole-5-carboxamide, 150 mL of [bmim][PF6], zinc granules13 g, 10 mL of water and 16 g of ammonium chloride were mixed. Stir at room temperature, and the reaction was followed by TLC until the starting material disappeared.Diethyl ether was added toextract (150 mL × 3), and the ether phase was combined and concentrated to dryness to give 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (16.9 g, yield 93percent, HPLC purity It is 97.2percent.
88%
With iron; ammonium chloride In ethanol; water at 80℃; for 4.5 h;
Step 6: Synthesis of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide:- 1- methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide (11.0 gin 5.1 m.ml) was dissolved in 40 ml EtOH/H20 (3:1), added Fe powder (8.7 gm 15.5 m.ml) and NH4C1 (2.75gm 5.1 m.ml). The mixture was heated up to 80 °C for 4.5 hours. The reaction mixture wascooled to 25 °C and filtered through celite and filterate was concentrated under vacuum. Trituration of the residue with either gave the 4-amino-l-methyl-3-propyl-1H-pyrazoe- 5-carboxamide as an off-white solid; Yield 88percent. ‘H NMR (400 MHz, CDC13) S 9.0l(s, 2H) 6.6(s, 2H) 4.10 (s, 3H) 2.50 (t, J=7.6Hz 3H) 1.70 (m, 2H) 1.02(t, J=7.6Hz, 3H).MASS: ESI[M+H]: 183.14
Reference：
[1] Patent: US2008/194529, 2008, A1, . Location in patent: Page/Page column 57
[2] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 81
[3] Patent: WO2016/20307, 2016, A1, . Location in patent: Page/Page column 51
[4] Patent: CN103044330, 2018, B, . Location in patent: Paragraph 0025; 0031-0032; 0034-0035
[5] Patent: WO2015/114647, 2015, A1, . Location in patent: Page/Page column 47; 48
[6] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907
[7] Patent: US5955611, 1999, A,
[8] Patent: US6207829, 2001, B1,
[9] Organic Process Research and Development, 2000, vol. 4, # 1, p. 17 - 22
[10] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
[11] Patent: CN108117555, 2018, A, . Location in patent: Paragraph 0031; 0032; 0049
2
[ 139755-99-0 ]
[ 139756-02-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 15, p. 1819 - 1824
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907
[3] Organic Process Research and Development, 2000, vol. 4, # 1, p. 17 - 22
[4] Patent: WO2014/131855, 2014, A1,
[5] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
[6] Patent: WO2015/114647, 2015, A1,
[7] Patent: WO2016/20307, 2016, A1,
3
[ 139756-00-6 ]
[ 139756-02-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907
[2] Organic Process Research and Development, 2000, vol. 4, # 1, p. 17 - 22
[3] Patent: WO2014/131855, 2014, A1,
[4] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
[5] Patent: WO2015/114647, 2015, A1,
[6] Patent: WO2016/20307, 2016, A1,
4
[ 133261-07-1 ]
[ 139756-02-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 17, p. 3900 - 3907
[2] Patent: WO2014/131855, 2014, A1,
[3] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
[4] Patent: WO2015/114647, 2015, A1,
[5] Patent: WO2016/20307, 2016, A1,
5
[ 92945-27-2 ]
[ 139756-02-8 ]
Reference：
[1] Patent: WO2014/131855, 2014, A1,
[2] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
[3] Patent: WO2015/114647, 2015, A1,
[4] Patent: WO2016/20307, 2016, A1,
Reference：
[1] Patent: WO2014/131855, 2014, A1,
[2] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
[3] Patent: WO2016/20307, 2016, A1,
8
[ 360068-47-9 ]
[ 139756-02-8 ]
Reference：
[1] Patent: WO2014/131855, 2014, A1,
[2] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 889 - 896
[3] Patent: WO2016/20307, 2016, A1,
9
[ 304435-81-2 ]
[ 139756-02-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 17, p. 1983 - 1986
10
[ 67-56-1 ]
[ 304435-83-4 ]
[ 139756-02-8 ]
[ 727408-28-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 17, p. 1983 - 1986
11
[ 2100-31-4 ]
[ 139756-02-8 ]
[ 139756-04-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: With thionyl chloride In dichloromethane for 3 h; Heating / reflux Stage #2: With dmap; triethylamine In dichloromethane at 0℃; for 1 h;
Step 8 2-Methyl-4-(2-propoxybenzoylamino)-5-propyl-2H-pyrazole-3-carboxamide: A solution of 2-propoxybenzoic acid (13.7 g, 76.1 mmol) and thionyl chloride (36.2 g, 304.4 mmol) in dry dichloromethane (80 mL) was heated for 3 hours at reflux. The solvent and excess thionyl chloride were distilled off under reduced pressure. The residue was taken up in dry dichloromethane (60 mL) and reacted with a solution of 4-amino-2-methyl-5-propyl-2H-pyrazole-3-carboxamide (12.6 g, 69.2 mmol), dry triethylamine (7 g, 69.2 mmol) and 4-(N,N-dimethylamino)pyridine (84.5 mg, 0.7 mmol) in dry dichloromethane (200 mL) at 0° C. Stirring was maintained for 1 hour, and the reaction mixture was successively washed with water (150 mL), saturated aqueous sodium carbonate solution (200 mL) and saturated brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 60 mL, and then hexane (150 mL) was added to give precipitate product as a white solid (22 g, 92percent). 1H NMR (300 MHz, CDCl3) δ 9.47 (s, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.87 (br.s, 1H), 7.57-7.52 (m, 1H), 7.16-7.05 (m, 2H), 5.53 (s, 1H), 4.20 (t, 2H, J=6.6 Hz), 4.09 (s, 3H), 2.54 (t, 2H, J=7.5 Hz), 1.97-1.85 (m, 2H), 1.69-1.26 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.95 (t, 3H, J=7.5 Hz). LC-MS: m/z=345 (M+H)+
With triethylamine; In ethyl acetate; at 0 - 25℃; for 2h;Product distribution / selectivity;
Preparation Ia: l-methyl-3-n-propyl-4- (2-ethoxybenzamido) -pyrazole-5-carbox- amide (V)In a 250 mL three-neck bottle, (XI) (21.8 g, 0.10 mol) was dissolved in ethylacetate (200 mL) and triethylamine (32 ml, 0.23 mol) to prepare a solution in an ice bath. 2- ethoxybenzoyl chloride (17.0 mL, 0.11 mmol) was added to the solution below 5 0C, and the mixture was stirred at room temperature for 2 hours. Water (170 mL) and petroleum ether (100 mL) were added to stop the reaction, and the mixture was stirred for another 0.5 h. The solid was filtrated and poured into water (170 mL) and stirred for 0.5 h, filtrated and dried (70 0C, 12 h) to afford compound (V) as a white solid (32.0 g, yield 95 %) . m.p. 153 - 154 0C. The product was re- crystallized from ethyl acetate/petroleum ether. 1H NMR (CDCI3, 300 MHz) delta: 0.93 (3H, t) , 1.54 (3H, t) , 1.65 (2H, m) , 2.54 (2H, t), 4.06 (3H, s), 4.31 (2H, q) , 5.62 (IH, br s) , 7.05 (IH, d) , 7.13 (IH, t), 7.54 (IH, t) , 7.91 (IH, br s) , 8.27 (IH, dd) , 9.47 (IH, s) .
