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HazMat fee for 500 gram (Estimated)
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Limited Quantity
USD 15-60
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USD 80+
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Structure of 23000-43-3 * 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.
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h;
A suspension of compound 2 (1.88 g, 0.012 mol) andNaH (0.864 g, 0.036 mol) in dry DMF (10 mL) was stirred at 0 °C for 30 min. Iodomethane (2.56 g,0.018 mol) was added, and the resulting mixture was stirred overnight. The reaction mixture wastreated with water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers wereremoved in vacuo to give compound 6. Yield: 70.8percent; 1H-NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H),8.44 (s, 1H), 4.08 (s, 3H).
38.5%
With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
In a 250 mL three-necked flask, 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 12.98 mmol), DMF (50 mL) and cesium carbonate (5.06 g, 15.57 mmol) were successively added.Cool to 0°C in an ice bath, methyl iodide (0.97 mL,15.57 mmol) was diluted with DMF (5 mL) and slowly added dropwise using a dropping funnel. Dripping to room temperature,Overnight, monitored by TLC. After the reaction was completed, the reaction solution was diluted with ethyl acetate (100 mL), and the mixture was washed with water (60 mL×1) and saturated NaCl solution (50 mL×2), respectively. Anhydrous MgSO4 was dried, the solvent was evaporated and dried to give a white solid (1.67 g, yield 38.5percent).
38.5%
With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
General procedure: A suspension of compound 3 (6.5mmol) and Cs2CO3 (13.0mol) in dry DMF (25mL) was stirred at 0°C for 30min, and then iodide alkane (7.8mmol) was added. After stirring overnight, the reaction mixture was extracted with EtOAc (60mL× 3), washed with water, dried over Na2SO4, and concentrated in vacuo to give compound 4.
Reference：
[1] Comptes Rendus Chimie, 2017, vol. 20, # 9-10, p. 927 - 933
[2] Molecules, 2017, vol. 22, # 4,
[3] Patent: CN107383014, 2017, A, . Location in patent: Paragraph 0079; 0080; 0081; 0082
[4] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 210 - 228
2
[ 5305-40-8 ]
[ 60-34-4 ]
[ 23000-43-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere
General procedure: To a 20 mL vial was added 1 (97percent, 88 mg, 0.5 mmol), Et3N (0.070mL, 0.5 mmol), and THF (1 mL). The reaction mixture was allowed to stir at 0 °C for 10 min under a N2 atmosphere. To the solution was added hydrazine monohydrate (2p; 0.026 mL, 0.525 mmol) in THF (1 mL) dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 1 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 (6 mL) and H2O (10 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 6 mL). The combined organic layers were dried(MgSO4) and concentrated in vacuo to obtain 4p; yield: 56 mg(74percent);
53%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 3.16667 h;
Example 2-Synthesis of 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 2 To 4,6-dichloro-pyrimidine-5-carbaldehyde (2.90 g, 16.39 g) and diisopropylethylamine (2.12 g, 2.85 mL, 16.39 mmol) in THF (100 mL) cooled at 0° C. was added dropwise methylhydrazine (0.83 g, 0.95 mL, 18.03 mmol) in 10 mL THF. The reaction mixture was stirred at 0° C. for 10 min, and warmed to room temperature and stirred for 3 h. Then, the solvent was removed at reduced pressure and the crude was chromatographed by Biotage (DCM: EtOAc) to afford 1.47 g, 53percent of the desired compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 8.17 (s, 1H), 4.17 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 154.83, 154.53, 153.23, 131.90, 113.65, 34.47.
