* 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.
Reference：
[1] Journal of the American Chemical Society, 1956, vol. 78, p. 784,787[2] Journal of the American Chemical Society, 1957, vol. 79, p. 6407,6413
[3] Patent: US2007/10523, 2007, A1, . Location in patent: Page/Page column 9
2
[ 5399-92-8 ]
[ 2380-63-4 ]
Yield
Reaction Conditions
Operation in experiment
57%
With ammonium hydroxide In tetrahydrofuran at 20 - 30℃; for 2 h;
To a solution of 36 (200 rng, 1.29 mmoi) in THF (2.0 mL) is added ammonium hydroxide (2,0 mL). After stirring at 20---30 °C for 2 hours, the mixture is concentrated. triturated with MeCN (0.5 niL), and collected by fiheration to give 37 as a red solid (100 mg, 57percent yield)
Reference：
[1] Patent: WO2017/161349, 2017, A1, . Location in patent: Paragraph 0250
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 784,787[3] Journal of the American Chemical Society, 1957, vol. 79, p. 6407,6413
[4] Patent: WO2016/187723, 2016, A1, . Location in patent: Page/Page column 51
3
[ 5305-40-8 ]
[ 5399-92-8 ]
Yield
Reaction Conditions
Operation in experiment
83%
With triethylamine; hydrazine In 1,4-dioxane at 20℃; for 1 h;
Synthesis of Compound 4.1. Hydrazine hydrate (11.5 mL, 23.7 mmol) was slowly added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol), and triethylamine (30 mL, 22 mmol) in 1,4-dioxane (600 mL), while cooling to maintain an internal temperature below 20° C. After the addition was complete, the reaction was warmed to RT. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford compound 4.1 (29 g, 83percent) as a light yellow solid. 1H NMR (400.13 MHz, DMSO-d6) δ14.52 (br. s, 1H), 8.83 (s, 1H), 8.45 (s, 1H). MS m/z 155 [M+1]+.
71%
With triethylamine; hydrazine In methanol at -60 - 20℃;
Hydrazine hydrate (2.0 ml, 41 mmol) was slowly added to a solution of 4,6- dichloropyrimidine-5-carbaldehyde (7.2 g, 41 mmol) in MeOH (150 ml) -60 0C (nitromethane-dry ice bath) followed by triethylamine (6.8 mL, 49 mmol). The mixture was allowed to warm to rt and stirred for 2 h. MeOH was removed in vacuo and water <n="65"/>(150 mL) was added. The mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered through a glass funnel. Removal of solvent gave 4-chloro-lH-pyrazolo[3,4-d]pyrimidine (4.45 g, 71percent). MS (ESI, pos. ion) m/z: 155 [M+H]+
68.9%
With hydrazine hydrate; triethylamine In methanol at -65 - 20℃;
To the solution of 4,6-dichloropyrimidine-5-carbaldehyde(1.0 g, 0.006 mol) in methanol (20 mL) at -65 °C, triethylamine (0.97 mL,1.2 equivalents (eq.)) wasadded. A solution of hydrazine monohydrate (0.274 mL 1.0 eq.) in methanol (10 mL) was slowlydripped into above stirred solution by using a constant-pressure dropping funnel. The mixture wasallowed to warm to room temperature and stirred for 2–3 h. The reaction mixture was concentratedin vacuo and crude product was diluted with water (20 mL), and extracted with EtOAc (60 mL x 3).The combined organic layer was washed with saturated solution of NaCl (60 mL x 3), dried overMgSO4 and concentrated to give compound 2. Yield: 68.9percent. 1H-NMR (400 MHz, deuteriated dimethylsulfoxide (DMSO-d6)) δ 14.51 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H). ESI-MS m/z: 153.00 [M - H]-.
68.9%
With hydrazine hydrate; triethylamine In methanol at -65 - 20℃;
In a 100 mL three-necked flask, 1.0 g of 4,6-dichloro-5-pyrimidinecarboxaldehyde and 20 mL of methanol were added and dissolved with stirring. The temperature was lowered to -65 ° C and 0.97 mL (1.2 eq) of triethylamine was added dropwise. 0.274 mL (1.0 eq) of hydrazine monohydrate was diluted with 10 mL of methanol and dropped slowly using a dropping funnel. Recovery was completed to room temperature, the reaction 2 ~ 3h, TLC monitoring. After the reaction was completed, the solvent was evaporated to dryness. The solid was dissolved with ethyl acetate (30 mL x 3), filtered, and combined, washed with saturated NaCl solution (60 mL x 3). Dried over anhydrous MgSO4, the solvent was removed by rotary evaporation and dried to give a pale yellow solid in a yield of 68.9percent.