87%
With triethylamine; In dichloromethane; at 0 - 25℃; for 2h;Product distribution / selectivity;
Preparation 1 : l-methyl-3-n-propyl-4- (2-ethoxybenzamido) -pyrazole-5-carbox- amide (V)In a 250 mL three-neck bottle, (XI) (20 g, 0.11 mol) was dissolved in dichloromethane (100 mL) and triethylamine (22.2 g, 0.22 mol) to prepare a solution in an ice bath. 2- ethoxybenzoyl chloride was added to the solution below 5 0C, and the mixture was stirred at room temperature for 2 hours. Water (40 mL) was added to stop the reaction, and the layers were separated. The organic phase was washed with brine (30 mL) and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, followed by concentration. The resulting residue was purified by re- crystallizing from ethyl acetate/petroleum ether to obtain (V) (31.5 g, yield 87 %) as a white solid, m.p. 153 - 154 0C. 1H NMR (CDCl3, 300 MHz) delta: 0.93 (3H, t), 1.54 (3H, t), 1.65 (2H, m) , 2.54 (2H, t) , 4.06 (3H, s) , 4.31 (2H, q) , 5.62 (IH, br s) , <n="19"/>7 . 05 ( IH, d) , 7 . 13 ( IH, t ) , 7 . 54 ( IH , t ) , 7 . 91 ( IH , br s ) , 8 . 27 ( IH , dd) , 9 . 47 ( IH, s ) .
87%
With triethylamine; In dichloromethane; at 25℃;Cooling with ice;
To a 250 mL three-neck flask, were added the compound of formula (XI) (20 g, 0.11 mol), dichloromethane (100 mL) and triethylamine (22.2 g, 0.22 mol) to prepare a solution in an ice bath below 5 C., followed by the slow addition of <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong>. After the mixture was stirred at room temperature for 2 hours, water (40 mL) was added to quench the reaction, and the layers were separated. The organic phase was washed with brine (30 mL) and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, followed by concentration. The resulting residue was purified by re-crystallising with ethyl acetate/petroleum ether to obtain the compound of formula (V) (31.5 g, yield 87%) as a white solid. m.p. 153154 C.; 1H NMR (CDCl3, 300 MHz) delta: 0.93 (3H, t), 1.54 (3H, t), 1.65 (2H, m), 2.54 (2H, t), 4.06 (3H, s), 4.31 (2H, q), 5.62 (1H, br s), 7.05 (1H, d), 7.13 (1H, t), 7.54 (1H, t), 7.91 (1H, br s), 8.27 (1H, dd), 9.47 (1H, s).
80%
With dmap; triethylamine; In dichloromethane; at 50℃; for 0.166667h;Microwave irradiation;
1-methyl-3-propyl-4 - (2-ethoxy methyl amido) pyrazole-5-carboxamide preparation: heating the prepared 7.5mmol2-ethoxy formyl chloride dissolved in 15 mu L methylene chloride (that is, the concentration of 500mol/L), adding 2.25mmol4-dimethyl aminopyridine, 19mmol triethylamine, stirring slowly dripping 19mmol4-amino-1-methyl-3-n-propyl -1H-pyrazole-5-carboxamide, microwave heating 50 C reaction 10 minutes, after the reaction of methylene chloride is removed by reduced pressure distillation, a small amount of ethanol re-crystallization, drying after filtration, a kind of white obtained 1-methyl-3-propyl-4 - (2-ethoxy methyl amido) pyrazole-5-carboxamide, the yield is 80%;
With triethylamine; In dichloromethane; at 20℃; for 1h;
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%
2.7
Step 7 4-Amino-2-methyl-5-propyl-2H-pyrazole-3-carboxamide: To a suspension of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxamide (14.7 g, 69.3 mmol) in ethyl acetate (130 mL), was added 10% palladium on carbon (3.3 g). The mixture was reacted at 50° C. and 4 atm hydrogen pressure overnight. The reaction mixture was cooled, and the catalyst was filtered off and washed with ethyl acetate and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (13.8 g, 98%). 1H NMR (300 MHz, CDCl3) δ 4.12 (s, 3H), 2.84 (s, 2H), 2.55 (t, 2H, J=7.2 Hz), 1.71-1.61 (m, 2H), 0.99 (t, 3H, J=7.2 Hz); LC-MS: m/z=183 (MH)+
98.83%
With palladium on activated charcoal; hydrogen In methanol at 30℃;
Preraration of intermediate I-07a: 4-Amino-i -methyl-3-rroryl-i H-ryrazole-5-carboxamide
To a solution of I-06a (10 g, 47.17 mmol) was dissolved in methanol (100 mL), then Pd/C (5 g) was added into the reaction mixture, and stirred at 30 °C under 50 Psi (345 kPa) at H2 atomsphere overnight. The reaction mixture was filtrated and the filtrate was concentrated under vacuo to give I-07a (8.5 g,98.83% yield). ESI-MS (Mi-i): 183 calc. for C8H14N40: 182.1.