With thionyl chloride In N,N-dimethyl-formamide for 2 h; Reflux
Step 1)Synthetic 1-methyl-pyrazolo[3,4-d]pyrimidin-4-one (2 g, 13.3 mmol)Add to 20 mL of dry thionyl chloride,After adding 1ml DMF to the reaction system,Heat reflux reaction for 2h,Cool to room temperature, evaporate the solvent under reduced pressure, and add the residue to ice water.Saturated sodium bicarbonate was adjusted to pH 7 and extracted with ethyl acetate (2 x 50 mL).The organic phase is washed with saturated sodium bicarbonate solution.Washing, drying over anhydrous sodium sulfate, rotary evaporation of the solvent,Obtained pale yellow solid 1.91g, yield 85percent,
85%
With thionyl chloride In N,N-dimethyl-formamide for 2 h; Reflux
The 1-methyl-pyrazole [3,4-d]pyrimidin-4-one (2 g, 13.3 mmol) synthesized in step 1) was added to 20 mL of dry thionyl chloride, and 1 ml of DMF was added to the reaction system. After heating, the reaction is refluxed for 2 hours.After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was added to ice water. The pH was adjusted to 7 with saturated sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The organic phase was washed with saturated sodium bicarbonate solution, and washed with water. Sodium sulfate drying, rotary evaporation of the solvent to give a pale yellow solid 1.91g, yield 85percent,HPLC: 96.69percent.
60.5%
With trichlorophosphate In Petroleum ether
(d) 1-Methyl-4-chloropyrazolo[3,4-d]pyrimidine 80 g. of 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]- pyrimidin-4-one are added to 300 ml. of phosphorus oxychloride and the mixture is refluxed. After distilling off the excess phosphorus oxychloride, the semi-solid residue is extracted with 3 * 100 ml. of boiling benzene. The benzene extracts are combined and concentrated to half-volume, then added to petroleum ether. After standing 12 hours in the refrigerator, the precipitated 1-methyl-4-chloropyrazolo[3,4-d]- pyrimidine is filtered under suction and recrystallized from cyclohexane to obtain 54 g. of white crystals, m.p. 93°-96° (yield 60.5percent).
Reference：
[1] Patent: CN107778316, 2018, A, . Location in patent: Paragraph 0036-0038
[2] Patent: CN107955008, 2018, A, . Location in patent: Paragraph 0034; 0038; 0040
[3] Patent: US4124764, 1978, A,
4
[ 5399-92-8 ]
[ 74-88-4 ]
[ 23000-43-3 ]
[ 959430-67-2 ]
Yield
Reaction Conditions
Operation in experiment
22%
With caesium carbonate In N,N-dimethyl-formamide at 0℃; for 3 h;
Compound 80; 4-Chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidine; Compound 81; 4-Chloro-1-methyl-2H-pyrazolo[3,4-d]pyrimidine; Cesium carbonate (Acros, 2.12 g, 6.51 mmol) was added to compound 79 (1.00 g, 5.9 mmol) in N,N-dimethylformamide (Acros, 30 mL) at 0° C. followed immediately by methyl iodide (Acros, 1.01 g, 7.1 mmol). The mixture was stirred for three hours. Cesium carbonate was removed by filtration and the filter cake was washed with a small amount of DMF. The filtrate and washings were concentrated and the reaction mixture was subjected to flash chromatography on silica gel (gradient elution 9:1 to 4:1 to 0:1 dichloromethane:ethyl acetate) to afford two white solids: Compound 80 (220 mg, 22percent) elutes second and Compound 81 (663 mg, 67percent) elutes first. Compound 80: mp 196-200° C.; MS (ES+calculated: 168.59; found: 169.57 M+H). HPLC (100percent purity, retention time 4.627 minutes-Method B); 1H NMR (300 MHz, DMSO-d6): 8.91 (s, 1H), 8.90 (s, 1H), 4.25 (s, 3H). Compound 81: mp 97-99° C.; MS (ES+calculated: 168.59; found: 169.37 M+H). HPLC (100percent purity, retention time 6.582 minutes-Method B); 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.48 (s, 1H), 4.09 (s, 3H).