68.9%
With hydrazine hydrate; triethylamine In methanol at -65 - 20℃;
In a 100 mL three-necked flask, 4,6-dichloro-5-pyrimidine formaldehyde (1.0 g, 5.68 mmol) was added.Methanol (20 mL) was dissolved by stirring, cooled to -65[deg.] C., and triethylamine (0.97 mL, 6.81 mmol) was added dropwise. Hydrazine monohydrate (0.274 mL, 5.68 mmol) was diluted with methanol (10 mL) and slowly dropped using a dropping funnel. After the completion of the addition, the reaction was allowed to return to room temperature for 2 to 3 h and monitored by TLC. The reaction is over,The solvent was evaporated and dried. The solid was dissolved in ethyl acetate (30 mL x 3), filtered and combined and washed with saturated NaCl solution (60 mL)×3). Dry over anhydrous MgSO4, evaporate the solvent, and dry to give a pale yellow solid (0.60 g, 68.9percent yield)
68.9%
With triethylamine; hydrazine In methanol at -65 - 20℃; for 4 h;
General procedure: To the solution of 4,6-dichloropyrimidine-5-carbaldehyde 2 (1.0g, 5.6mmol) in methanol (20mL) at−65°C, triethylamine (0.97mL) was added. A solution of hydrazine monohydrate (0.274mL 1.0 eq.) in methanol (10mL) was slowly dripped into above stirred solution by using a constant-pressure dropping funnel. The mixture was allowed to warm to room temperature and stirred for 2–3h. The reaction mixture was concentrated in vacuo and crude product was diluted with water (20mL), and extracted with EtOAc (60mL×3). The combined organic layer was washed with saturated solution of NaCl (60mL×3), dried over MgSO4 and concentrated to give compound 3 (0.602g, yield: 68.9percent.) 1H NMR (400MHz, deuteriated dimethyl sulfoxide (DMSO-d6)) δ 14.51 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H). ESI-MS m/z: 153.00 [M− H]−.
27%
With triethylamine; hydrazine In tetrahydrofuran at 160℃; for 0.333333 h; Molecular sieve; microwave irradiation
A suspension of 4,6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (lOmL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 μ, 5.650 mmol). The reaction was allowed to stir at RT for 10 minutes before being heated to 160°C for 20 minutes in the microwave. The mixture was diluted with EtOAc/water and the organic layer washed with saturated NaCl, dried (MgSC ), and concentrated in vacuo. This was purified by column chromatography (ISCO Companion.(TM)., 40g column, MeOH / DCM) to give the required product (117mg, 27percent Yield).JH NMR (DMSO, 400 MHz) δ 8.45 (IH, s), 8.84 (IH, s), 14.54 (IH, br s) ppm; MS (ES*) 154.96
27%
With triethylamine; hydrazine In tetrahydrofuran at 20 - 160℃; for 0.5 h; Molecular sieve; Microwave irradiation
A suspension of 4,6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (10 mL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 μL, 5.650 mmol). The reaction was allowed to stir at RT for 10 minutes before being heated to 160° C. for 20 minutes in the microwave. The mixture was diluted with EtOAc/water and the organic layer washed with saturated NaCl, dried (MgSO4), and concentrated in vacuo. This was purified by column chromatography (ISCO Companion.(TM)., 40 g column, MeOH/DCM) to give the required product (117 mg, 27percent Yield). 1H NMR (DMSO, 400 MHz) δ 8.45 (1H, s), 8.84 (1H, s), 14.54 (1H, br s) ppm; MS (ES+) 154.96
Reference：
[1] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 18
[2] Patent: WO2008/153947, 2008, A2, . Location in patent: Page/Page column 42; 63-64
[3] Molecules, 2017, vol. 22, # 4,
[4] Patent: CN106496232, 2017, A, . Location in patent: Paragraph 0049; 0050; 0051; 0052
[5] Patent: CN107383014, 2017, A, . Location in patent: Paragraph 0075; 0076; 0077; 0078
[6] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 210 - 228
[7] Patent: WO2011/139273, 2011, A1, . Location in patent: Page/Page column 48; 49
[8] Patent: US2012/172379, 2012, A1, . Location in patent: Page/Page column 23
[9] Patent: US2007/10523, 2007, A1, . Location in patent: Page/Page column 9
[10] Patent: WO2011/29043, 2011, A1, . Location in patent: Page/Page column 126
4
[ 315-30-0 ]
[ 5399-92-8 ]
Yield
Reaction Conditions
Operation in experiment
70.45%
Stage #1: With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 80℃; for 2 h; Stage #2: With dipotassium hydrogenphosphate In water; toluene at 4 - 20℃;
Preparation 95; 4-Chloro-lH -pyrazolo[3,4-t/1pyrimidine; To a solution of allopurinol (20 g, 146.94 mmoles) in toluene (205.71 mL), add phosphoryl chloride (68.27 mL, 734.68 mmoles) and diisopropylethylamine (56.38 mL, 323.26 mmoles) and heat the mixture at 8O0C for 2 hours. Remove the solvent in vacuo to half and pour the mixture into 2 M potassium phosphate, dibasic (734.68 mL, 1.47 moles) in water at 40C. Stir the mixture overnight at room temperature. Filter off the precipitate through a pad of celite and wash it subsequently with EtOAc. Separate the filtrate, wash the aqueous layer with more EtOAc, join the organic layers, dry it over <n="38"/>MgSO4, filter and concentrate in vacuo to afford 4-Chloro-lH-pyrazolo[3,4-
70%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 85℃; for 2 h;
Example I.A.I. Intermediate 1 : 4-chloro-lH-pyrazolo[3,4-d]pyrimidine [0185] To a suspension of allopurinol (2.0 g, 15 mmol) in toluene (20 mL) was added POCI3 (7 mL, 74 mmol) and DIPEA (6 mL, 32 mmol). The mixture was heated to 85°C with stirring for 2hrs. The mixture was allowed to cool, concentrated to half of the volume and poured into 2M K2HP04 (200 mL). The mixture was stirred overnight at room temperature and filtered. The filter mass was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04 and concentrated to afford the title compound as pale orange powder (1.6 g, 70percent). MS (ESI) calcd for C5H3C1N4: 154.0; found: 155 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.47 (brs, 1H), 8.82 (s, 1H), 8.43 (s, 1H).