98.83%
With palladium on activated charcoal; hydrogen In methanol at 30℃;
Preparation of intermediate l-07a: 4-Amino-1 -methyl-3-propyl-1 /-/-pyrazole-5- carboxamide
Preparation of intermediate l-07a: 4-Amino-1 -methyl-3-propyl-1 /-/-pyrazole-5- carboxamide To a solution of l-06a (10 g, 47.17 mmol) was dissolved in methanol (100 ml_), then Pd/C (5 g) was added into the reaction mixture, and stirred at 30 °C under 50 Psi (345 kPa) at H2 atomsphere overnight. The reaction mixture was filtrated and the filtrate was concentrated under vacuo to give l-07a (8.5 g, 98.83% yield). ESI-MS (M+1 ): 183 calc. for C8H14N4O: 182.1 .
93%
With ammonia hydrochloride; zinc powder In water monomer at 20℃; Ionic liquid; Green chemistry;
4; 3 Example 4: Preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)
21.2 g of 4-nitro-1-methyl-3-n-propylpyrazole-5-carboxamide, 150 mL of [bmim][PF6], zinc granules13 g, 10 mL of water and 16 g of ammonium chloride were mixed. Stir at room temperature, and the reaction was followed by TLC until the starting material disappeared.Diethyl ether was added toextract (150 mL × 3), and the ether phase was combined and concentrated to dryness to give 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (16.9 g, yield 93%, HPLC purity It is 97.2%.
92%
With ammonia hydrochloride; zinc powder In ethanol at -20 - 10℃; for 4.5h; Inert atmosphere;
2-3; 1-3 Example 2 Preparation of Intermediate Compound E
Under nitrogen protection, add 50.00g 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide, 75% ethanol (10.34g/g), ammonium chloride (10.0eq) into the reaction flask Add zinc powder (13.0eq) in batches with temperature control from -20 to 10. After adding the temperature control at 0 to 10, react for 4.5h, filter, wash the filter cake with 3.94g/g absolute ethanol, and control the temperature of the filtrate from 20 to 30. , add oxalic acid ethanol solution (1.0eq) dropwise to salt for 1.0h, filter, and wash the filter cake with absolute ethanol twice, 2.0g/g each time, filter cake at 40-50, vacuum degree not less than -0.09 Mpa, dried to obtain white crystalline solid intermediate compound E with a yield of 92.0% and a purity of 99.9%.
88%
With iron(0); ammonia hydrochloride In ethanol; water monomer at 80℃; for 4.5h;
1.6 Step 6: Synthesis of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide:-
Step 6: Synthesis of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide:- 1- methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide (11.0 gin 5.1 m.ml) was dissolved in 40 ml EtOH/H20 (3:1), added Fe powder (8.7 gm 15.5 m.ml) and NH4C1 (2.75gm 5.1 m.ml). The mixture was heated up to 80 °C for 4.5 hours. The reaction mixture wascooled to 25 °C and filtered through celite and filterate was concentrated under vacuum. Trituration of the residue with either gave the 4-amino-l-methyl-3-propyl-1H-pyrazoe- 5-carboxamide as an off-white solid; Yield 88%. ‘H NMR (400 MHz, CDC13) S 9.0l(s, 2H) 6.6(s, 2H) 4.10 (s, 3H) 2.50 (t, J=7.6Hz 3H) 1.70 (m, 2H) 1.02(t, J=7.6Hz, 3H).MASS: ESI[M+H]: 183.14
87.5%
With dichloro-λ2-stannane dihydrate In ethanol for 4h; Reflux;
Preparation of Intermediate-5:
Add Intermediate-4 (260g, 1.23mol) and 1050ml of ethanol to the 3L there-necked flask, add stannous chloride dihydrate (833g, 3.69mol) under stirring, heat to reflux for 4 hours, remove the heat bath, and cool to Below 30°C, the ice-water bath controls the internal temperature to be below 30°C, adjust the pH to 10 with 2N sodium hydroxide, cool to room temperature, extract with dichloromethane 1050ml×3, combine the extracts, wash the filtrate once with 500ml purified water, and divide Take the dichloromethane phase, concentrate under reduced pressure, add 520 ml of isopropyl ether to the residue at room temperature, stir for 1 hour, filter out the solid, use 200 ml of cold isopropyl ether to wash the filter cake once, and drain, and the wet material is at 40~ Blow dry at 50°C for 12 hours to obtain 196 g of off-white solid, yield: 87.5%.
With stannous chloride
In ethyl acetate
3 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide
PREPARATION 3 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide A stirred suspension of 1-methyl4-nitro-3-n-propylpyrazole-5-carboxamide (EP-A-0463756; 237.7 g, 1.12 mol) and 5% palladium on charcoal (47.5 g) in ethyl acetate (2.02 l) was hydrogenated at 344.7 kPa (50 psi) and 50° C. for 4 hours, when the uptake of hydrogen was complete. The cool reaction mixture was filtered, then the filter pad washed with ethyl acetate, the combined filtrate and washings thus furnishing an ethyl acetate solution of the title compound (EP-A-0463756) which was of sufficient purity to use directly in the next stage of the reaction sequence (see Preparation 4).