Reference：
[1] Patent: US2007/281949, 2007, A1, . Location in patent: Page/Page column 37
[2] Journal of Organic Chemistry, 2018, vol. 83, # 12, p. 6334 - 6353
[3] Journal of Organic Chemistry, 2018, vol. 83, # 12, p. 6334 - 6353
With caesium carbonate In N,N-dimethyl-formamide at 0℃; for 3h;
Compound 80; 4-Chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidine; Compound 81; 4-Chloro-1-methyl-2H-pyrazolo[3,4-d]pyrimidine; Cesium carbonate (Acros, 2.12 g, 6.51 mmol) was added to compound 79 (1.00 g, 5.9 mmol) in N,N-dimethylformamide (Acros, 30 mL) at 0° C. followed immediately by methyl iodide (Acros, 1.01 g, 7.1 mmol). The mixture was stirred for three hours. Cesium carbonate was removed by filtration and the filter cake was washed with a small amount of DMF. The filtrate and washings were concentrated and the reaction mixture was subjected to flash chromatography on silica gel (gradient elution 9:1 to 4:1 to 0:1 dichloromethane:ethyl acetate) to afford two white solids: Compound 80 (220 mg, 22%) elutes second and Compound 81 (663 mg, 67%) elutes first. Compound 80: mp 196-200° C.; MS (ES+calculated: 168.59; found: 169.57 M+H). HPLC (100% purity, retention time 4.627 minutes-Method B); 1H NMR (300 MHz, DMSO-d6): 8.91 (s, 1H), 8.90 (s, 1H), 4.25 (s, 3H). Compound 81: mp 97-99° C.; MS (ES+calculated: 168.59; found: 169.37 M+H). HPLC (100% purity, retention time 6.582 minutes-Method B); 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.48 (s, 1H), 4.09 (s, 3H).
1: 47%
2: 11%
With sodium hexamethyldisilazane In tetrahydrofuran; dimethyl sulfoxide at 20℃; for 1.5h;
1: 36%
2: 6%
With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 1h;
With thionyl chloride In N,N-dimethyl-formamide for 2h; Reflux;
1.2 2) Synthesis of 4-Chloro-1-methylpyrazo[3,4-d]pyrimidine
Step 1)Synthetic 1-methyl-pyrazolo[3,4-d]pyrimidin-4-one (2 g, 13.3 mmol)Add to 20 mL of dry thionyl chloride,After adding 1ml DMF to the reaction system,Heat reflux reaction for 2h,Cool to room temperature, evaporate the solvent under reduced pressure, and add the residue to ice water.Saturated sodium bicarbonate was adjusted to pH 7 and extracted with ethyl acetate (2 x 50 mL).The organic phase is washed with saturated sodium bicarbonate solution.Washing, drying over anhydrous sodium sulfate, rotary evaporation of the solvent,Obtained pale yellow solid 1.91g, yield 85%,
85%
With thionyl chloride In N,N-dimethyl-formamide for 2h; Reflux;
1.2 Example 1 2) Synthesis of 4-Chloro-1-methylpyrazo[3,4-d]pyrimidine
The 1-methyl-pyrazole [3,4-d]pyrimidin-4-one (2 g, 13.3 mmol) synthesized in step 1) was added to 20 mL of dry thionyl chloride, and 1 ml of DMF was added to the reaction system. After heating, the reaction is refluxed for 2 hours.After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was added to ice water. The pH was adjusted to 7 with saturated sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The organic phase was washed with saturated sodium bicarbonate solution, and washed with water. Sodium sulfate drying, rotary evaporation of the solvent to give a pale yellow solid 1.91g, yield 85%,HPLC: 96.69%.
60.5%
With trichlorophosphate In Petroleum ether
1.d (d)
(d) 1-Methyl-4-chloropyrazolo[3,4-d]pyrimidine 80 g. of 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]- pyrimidin-4-one are added to 300 ml. of phosphorus oxychloride and the mixture is refluxed. After distilling off the excess phosphorus oxychloride, the semi-solid residue is extracted with 3 * 100 ml. of boiling benzene. The benzene extracts are combined and concentrated to half-volume, then added to petroleum ether. After standing 12 hours in the refrigerator, the precipitated 1-methyl-4-chloropyrazolo[3,4-d]- pyrimidine is filtered under suction and recrystallized from cyclohexane to obtain 54 g. of white crystals, m.p. 93°-96° (yield 60.5%).