67%
at 125℃; for 1 h;
To a solution of 1 ,5-dihydro-4/-/-pyrazolo[3,4-c/]pyrimidin-4-one (2.0 g, 14.8 mmol) in POCI3 (40 ml_) was added Λ/,/V-dimethylaniline (5 ml_). The mixture was heated at 125 0C for 1 h. The majority of the POCI3 was removed by vacuum distillation. The residue was poured onto ice-water with stirring, and then extracted with diethyl ether (20 ml_ x 3). The organic fractions were dried, and concentrated to give title compound (1.5 g, 67percent ) as a white solid.
56%
at 20℃; Reflux
Intermediate 30: 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine; Phosphorus oxychloride (300 mL, 3.2 mol) was added to allopurinol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 20 g, 0.15 mol) and then N,N-dimethylaniline (30 mL, 0.24 mol) was added at room temperature. The resulting mixture was heated at reflux for 90 min and then cooled. The solvent was removed under vacuum. The residue was co-evaporated twice with toluene, and the resulting dark colored syrup was poured into a mixture of ice and water (500 mL). The mixture was stirred for 15 min, then transferred to a separatory funnel and extracted with ether (4.x.500 mL) and ethyl acetate (2.x.500 mL). The combined organic layers were washed twice with ice-water, dried (sodium sulfate), and concentrated to approximately 1.5 L. Charcoal was added to the slightly purple solution and the mixture was filtered through Celite. The Celite was washed with ethyl acetate and the combined filtrates were evaporated to dryness to give 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (13 g, 56percent) as a pale green solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.81 (s, 1H), 14.50 (br s, 1H).
56.4%
With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In N,N-dimethyl-formamide at 0 - 120℃; for 5 h;
Example 1 Preparation of 4-chloro-1H-pyrazolopyrimidine (2) Ten mL phosphorus oxychloride (POCl3) was added to 5g allopurinol (compound 1), and DMF (5mL N,N-dimethylformamide) was dropwise added slowly at 0°C, then DMA (1mL N,N-dimethylaniline) was dropwise added slowly, and temperature of the reaction system was increased to 120 °C for 5h reaction after resulting mixture was stirred at normal temperature for several minutes. Upon thorough cooling of the reaction product, a large amount of ice water was added to quench excessive phosphorus oxychloride, then the reaction product was extracted twice with ethyl acetate, and the ethyl acetate layer was spun dry to obtain 3.2g solid at a yield of 56.4percent. 1H NMR (400 MHz, DMSO-d6): δ 14.12(s, 1H), 9.32(s, 1H), 7.55(s, 1H) ppm.
Reference：
[1] Patent: WO2008/140947, 2008, A1, . Location in patent: Page/Page column 36-37
[2] Patent: WO2015/187845, 2015, A1, . Location in patent: Paragraph 0185
[3] Patent: WO2007/76423, 2007, A2, . Location in patent: Page/Page column 181
[4] ChemMedChem, 2014, vol. 9, # 11, p. 2516 - 2527
[5] Patent: US2009/286812, 2009, A1, . Location in patent: Page/Page column 28
[6] Patent: EP2889298, 2015, A1, . Location in patent: Paragraph 0101
[7] Journal of the American Chemical Society, 1956, vol. 78, p. 784,787[8] Journal of the American Chemical Society, 1957, vol. 79, p. 6407,6413
[9] Journal of Medicinal Chemistry, 2013, vol. 56, # 4, p. 1641 - 1655
5
[ 315-30-0 ]
[ 5399-92-8 ]
Yield
Reaction Conditions
Operation in experiment
70%
With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline at 80℃; for 2 h;
A mixture of allopurinol (2.00 g, 14.69 mmol) and N,N-dimethylaniline (2.00 g, 16.52 mmol) wasstirred in POCl3 (25 mL) at 80 °C for 2 h. The reaction mixture was diluted with water (35 mL), andextracted with ethyl acetate. The organic layer was washed with water and the organic phase wasconcentrated to dryness, and the residue was purified by column chromatography on silica gel using4:1.5 petroleum ether/ethyl acetate as eluent to give 2 [22]: white flake solid, 70 percent yield.