In ethyl acetate
1.c (1c)
(1c) 4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide A stirred suspenson of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide (EP-A-0463756; 237.7 g, 1.12 mol) and 5% palladium on charcoal (47.5 g) in ethyl acetate (2.02 1) was hydrogenated at 344.7 kPa (50 psi) and 50° C. for 4 hours, when the uptake of hydrogen was complete. The cool reaction mixture was filtered, then the filter pad washed with ethyl acetate, the combined filtrate and washings thus furnishing an ethyl acetate solution of the title compound (EP-A-0463756) which was of sufficient purity to use directly in the next stage of the reaction sequence.
With 5%-palladium/activated carbon; hydrogen In ethyl acetate at 50℃; for 4h;
With dichloro-λ2-stannane dihydrate In ethanol for 2h; Reflux;
Stage #1: 1-methyl-4-nitro-3-propyl-1H-pyrazole-5 carboxamide With sulfuric acid In ethyl acetate at 40 - 45℃; for 0.5h;
Stage #2: With iron(0) In water monomer at 60 - 65℃; for 3.83333h;
1
Into a 50 ml three-necked flask was placed 20 ml of ethyl acetate, and 2 g of the compound 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide of the structure represented by the formula (IV) was added thereto.After stirring and dissolving, heat to 40-45°C, adjust the pH to 2 to 3 with sulfuric acid, maintain the temperature for 30 minutes, and rapidly put 5g of iron powder into the three-neck flask.The temperature is raised to 60-65°C and refluxed for 50 minutes. At the reflux temperature, the purified water is introduced at 60-65°C, and the temperature is maintained for 3 hours.The reduction was carried out until the reactant 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide disappeared. Cool to 40-45°C,After extraction with 20 ml of ethyl acetate, the ethyl acetate was collected, and the organic layer was dried over 5 g of anhydrous magnesium sulfate. The organic layer was cooled to 10-15 DEG C and adjusted to a pH of 10-11 with triethylamine. 1.5 g of 2-ethoxybenzoic acid was added to the reactor and 3.2 g of thionyl chloride was added to the reaction at 25-35°C.Raise the temperature to 70-80°C, stir for 1 hour. After the ring-closing reaction is completed, distill thionyl chloride below 80°C and cool to 10-20°C.To the reaction flask was added 2.1 g of 2-ethoxybenzoic acid, the pH was adjusted to 7-8, and the mixture was heated and stirred at 30-35°C for 2 hours.After the reaction product was not detected, 50 ml of purified water was added. After stirring for 0.5 h, the reaction was layered and extracted three times with ethyl acetate.Ethyl acetate was distilled off, toluene was refluxed for three hours, purified water was added, pH was adjusted to 6 to 7, filtered and dried., that is, a compound of the structure shown by formula (I)5-(2-Ethoxyphenyl)-l-methyl-3-propyl-lH-pyrazolo[4,3-d]pyrimidin-7(6H)-one.
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
5-(3-fluorophenyl)-1-methyl-3-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 3-Fluorobenzaldehyde In ethanol at 75℃; for 2h;
Stage #2: With oxygen; copper dichloride In ethanol at 75℃; for 2h;
30.7 Example 30: Compound Bn (5-(3-fluorophenyl)-1-methyl-3-propyl-1H- pyrazolo [4,3-dj pyrimidin-7(6H)-one):
Synthesis of Bn; Step 7: 4-amino-i -methyl-3 -propyl- 1 H-pyrazole-5-carboxamide (1 eq) and 3-fluorobenzaldehyde (1.1 eq) were suspended in ethanol 5 ml and the mixtureheated at 75 °C for 2 hours after conformation of forming of imine by TLC. Added CuC12 (3 eq ) and the reaction mixture heated at 75 °C under 02 for 2 hours. After completion of the reaction, the ethanol was removed under vacuum. Then workup with ethyl acetate and water. Separate the organic layer and Water layer re-extracted with 2x25 ml ethyl acetate. The combined organic layers are washed with brine solution,concentrated under vacuum. The residue was purified by column chromatography onsilica the desired product Bn as a white solid; yield 90%. ‘H NMR (200 MHz CDC13) ö12.06 (s lH), 7.91 (m 1H), 7.48 (m 1H), 7.40 (m lH), 7.31 (m 1H), 4.05 (s, 3H), 3.03 (t,J= 7.4 Hz, 2H), 1.86 (m, 2H), 1.06 (t, J= 7.4 Hz, 3H). MASS: ESI [M + H] : 329.16; Elemental anal. calcd. for C15H15FN40; C, 62.93; H, 5.28; F, 6.64; N, 19.57; 0, 5.59; found C, 62.95; H, 5.31; F, 6.59; N, 19.52; 0, 5.64.
85%
With copper chloride In ethanol at 70℃; for 0.5h;
85%
With dipotassium peroxodisulfate In water; dimethyl sulfoxide at 100℃; Sealed tube; Microwave irradiation;
2.1.1 Synthesis of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs
General procedure: 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).
With triethylamine In dichloromethane at 0 - 25℃; for 12.5h;
20
Preparation 20: 4-(3, 4-Dimethoxyphenylcarboxamido)-1-methyl-3-propyl-lH-5-pyrazolecarboxamide A mixture of 4-amino-l-methyl-3-propyl-lH-5-pyrazolecarboxmide (19.57g, 107.5 mmol) and triethylamine (54.4g, 134.38 mmol) in dichloromethane (300 mL) were taken in a 1 liter 3 neck round bottom flask fitted with a nitrogen balloon, pressure equalizing addition funnel and a septum. To the mixture was added a solution of 3, 4-dimethoxy-1- benzenecarbonylchloride (21. 5g, 107. 5mmol) in dichloromethane (lOOmL) at 0 °C through a pressure equalizing addition funnel over a period of 0.5 h under nitrogen atmosphere. The reaction temperature was raised to 25 °C after addition and the contents were stirred for another 12 h. Dichloromethane was removed from the reaction mixture under reduced pressure and the solid obtained was washed with cold water (2 x 150 mL), filtered and dried under vacuum to get the title compound 33g, (89 %) as a white solid.