A suspension of compound 2 (1.88 g, 0.012 mol) andNaH (0.864 g, 0.036 mol) in dry DMF (10 mL) was stirred at 0 C for 30 min. Iodomethane (2.56 g,0.018 mol) was added, and the resulting mixture was stirred overnight. The reaction mixture wastreated with water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers wereremoved in vacuo to give compound 6. Yield: 70.8%; 1H-NMR (400 MHz, DMSO-d6) delta 8.85 (s, 1H),8.44 (s, 1H), 4.08 (s, 3H).
46%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
[0503] Procedure: To a stirred solution of <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (1.0 g, 6.49 mmol) in DMF (20 mL) were added methyl iodide (0.48 mL, 7.79 mmol), cesium carbonate (2.5 g, 7.79 mmol). Resulting mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice-water (20mL) and extracted with ethyl acetate (2 x 30mL). The combined organic layer was washed with brine (10mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by combiflash using 15% ethyl acetate in hexane to afford 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as white solid (0.5 g, 46%). LC-MS (ES) m/z = 169.1 [M+H]+ .
38.5%
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
In a 250 mL three-necked flask, <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (2.0 g, 12.98 mmol), DMF (50 mL) and cesium carbonate (5.06 g, 15.57 mmol) were successively added.Cool to 0C in an ice bath, methyl iodide (0.97 mL,15.57 mmol) was diluted with DMF (5 mL) and slowly added dropwise using a dropping funnel. Dripping to room temperature,Overnight, monitored by TLC. After the reaction was completed, the reaction solution was diluted with ethyl acetate (100 mL), and the mixture was washed with water (60 mL×1) and saturated NaCl solution (50 mL×2), respectively. Anhydrous MgSO4 was dried, the solvent was evaporated and dried to give a white solid (1.67 g, yield 38.5%).
38.5%
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
General procedure: A suspension of compound 3 (6.5mmol) and Cs2CO3 (13.0mol) in dry DMF (25mL) was stirred at 0C for 30min, and then iodide alkane (7.8mmol) was added. After stirring overnight, the reaction mixture was extracted with EtOAc (60mL× 3), washed with water, dried over Na2SO4, and concentrated in vacuo to give compound 4.
4-[(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy]-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.3%
In a 100 mL three-neck flask, 3-nitro-4-aminophenol (0.92 g, 6.96 mmol), Cs2CO3 (2.90 g, 8.92 mmol) powder was added.DMF (40 mL) was added dropwise under N2 protection.Stir at room temperature for 1.5-2 h. Dissolve 4-chloro-1-(2-methyl)-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 5.95 mmol) in an appropriate amount of DMF (10 mL) and react for 22-24 h. , TLC monitoring.The reaction was completed, diluted with ethyl acetate (50 mL), washed successively with water (80 mL×1), saturated NaCl solution (50 mL×2), dried over anhydrous MgSO 4 , evaporated to remove the solvent, and dried to give a yellow solid (1.40 g, yield 82.3%).
82.3%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
General procedure: To the mixture of <strong>[610-81-1]4-amino-3-nitrophenol</strong> (1.0g, 6.4mmol) in DMF (50mL), Cs2CO3 (3.12g, 9.6mmol) was added under the protection of nitrogen. The reaction mixture was stirred at r. t. for 1.5-2h, and then compound 4 (6.4mmol) was added slowly. After stirring overnight, the reaction mixture was diluted with EtOAc (50mL), washed with water and brine, dried over Na2SO4 and concentrated to give compound 5 as an orange solid.
Stage #1: 4-chloro-2H-pyrazolo[3,4-d]pyrimidine With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.0833333h;
Stage #2: methyl iodide In tetrahydrofuran at 0 - 25℃; for 1.08333h; Inert atmosphere;
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