61%
for 1.5 h; Heating / reflux
Compound 79; 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine; To a mixture of commercially available 4-hydroxypyrazolo[3,4-d]pyrimidine (78) (Acros, 14.5 g, 106.5 mmol) stirred in POCl3 (375 mL) was added N,N-dimethylaniline (21 mL). The mixture was refluxed for 1.5 h. After cooling, excess POCl3 was removed by rotarty evaporation and pumped on high vacuum before pouring over 500 mL ice while stirring. The mixture was stirred for 10 min before extracting with ethyl ether (6.x.250 mL). The combined organic layer was washed with ice water (3.x.100 mL) and dried over MgSO4 and filtered. The ethyl ether was stripped and the resulting pale yellow solid (10 g, 61percent) was pumped on high vacuum overnight. Compound 79: mp >300° C., dec. 125° C.; MS (ES+ calculated: 154.56; found: 156.21 M+H). HPLC (98percent purity, retention time 6.033 minutes-method D) 1H NMR (400 MHz, DMSO-d6) δ 14.55 (bs, 1H), 8.84 (s, 1H), 8.46 (s, 1H).
39%
at 120℃; for 1.5 h;
The 4-hydroxypyrazolopyrimidine (2.5 g, 18 mmol) was dissolved in POC13 (34 mL, 0. 37mol) and N, N-dimethyl aniline (4.7 mL, 37 mmol.) This mixture was heated to reflux (120 °C) for 1.5 hours to afford a dark red solution. The mixture was concentrated to a viscous oil and cooled to 0 °C in an ice bath. The oil was poured into a mixture of ice-water and was stirred for 5 minutes. The acidic melt was extracted with ether (4 x 100mL), and the organics were combined. The organic was washed with cold water, then cold half saturated NaHC03 solution, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-Chloro-lH-pyrazolo [3, 4-d] pyrimidine (l. lg, 39percent) as a light yellow powder. lH NMR (DMSO-d6,400 MHz) 8 8.79 (1H, s), 8.41 (1H, s. )The 1H-Pyrazolo [3, 4-d] pyrimidin-4-ol (5.00 g, 36.73 mmol) was dissolved in 68.5 mL of phosphorous oxychloride and 9.31 mL of N, N-dimethyl aniline (73.47 mmol). This mixture was heated to reflux (120C) for 90 minutes to completion affording a dark red solution. The mixture was concentrated in vacuo and cooled to 0 °C in an ice bath. The residue was poured into ice water and stirred for three minutes. The acidic melt was extracted with ether, and the organics were combined. The organic was washed with cold water, cold half saturated NaHC03 solution, brine, separated, dried over MgS04, filtered, and concentrated in vacuo to afford the 4-chloro-lH-pyrazolo [3, 4-d] pyrimidine as a light yellow powder (2.30 g, 41percent). IH NMR (DMSO-d6, 400 MHz) 8 8.84 (s, 1H), 8.46 (s, 1H), NH not observed.
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5382 - 5394
[2] Comptes Rendus Chimie, 2017, vol. 20, # 9-10, p. 927 - 933
[3] Molecules, 2016, vol. 21, # 6,
[4] Patent: US2007/281949, 2007, A1, . Location in patent: Page/Page column 36
[5] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 115; 162-163
[6] Patent: WO2005/51304, 2005, A2, . Location in patent: Page/Page column 115; 162-163
[7] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2519 - 2525
[8] Patent: EP1772454, 2007, A1, . Location in patent: Page/Page column 60
[9] Patent: EP1772454, 2007, A1, . Location in patent: Page/Page column 60-61
[10] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 152 - 157
[11] Patent: WO2016/170163, 2016, A1, . Location in patent: Page/Page column 94
[12] Proceedings of the National Academy of Sciences of the United States of America, 2017, vol. 114, # 16, p. E3178 - E3187
6
[ 184789-03-5 ]
[ 5399-92-8 ]
Yield
Reaction Conditions
Operation in experiment
70%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 85℃; for 2 h;
[0149] To a suspension of allopurinol (2.0 g, 15 mmol) in toluene (20 mL) was added POCI3 (7 mL, 74 mmol) and DIPEA (6 mL, 32 mmol). The mixture was heated to 85°C with stirring for 2hrs. The mixture was allowed to cool, concentrated to half of the volume and poured into 2M K2HPO4 (200 mL). The mixture was stirred overnight at room temperature and filtered. The filter mass was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to afford the title compound as pale orange powder (1.6 g, 70percent). MS (ESl) calcd for C5H3CIN4: 154.0; found: 155 [M+H]. 1H NMR (400 MHz, dG-DMSO) 6 14.47 (brs, 1H), 8.82 (s, 1H), 8.43 (s, 1H).