Step 8 2-Methyl-4-(2-propoxybenzoylamino)-5-propyl-2H-pyrazole-3-carboxamide: A solution of <strong>[2100-31-4]2-<strong>[2100-31-4]propoxybenzoic acid</strong></strong> (13.7 g, 76.1 mmol) and thionyl chloride (36.2 g, 304.4 mmol) in dry dichloromethane (80 mL) was heated for 3 hours at reflux. The solvent and excess thionyl chloride were distilled off under reduced pressure. The residue was taken up in dry dichloromethane (60 mL) and reacted with a solution of 4-amino-2-methyl-5-propyl-2H-pyrazole-3-carboxamide (12.6 g, 69.2 mmol), dry triethylamine (7 g, 69.2 mmol) and 4-(N,N-dimethylamino)pyridine (84.5 mg, 0.7 mmol) in dry dichloromethane (200 mL) at 0 C. Stirring was maintained for 1 hour, and the reaction mixture was successively washed with water (150 mL), saturated aqueous sodium carbonate solution (200 mL) and saturated brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 60 mL, and then hexane (150 mL) was added to give precipitate product as a white solid (22 g, 92%). 1H NMR (300 MHz, CDCl3) delta 9.47 (s, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.87 (br.s, 1H), 7.57-7.52 (m, 1H), 7.16-7.05 (m, 2H), 5.53 (s, 1H), 4.20 (t, 2H, J=6.6 Hz), 4.09 (s, 3H), 2.54 (t, 2H, J=7.5 Hz), 1.97-1.85 (m, 2H), 1.69-1.26 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.95 (t, 3H, J=7.5 Hz). LC-MS: m/z=345 (M+H)+
With 2-(Dimethylamino)pyridine; thionyl chloride; triethylamine; In dichloromethane;
Preparation of 4-[2-Propoxy Benzamido]-1-Methyl-3-Propyl-5-Carbamoyl Pyrazole To a solution of 25 g of 2-propoxy benzoic acid dissolved in dichloromethane, 66 g of thionyl chloride was added and stirred for 3 hours under reflux. After reaction was completed, the solvent and excessive thionyl chloride were distilled off under reduced pressure. To the residue was added 200 ml of dichloromethane (reaction solution 1). In another container, to 24 g of 1-methyl-3-propyl-4-amino-5-carbamoyl pyrazole in dichloromethane was added 13.4 g of triethylamine and 100 mg of dimethylaminopyridine and then cooled to 0 C., to which said reaction solution 1 was slowly added while maintaining the temperature of the solution at 0 C., and then stirred for 1 hour. The reaction mixture was successively washed with water, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product and then triturated with hexane to give 39 g of the title compound. 1H NMR (CDCl3): 0.91(t,3H), 1.05(t,3H), 1.62(m,2H), 1.89(m,2H), 2.52(t,2H), 4.06(s,3H), 4.18(t,2H), 5.57(br s,1H), 7.09(m,2H), 7.52(m,1H), 7.73(br s,1H), 8.26(dd,1H), 9.45(br s,1H)
With indium(III) chloride; In acetonitrile; at 20.0℃; for 1.25h;
General procedure: To a solution of aromatic aldehydes 8 (1.0 mmol) in acetonitrile, 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide 10 (1.0 mmol) and InCl3 (10 mol%) were added at room temparature and the reaction mixture was stirred till the completion of the starting materials (indicated by TLC). The solvent was evoparated and the crude product was triturated with 10% diethyl ether in hexane to obtain the pure product. The product was identified by 1H NMR, 13 C NMR and Mass.
With indium(III) chloride; In acetonitrile; at 20℃; for 1.08333h;
General procedure: To a solution of aromatic aldehydes 8 (1.0 mmol) in acetonitrile, 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide 10 (1.0 mmol) and InCl3 (10 mol%) were added at room temparature and the reaction mixture was stirred till the completion of the starting materials (indicated by TLC). The solvent was evoparated and the crude product was triturated with 10% diethyl ether in hexane to obtain the pure product. The product was identified by 1H NMR, 13 C NMR and Mass.
With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 80℃; for 0.0833333h;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).
75%; 20%
With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 80℃; for 0.05h;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).
With dipotassium peroxodisulfate; In ethanol; 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).
In ethanol; at 70℃; for 1.5h;
General procedure: 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (5.0g, 2.74mmol) and <strong>[613-69-4]2-ethoxybenzaldehyde</strong> (4.32g, 2.88mmol) were suspended in ethanol and the mixture was heated at 70C for 1.5h after confirmation of forming an imine by TLC. Added CuCl2 (10.87g, 8.2mmol) and the reaction mixture again heated at 70C under O2 for 1.5h. After completion of reaction, ethanol was removed under vacuum and to this crude residue was added ethyl acetate (50mL) and water (50mL). The organic layer was separated and water layer was re-extracted with (2×50mL) ethyl acetate. The combined organic layers were washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 85%.
With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 100℃;Sealed tube; Microwave irradiation;
General procedure: 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).
85%
Synthesis of Ba; Step 7. 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1 eq) and 3-Bromo-4-methoxybenzaldehyde (1.1 eq) were suspended in ethanol 5 ml and the mixture heated at 70 C for 2 hours after conformation of forming of imine by TLC. Added CuC12 (3 eq) and the reaction mixture heated at 75 C under 02 for 3 hours. After completion of the reaction, the ethanol was removed under vacuum. Then workupwith ethyl acetate and water. Separate the organic layer and Water layer re-extracted with 2x25 ml ethyl acetate. The combined organic layers are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ba as a white solid; yield 85%. 1H NMR (400 MHz DMSO): 8.31(d J = 2.0Hz 1H),8.29(s 1H),8.14(dd J = 8.8,2.0Hz1H),7.24(dJ= 8.8Hz) 4.14(s 3H),3.93(s 3H)2.8(tJ 7.3Hz 2H),1.76(m 2H),0.95(tJ=7.3Hz 3H). MASS: ESI [M+2 + H] + 377.05; Elemental anal. calcd. for C16H17BrN4O2C, 50.94; H, 4.54; Br, 21.18; N, 14.85; 0, 8.48; found C, 50.89; H, 4.56; Br, 21.21; N,14.83; 0, 8.50.
Synthesis of Bc; Step 7: 4-amino- 1 -methyl-3 -propyl- 1 H-pyrazole-5-carboxamide (1 eq) and <strong>[77771-02-9]3-bromo-4-fluorobenzaldehyde</strong> (1.1 eq) were suspended in isopropanol 5 ml andthe mixture heated at 75 C for 2 hours after conformation of forming of imine by TLC. Added CuC12 (3 eq) and the reaction mixture heated at 75 C under 02 for 3 hours. After completion of the reaction, the isopropanol was removed under vacuum. Then workup with ethyl acetate and water. Separate the organic layer and Water layer re59 extracted with 2x25 ml ethyl acetate. The combined organic layers are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Bc as a white solid; yield 87%. H NMR (400 MHz DMSO): o; l2.51(s 1H), 8.40(d J=5.2Hz 1H), 8.13(S 111), 7.56(m 1H) 4.15(s3H), 2.8(t J = 7.3Hz 2H), 1 .76(m 2H), 0.95(t J = 7.3Hz 3H). MASS: ESI [M + H] ?365.04; Elemental anal. calcd. for C,5H,4BrFN4O; C, 49.33; H, 3.86; Br, 21.88;F,5.20; N, 15.34; 0, 4.38; found C, 49.30; H, 3.87; Br, 21.85; F, 5.22; N, 15.34; 0, 4.41.
80%
With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 100℃;Sealed tube; Microwave irradiation;
General procedure: 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).
Synthesis of Bd; Step 7. 4-amino-i -methyl-3-propyl- 1 H-pyrazole-5 -carboxamide (1 eq) and <strong>[698-63-5]5-Nitro-2-furaldehyde</strong> (1.1 eq) were suspended in ethanol 5 ml and the mixture heated at 60 C for 0.5 hours after conformation of forming of imine by TLC. Added CuC12 (3 eq) and the reaction mixture heated at 65 C under 02 for 0.5 hours. After completion of the reaction, the ethanol was removed under vacuum. Then workup withethyl acetate and water. Separate the organic layer and Water layer re-extracted with2x25 ml ethyl acetate. The combined organic layers are washed with brine solution,concentrated under vacuum. The residue was purified by column chromatography onsilica the desired product Bd as a yellow solid; yield 93%. ?H NMR (200 MHz CDC13):l2.87(br 1H) 7.85(br 1H), 7.74(br 1H), 4.16(s 3H), 2.8(br 2H), l.76(m 2H), 0.95(t J= 7.3Hz 3H). MASS: ESI [M + H] + 304.10; Elemental anal. calcd. for C,3H13N504C, 51.48; H, 4.32; N, 23.09; 0, 21.10; found C, 51.39; H, 4.34; N, 23.12; 0, 21.14.
90%
With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 100℃;Sealed tube; Microwave irradiation;
General procedure: 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).
Synthesis of BJ Step 7. 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1 eq) and <strong>[31680-08-7]4-methoxy-3-nitrobenzaldehyde</strong> (1.1 eq) were suspended in ethanol 5 ml and the mixture heated at 75 C for 2 hours after conformation of forming of imine by TLC. Added CuC12 (3 eq) and the reaction mixture heated at 75 C under 02 for 2 hours. Aftercompletion of the reaction, the ethanol was removed under vacuum. Then workup with ethyl acetate and water. Separate the organic layer and Water layer re-extracted with 2x25 ml ethyl acetate. The combined organic layers are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Bf as a brown solid; yield 88%. ‘H NMR (400 MHz, DMSO)6: 12.54 (s 1H) 8.61 (s, 1H), 8.37 (d J=8.8 Hz 1H), 7.39 (d, J8.8 Hz 1H), 4.13 (s, 3H),3.84 (s, 3H), 2.78(t J=7.4Hz 2H), 1.76(m 2H), 0.95(tJ= 7.4Hz 3H). MASS: ESI [M +H] . 344.13; Elemental anal. calcd. for C16H17N504 C, 55.97; H, 4.99; N, 20.40; 0,18.64; found C, 55.87; H, 5.03; N, 20.43; 0, 18.67.
85%
With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 100℃;Sealed tube; Microwave irradiation;
General procedure: 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).
With dipotassium peroxodisulfate In water; dimethyl sulfoxide at 100℃; Sealed tube; Microwave irradiation;
2.1.1 Synthesis of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs
General procedure: 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).
90%
Stage #1: 3,5-dimethoxybenzaldehdye; 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide In ethanol at 60℃; for 1h;
Stage #2: With oxygen; copper dichloride In ethanol at 70℃; for 0.5h;
27.7 Example 27: Compound Bk (5-(3,5-dimethoxyphenyl)-1-methyl-3-propyl-1H- pyrazolo [4,3-di pyrimidin-7(6H)-one):
Synthesis of Bk, Step 7: 4-amino-i -methyl-3-propyl- 1 H-pyrazole-5-carboxamide (1 eq) and 3,5-dimethoxybenzaldehyde (1.1 eq) were suspended in ethanol 5 ml and the mixture heated at 60 °C for 1 hours after conformation of forming of imine by TLC. Added CuC12 (3 eq) and the reaction mixture heated at 70 °C under 02 for 0.5 hours. After completion of the reaction, the ethanol was removed under vacuum. Then workupwith ethyl acetate and water. Separate the organic layer and Water layer re-extracted with 2x25 ml ethyl acetate. The combined organic layers are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Bk as a white solid; yield 90%. ‘H NMR (200 MHz CDC13): 7.25(d J2.OHz 2H), 6.6(d J2.OHz 1H), 4.29(s 3H), 3.88(s 6H),2.93(t J=7.4Hz 2H), 1 .87(m 2H), 1 .04(t J = 7.3Hz 3H). MASS: ESI [M + H] : 329.16; Elemental anal. calcd. for C17H20N403 C, 62.18; H, 6.14; N, 17.06; 0, 14.62; found C, 62.21; H, 6.l1;N, 17.12; 0, 14.56.