Stage #1: With triethylamine 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);
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
11
[ 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 N-Bromosuccinimide In chloroform at 20℃; for 5 h;
To a suspension of 4-Chloro-lH-pyrazolo [3,4-d] pyrimidine (1. lg, 7.1 mmol) in CHC13 (50 mL) was added NBS (1.49 g, 8. 4 mmol. ) The mixture was stirred at room temperature for 5 hours, cooled to OC and the solids were isolated by vacuum filtration, rinsed with cold CHC13, and air dried. The solid was purified by column chromatography on silica (50percent EtOAc/hexanes) to give 3-Bromo-4-chloro-lH-pyrazolo [3, 4-d] pyrimidine (1.3, 77percent. )
Preparation 95; 4-Chloro-lH -pyrazolo[3,4-t/1pyrimidine; To a solution of allopurinol (20 g, 146.94 mmoles) in toluene (205.71 mL), add phosphoryl chloride (68.27 mL, 734.68 mmoles) and diisopropylethylamine (56.38 mL, 323.26 mmoles) and heat the mixture at 8O0C for 2 hours. Remove the solvent in vacuo to half and pour the mixture into 2 M potassium phosphate, dibasic (734.68 mL, 1.47 moles) in water at 40C. Stir the mixture overnight at room temperature. Filter off the precipitate through a pad of celite and wash it subsequently with EtOAc. Separate the filtrate, wash the aqueous layer with more EtOAc, join the organic layers, dry it over <n="38"/>MgSO4, filter and concentrate in vacuo to afford 4-Chloro-lH-pyrazolo[3,4-<i]pyrimidine (16 g, 70.45% yield) as a yellow solid. MS (APCI): m/z = 155.1 [M + eta]
70%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In toluene; at 85℃; for 2h;
Example I.A.I. Intermediate 1 : 4-chloro-lH-pyrazolo[3,4-d]pyrimidine [0185] To a suspension of allopurinol (2.0 g, 15 mmol) in toluene (20 mL) was added POCI3 (7 mL, 74 mmol) and DIPEA (6 mL, 32 mmol). The mixture was heated to 85C with stirring for 2hrs. The mixture was allowed to cool, concentrated to half of the volume and poured into 2M K2HP04 (200 mL). The mixture was stirred overnight at room temperature and filtered. The filter mass was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04 and concentrated to afford the title compound as pale orange powder (1.6 g, 70%). MS (ESI) calcd for C5H3C1N4: 154.0; found: 155 [M+H]. 1H NMR (400 MHz, DMSO) delta 14.47 (brs, 1H), 8.82 (s, 1H), 8.43 (s, 1H).
67%
With N,N-dimethyl-aniline; trichlorophosphate; at 125℃; for 1h;
To a solution of 1 ,5-dihydro-4/-/-pyrazolo[3,4-c/]pyrimidin-4-one (2.0 g, 14.8 mmol) in POCI3 (40 ml_) was added Lambda/,/V-dimethylaniline (5 ml_). The mixture was heated at 125 0C for 1 h. The majority of the POCI3 was removed by vacuum distillation. The residue was poured onto ice-water with stirring, and then extracted with diethyl ether (20 ml_ x 3). The organic fractions were dried, and concentrated to give title compound (1.5 g, 67% ) as a white solid.
56%
With N,N-dimethyl-aniline; trichlorophosphate; at 20℃;Reflux;
Intermediate 30: 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine; Phosphorus oxychloride (300 mL, 3.2 mol) was added to allopurinol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 20 g, 0.15 mol) and then N,N-dimethylaniline (30 mL, 0.24 mol) was added at room temperature. The resulting mixture was heated at reflux for 90 min and then cooled. The solvent was removed under vacuum. The residue was co-evaporated twice with toluene, and the resulting dark colored syrup was poured into a mixture of ice and water (500 mL). The mixture was stirred for 15 min, then transferred to a separatory funnel and extracted with ether (4×500 mL) and ethyl acetate (2×500 mL). The combined organic layers were washed twice with ice-water, dried (sodium sulfate), and concentrated to approximately 1.5 L. Charcoal was added to the slightly purple solution and the mixture was filtered through Celite. The Celite was washed with ethyl acetate and the combined filtrates were evaporated to dryness to give 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (13 g, 56%) as a pale green solid. 1H NMR (300 MHz, DMSO-d6) delta 8.44 (s, 1H), 8.81 (s, 1H), 14.50 (br s, 1H).
56.4%
With N,N-dimethyl-aniline; trichlorophosphate; In N,N-dimethyl-formamide; at 0 - 120℃; for 5h;
Example 1 Preparation of 4-chloro-1H-pyrazolopyrimidine (2) Ten mL phosphorus oxychloride (POCl3) was added to 5g allopurinol (compound 1), and DMF (5mL N,N-dimethylformamide) was dropwise added slowly at 0C, then DMA (1mL N,N-dimethylaniline) was dropwise added slowly, and temperature of the reaction system was increased to 120 C for 5h reaction after resulting mixture was stirred at normal temperature for several minutes. Upon thorough cooling of the reaction product, a large amount of ice water was added to quench excessive phosphorus oxychloride, then the reaction product was extracted twice with ethyl acetate, and the ethyl acetate layer was spun dry to obtain 3.2g solid at a yield of 56.4%. 1H NMR (400 MHz, DMSO-d6): delta 14.12(s, 1H), 9.32(s, 1H), 7.55(s, 1H) ppm.
With hydrogen;palladium dihydroxide; In methanol; at 20℃;
Preparation of 1H-Pyrazolo[3,4-d]pyrimidine: 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine Pd(OH)2 and are combined in methanol in a reaction vessel. The reaction vessel is evacuated and backfilled with hydrogen gas and the resultant mixture is stirred at rt for several hours. The resultant mixture is filtered and concentrated in vacuo to provide the dehalogenated product, which was used without further purification.
With ammonium hydroxide; In tetrahydrofuran; at 20 - 30℃; for 2h;
To a solution of 36 (200 rng, 1.29 mmoi) in THF (2.0 mL) is added ammonium hydroxide (2,0 mL). After stirring at 20---30 C for 2 hours, the mixture is concentrated. triturated with MeCN (0.5 niL), and collected by fiheration to give 37 as a red solid (100 mg, 57% yield)
With ammonium hydroxide; In isopropyl alcohol; at 95℃;
Intermediate 1-b To a solution of intermediate 1-a (20.0 g, 129.0 mmol) in 2-propanol (90 ml) was added ammonium hydroxide (126 ml). The reaction was heated in a pressure vessel at 95C overnight then cooled to room temperature. Volatiles were removed under reduced pressure. The residue was triturated in water; a precipitate formed and was collected by filtration to provide intermediate 1-b as a white solid.
With N-Bromosuccinimide; In chloroform; at 20℃; for 5h;
To a suspension of 4-Chloro-lH-pyrazolo [3,4-d] pyrimidine (1. lg, 7.1 mmol) in CHC13 (50 mL) was added NBS (1.49 g, 8. 4 mmol. ) The mixture was stirred at room temperature for 5 hours, cooled to OC and the solids were isolated by vacuum filtration, rinsed with cold CHC13, and air dried. The solid was purified by column chromatography on silica (50% EtOAc/hexanes) to give 3-Bromo-4-chloro-lH-pyrazolo [3, 4-d] pyrimidine (1.3, 77%. )
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃;
Intermediate 1-b' To a solution of intermediate 1-a (10.0 g, 64.7 mmol) in DMF (162 ml) was added slowly added NBS (12.7 g, 71.2 mmol)). The reaction was stirred for 15 minutes at 0C and at room temperature overnight. Water was added; a precipitate formed and was collected by filtration then dried under vacuum to provide intermediate 1-b' as a white solid.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;
To a stirred solution of 4 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.17 mmol, 1 equiv) in DMF (50 mL) was added NBS (3.2 g, 17.78 mmol, 1.1 equiv) at 000. The reaction mixture was warmed to room temperature and stirred for 3h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain 3-bromo-4-chloro-1H-pyrazolo[3,4- d]pyrimidine (3.5 g, crude) as pale yellow solid. LCMS (ES) m/z = 233.4, 235.4 [M+H. ]. 1H NMR (400 MHz, DMSO-d6) O ppm - 8.82 (5, 1 H), 14.80 (br.s, 1 H)
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 50℃; for 16h;
Preparation 95-D; 4-Chloro-3-iodo-lH-pyrazolor3,4-(i1pyrimidine; Charge 4-chloro-lH-pyrazolo[3,4-<i]pyrimidine (6.1g, l.Oeq), N-iodosuccinimide (NIS) (21.55g, 2.0eq) and DMF (213.5 mL) in a round bottom flask . Stir the reaction mass at 500C for 16h. Monitor the reaction by TLC (10% acetone in DCM). Concentrate the reaction mass under reduced pressure. Charge ethyl acetate and wash with water and saturated aq. sodium chloride. Dry the organic layer over anhydrous sodium sulfate and concentrate the organic layer under reduced pressure to give 4-chloro-3-iodo-lH- pyrazolo[3,4-fiT]pyrimidine (6.8g, 61.43%).