With dipotassium peroxodisulfate In water; dimethyl sulfoxide at 100℃; for 0.05h; Sealed tube; Microwave irradiation;
1 4.1.1 Synthesis of 1-methyl-3-propyl-5-(2,4,5-trimethoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one
In a typical procedure, a solution of aromatic aldehyde i.e. 2,4,5-trimethoxybenzaldehyde (0.196g, 1eq.) and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (0.191g, 1.05eq) in DMSO:H2O (1:1) add K2S2O8 (0.810 g, 3 eq.) was taken in a sealed reaction tube and the reaction mixture was irradiated under microwave conditions for 3min with a power of 350 Watts at 100°C. After completion, the reaction mass was diluted with EtOAc (20mL) and added water (30mL). Separated the organic layer and extracted with EtOAc (2×10 mL). The combined organic layer was then washed with brine solution, concentrated under vacuum and purified on silica-gel (100-200 mesh) column chromatography, affording white solid 1-methyl-3-propyl-5-(2,4,5-trimethoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one i.e.compound 3j in (0.351g) 98% yield.
87%
Stage #1: asaraldehyde; 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide In ethanol at 60℃; for 0.5h;
Stage #2: With oxygen; copper dichloride In ethanol at 75℃; for 0.5h;
25.7 Example 25: Compound Ri (1-methyl-3-propyl-5-(2,4,5-trimethoxyphenyl)-1H- pyrazolo [4,3-dlpyrimidin-7(6H)-one):
Synthesis of Bi; Step 7: 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1 eq) and 2,4,5-trimethoxybenzaldehyde (1 eq) were suspended in ethanol 5m1 and the mixture heated at 60 °C for 0.5 hours after conformation of forming of imine by TLC. Added CuCl2 (3 eq) and the reaction mixture heated at 75 °C under 02 for 0.5 hours.After completion of the reaction, the ethanol was removed under vacuum. Then workup with ethyl acetate and water. Separate the organic layer and Water layer re-extracted with 2x 25 ml ethyl acetate. The combined organic layers are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Bi as a white solid; yield 87%. ‘H NMR(200 MHz CDC13): o; 1l.0(s 1H), 8.03(s 111), 6.59(s 1H), 4.42(s 3H), 4.06(s 3H), 3.98(s6H), 2.93(t J=7.3Hz 2H), 1.57(m 2H), 1.04(t J= 7.3Hz 3H). MASS: ESI [M + H] :359.17; Elemental anal. calcd. for C,8H22N404 C, 60.32; H, 6.19; N, 15.63; 0, 17.86; found C, 60.29; H, 6.23; N, 15.67; 0, 17.91.
5-(2-ethoxyphenylcarbonylaminocarbonyl)-1-methyl-3-propyl-1H-pyrazol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With triethylamine; In dichloromethane; at 20℃;
To a solution of I-07a (6 g, 32.97 mmol) in DCM (100 mL) was added Et3N(6.6 g, 65.34 mmol), <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong> (R-04a, 6.ig, 32.97 mmol). The reaction mixture was stirred at r.t. overnight. The reaction mixture was washed quenched by adding water and extracted with DCM. The organic phase was collected, dried over Na2SO4 and concentrated under vacuo to give I-08a (10.85 g, 98% yield). ESI-MS (Mi-i): 331 calc. for C17H22N403:330.2.
98%
With triethylamine; In dichloromethane; at 20℃;
Preparation of intermediate l-08a: 5-(2- Ethoxyphenylcarbonylaminocarbonyl)-1 -methyl-3-propyl-1 /-/-pyrazol-4-amine To a solution of l-07a (6 g, 32.97 mmol) in DCM (100 ml_) was added Et3N (6.6 g, 65.34 mmol), <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong> (R-04a, 6.1 g, 32.97 mmol). The reaction mixture was stirred at r.t. overnight. The reaction mixture was washed quenched by adding water and extracted with DCM. The organic phase was collected, dried over Na2SO4 and concentrated under vacuo to give l-08a (10.85 g, 98% yield). ESI-MS (M+1 ): 331 calc. for C17H22N4O3: 330.2.
With dmap; triethylamine; In dichloromethane; at 100℃; for 0.0833333h;Microwave irradiation;
2) 1-methyl-3-propyl-4 - (2-propoxy benzamido- ) pyrazole-5-carboxamide preparation: heating 7.5mmol2-propoxy benzoyl chloride is dissolved in a 50 mu L methylene chloride, by adding 0.07g4-dimethyl aminopyridine, 0.5 ml triethylamine, stirring slowly dripping 6.8mmol4-amino-1-methyl-3-n-propyl -1H-pyrazole-5-carboxamide, microwave heating 100 C reaction 5 minutes, after the reaction of the organic solvent is removed by reduced pressure distillation, a small amount of ethanol re-crystallization, drying after filtration, a kind of white obtained 1-methyl-3-propyl-4 - (2-propoxy benzamido- ) pyrazole-5-carboxamide, the yield is 80-84%;
1',4,4-trimethyl-3'-propyl-4',6'-dihydrospiro[cyclohexane-1,5'-pyrazolo[4,3-d]pyrimidin]-7'(1'H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With indium(III) chloride In acetonitrile at 20℃; for 3h;
General procedure for the preparation of compounds 3(a-h)
General procedure: A mixture of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide 1a (1.0 mmol), Ketones 2(1.0 mmol) and InCl3 (10 mol%,) in acetonitrile (6 mL) was stirred at room temperature for the time indicated in Table 3. After completion of the reaction (indicated by TLC) the reaction mixture was filtered and wash with acetonitrile (2 X 5 mL) to remove the insoluble catalyst. The filtrate was collected and concentrated under vacuum. The solid isolated was triturated with MTBE (10 mL), filtered and dried to give the desired product.