With trichlorophosphate; In N,N-dimethyl-aniline; at 80℃; for 2h;
A mixture of allopurinol (2.00 g, 14.69 mmol) and N,N-dimethylaniline (2.00 g, 16.52 mmol) wasstirred in POCl3 (25 mL) at 80 C for 2 h. The reaction mixture was diluted with water (35 mL), andextracted with ethyl acetate. The organic layer was washed with water and the organic phase wasconcentrated to dryness, and the residue was purified by column chromatography on silica gel using4:1.5 petroleum ether/ethyl acetate as eluent to give 2 [22]: white flake solid, 70 % yield.
61%
With N,N-dimethyl-aniline; trichlorophosphate; for 1.5h;Heating / reflux;
Compound 79; 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine; To a mixture of commercially available 4-hydroxypyrazolo[3,4-d]pyrimidine (78) (Acros, 14.5 g, 106.5 mmol) stirred in POCl3 (375 mL) was added N,N-dimethylaniline (21 mL). The mixture was refluxed for 1.5 h. After cooling, excess POCl3 was removed by rotarty evaporation and pumped on high vacuum before pouring over 500 mL ice while stirring. The mixture was stirred for 10 min before extracting with ethyl ether (6×250 mL). The combined organic layer was washed with ice water (3×100 mL) and dried over MgSO4 and filtered. The ethyl ether was stripped and the resulting pale yellow solid (10 g, 61%) was pumped on high vacuum overnight. Compound 79: mp >300 C., dec. 125 C.; MS (ES+ calculated: 154.56; found: 156.21 M+H). HPLC (98% purity, retention time 6.033 minutes-method D) 1H NMR (400 MHz, DMSO-d6) delta 14.55 (bs, 1H), 8.84 (s, 1H), 8.46 (s, 1H).
39 - 41%
With N,N-dimethyl-aniline; trichlorophosphate; at 120℃; for 1.5h;Product distribution / selectivity;
The 4-hydroxypyrazolopyrimidine (2.5 g, 18 mmol) was dissolved in POC13 (34 mL, 0. 37mol) and N, N-dimethyl aniline (4.7 mL, 37 mmol.) This mixture was heated to reflux (120 C) for 1.5 hours to afford a dark red solution. The mixture was concentrated to a viscous oil and cooled to 0 C in an ice bath. The oil was poured into a mixture of ice-water and was stirred for 5 minutes. The acidic melt was extracted with ether (4 x 100mL), and the organics were combined. The organic was washed with cold water, then cold half saturated NaHC03 solution, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-Chloro-lH-pyrazolo [3, 4-d] pyrimidine (l. lg, 39%) as a light yellow powder. lH NMR (DMSO-d6,400 MHz) 8 8.79 (1H, s), 8.41 (1H, s. )The 1H-Pyrazolo [3, 4-d] pyrimidin-4-ol (5.00 g, 36.73 mmol) was dissolved in 68.5 mL of phosphorous oxychloride and 9.31 mL of N, N-dimethyl aniline (73.47 mmol). This mixture was heated to reflux (120C) for 90 minutes to completion affording a dark red solution. The mixture was concentrated in vacuo and cooled to 0 C in an ice bath. The residue was poured into ice water and stirred for three minutes. The acidic melt was extracted with ether, and the organics were combined. The organic was washed with cold water, cold half saturated NaHC03 solution, brine, separated, dried over MgS04, filtered, and concentrated in vacuo to afford the 4-chloro-lH-pyrazolo [3, 4-d] pyrimidine as a light yellow powder (2.30 g, 41%). IH NMR (DMSO-d6, 400 MHz) 8 8.84 (s, 1H), 8.46 (s, 1H), NH not observed.
With trichlorophosphate; for 1.5h;Heating / reflux;
(1) A suspension of allopurinol (4-hydroxy-1H-pyrazolo[3,4-d]pyrimidine, 25 g) and dimethylaniline (75 mL) in phosphorus oxychloride (350 mL) was stirred under heating for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was poured to ice water. The mixture was extracted with ethyl acetate (x 3, 2.2 L in total). The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (19 g) as crystals.
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In trichlorophosphate; for 3h;Heating / reflux;
(1) A suspension of allopurinol (20 g) and N,N-diisopropylethylamine (41 mL) in phosphorus oxychloride (245 mL) was refluxed under heating for 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate. Thereto was added cold water and the mixture was extracted with ethyl acetate (x 3, 2.5 L in total). The organic layer was separated and concentrated in vacuo to give crude 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (21.3 g) as crystals.