Into a 50 ml three-necked flask was placed 20 ml of ethyl acetate, and 2 g of the compound 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide of the structure represented by the formula (IV) was added thereto.After stirring and dissolving, heat to 40-45C, adjust the pH to 2 to 3 with sulfuric acid, maintain the temperature for 30 minutes, and rapidly put 5g of iron powder into the three-neck flask.The temperature is raised to 60-65C and refluxed for 50 minutes. At the reflux temperature, the purified water is introduced at 60-65C, and the temperature is maintained for 3 hours.The reduction was carried out until the reactant 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide disappeared. Cool to 40-45C,After extraction with 20 ml of ethyl acetate, the ethyl acetate was collected, and the organic layer was dried over 5 g of anhydrous magnesium sulfate. The organic layer was cooled to 10-15 DEG C and adjusted to a pH of 10-11 with triethylamine. 1.5 g of <strong>[134-11-2]2-ethoxybenzoic acid</strong> was added to the reactor and 3.2 g of thionyl chloride was added to the reaction at 25-35C.Raise the temperature to 70-80C, stir for 1 hour. After the ring-closing reaction is completed, distill thionyl chloride below 80C and cool to 10-20C.To the reaction flask was added 2.1 g of <strong>[134-11-2]2-ethoxybenzoic acid</strong>, the pH was adjusted to 7-8, and the mixture was heated and stirred at 30-35C for 2 hours.After the reaction product was not detected, 50 ml of purified water was added. After stirring for 0.5 h, the reaction was layered and extracted three times with ethyl acetate.Ethyl acetate was distilled off, toluene was refluxed for three hours, purified water was added, pH was adjusted to 6 to 7, filtered and dried., that is, a compound of the structure shown by formula (I)5-(2-Ethoxyphenyl)-l-methyl-3-propyl-lH-pyrazolo[4,3-d]pyrimidin-7(6H)-one.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 120℃; for 20h; Inert atmosphere; Autoclave;
4.3 General procedure for the heterogeneous palladium-catalyzed carbonylative synthesis of quinazolinones
General procedure: A 12mL vial was charged with MCM-41-2P-Pd(OAc)2 (2mol%), 2-aminobenzamide (1mmol), aryl iodide (1mmol) (if solid) and a stirring bar. Then, DMF (2mL), aryl iodide (1mmol) (if liquid) and DBU (2mmol) were injected by syringe under an argon atmosphere. The vial was placed in an alloy plate, which was transferred into a 300mL Parr Instruments 4560 series autoclave under an argon atmosphere. After flushing the autoclave three times with CO, a pressure of 10bar CO was fixed at ambient temperature. The autoclave was heated for 20hat 120°C. After completion of the reaction, the autoclave was cooled to room temperature and the pressure was released carefully. The reaction mixture was diluted with ethyl acetate (10mL) and filtered. The palladium catalyst was washed with distilled water (2×5mL) and acetone (2×5mL), and reused in the next run. The filtrate was concentrated in vacuo and the pure product was isolated by either washed with water, ethyl acetate and finally hexane or recrystallization from MeOH.
With [2,2]bipyridinyl; palladium(II) trifluoroacetate In dimethyl sulfoxide at 100℃; for 12h;
3 Example 3: Synthesis of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H,6H,7H-pyrazolo[4,3-d]pyrimidin-7-one
The starting material 4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide (0.3 mmol, 1 equiv),Catalyst palladium trifluoroacetate (Pd(TFA) 2, 0.03 mmol, 10%) andThe ligand 2,2'-bipyridine (bpy, 0.06 mmol, 20%) was added to the reaction vessel.Performing three extraction-oxygenation operations on the reaction vessel continuously.Then, the reaction solvent was added to the reaction vessel, dimethyl sulfoxide (DMSO, 0.4 mL) and the starting material 2-ethoxystyrene (0.9 mmol, 3 equiv).After that, it is stirred at a reaction temperature of 100 ° C in an oil bath until the end of the reaction (about 12 h).Then, the reaction solvent is spun off and subjected to column chromatography (the column is filled with 300 mesh to 400 mesh silica gel,Separation with a volume ratio of dichloromethane to ethyl acetate of 10:1 as the eluent,After separation and purification, a white solid was obtained with a yield of 64%.
64%
With [2,2]bipyridinyl; palladium(II) trifluoroacetate; oxygen In dimethyl sulfoxide at 100℃; for 12h;
1; 2; 3; 5; 8; 9 Synthesis of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-one Compound
2-ethoxystyrene (0.9 mmol, 3 equiv), at room temperature4-amino-1-methyl-3-propylpyrazole-5-carboxamide (0.3 mmol, 1 equiv),Palladium trifluoroacetate (0.03 mmol, 0.1 equiv),2,2-bipyridine (0.06 mmol, 0.2 equiv) and2 mL of dimethyl sulfoxide was added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 100 ° C for 12 h. Cooling the reaction mixture,Then add ethyl acetate for dilution.Transfer the diluted solution to a separatory funnel and extract with saturated brine.The aqueous phase and the organic phase were separated, and the aqueous phase was extracted three times with ethyl acetate.The organic phases were combined, 5 g of anhydrous sodium sulfate was added, and the mixture was stood still for 30 min.The filter cake was washed 3 times with 5 mL of ethyl acetate each time, then the solvent was spun off.The product was isolated by column chromatography (eluent: petroleum ether: diethyl ether = 8:1).The product is a colorless liquid, yield 64%, by weight of the product 60mg.
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