With N,N-dimethyl-aniline; trichlorophosphate; at 80℃; for 2h;
A mixture of allopurinol 1 (2.00g, 14.69 mmol) and N,N-dimethylaniline (2.00g, 16.52mmol) was stirred in POCl3 (25mL) at 80C for 2 h. The reaction mixture was diluted with water (35mL), and extracted with ethyl acetate. The organic layer was washed with water and the organic phase was concentrated to dryness, and the residue was purified by column chromatography on silica gel using 4:1.5 petroleum ether/ethyl acetate as the eluent to give 2.
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 20 - 110℃; for 4h;Inert atmosphere;
1 H-Pyrazolo [3,4-d]pyrimidin-4-ol (5.0 g, 36.7 mmol) was dissolved in POCI3 (61.2 mL, 100.67g, 657 mmol) at room temperature under nitrogen. Nu,Nu-diisopropyl ethylamine (10.2 mL, 58.5 mmol) was added into the reaction mixture and the resulting mixture was refiuxed at 1 10C for 4 hrs. After 4 hrs, POCI3 was distilled off under vacuum at 40C to obtain a blackish red thick gum. The thick gum was dumped into ice cold water (25 mL) and extracted by DC (25 mL chi 3). The organic layer was concentrated to 25 mL. The product was used as crude for the next step.
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;
To a solution of 4-chloro-lH-pyrazolo[3,4-^pyrimidine (J. Amer. Chem. SQC. 1957, 79, 6407-6413) (51 mg, 0.33 mmol) in ethanol (2 ml) was added triethylamine (100 mul, 0.72 mmol) and 4-(N-Boc-aminomethyl)piperidine (87 mg, 0.41 mmol). The solution was heated at 80 C for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the intermediate NH-BOC protected product (33 mg, 30% yield).To the intermediate NH-BOC protected product (32 mg, 0.096 mmol) was added HCl (1 ml, 4M solution in dioxane, 4 mmol). The suspension was stirred at room temperature for 1 hour, and then diluted with diethyl ether (4 ml). The ethereal layer was discarded and the solid washed with a further portion of diethyl ether (2 ml). The ethereal layer was again discarded, and the resultant solid dried under high vacuum. The free base was liberated by dissolution of this material in methanol, loading onto an acidic resin SCX-2 cartridge, and elution from the cartridge with ammonia in methanol to give the title compound (21 mg, quantitative). LC/MS Rt 0.86 [M+H]+233
30%
With triethylamine; In ethanol; at 80℃; for 3h;
EXAMPLE 17; C-M-fiH-Pyrazolobeta^-c/ipyrimidin^-vO-piperidin^-v?-methvlamine <n="123"/>To a solution of 4-chloro-1/-/-pyrazolo[3,4-d]pyrimidine (J. Amer. Chem. Soc. 1957, 79, 6407-6413) (51 mg, 0.33 mmol) in ethano] (2 ml) was added triethylamine (100 mul, 0.72 mmol) and 4-(N-Boc-aminomethyl)piperidine (87 mg, 0.41 mmol). The solution was heated at 80 0C for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the intermediate NH-BOC protected product (33 mg, 30% yield).
tert-butyl (1-(1H-pyrazolo [3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With triethylamine; In ethanol; at 80℃; for 3h;
To a solution of 4-chloro-lH-pyrazolo[3,4-</]pyrimidine (J. Amer. Chem. Soc. 1957, 79, 6407-6413) (59 mg, 0.38 mmol) in ethanol (2 ml) was added triethylamine (100 mul, 0.72 mmol) and 4-(N-Boc-amino)piperidine (134 mg, 0.67 mmol). The solution was heated at 80 0C for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the product (32 mg, 26% yield).
26%
With triethylamine; In ethanol; at 80℃; for 3h;
EXAMPLE 111 -(1 H-Pyrazolof3.4-dlpyrimidin-4-yl)-piperidin-4-ylanriine11A. f1-(1/-/-Pyrazolof3,4-cnpyrimidin-4-yl)-piperidin-4-yll-carbamic acid ferf-butyl esterTo a solution of 4-chloro-1/-/-pyrazolo[3,4-d]pyrimidine (J. Amer. Chem. Soc. 1957, 79, 6407-6413) (59 mg, 0.38 mmol) in ethanol (2 ml) was added triethylamine (100 mul, 0.72 mmol) and 4-(N-Boc-amino)piperidine (134 mg, 0.67 mmol). The solution was heated at 80 0C for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the product (32 mg, 26% yield).
With triethylamine; hydrazine; In 1,4-dioxane; at 20℃; for 1h;
Synthesis of Compound 4.1. Hydrazine hydrate (11.5 mL, 23.7 mmol) was slowly added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol), and triethylamine (30 mL, 22 mmol) in 1,4-dioxane (600 mL), while cooling to maintain an internal temperature below 20 C. After the addition was complete, the reaction was warmed to RT. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford compound 4.1 (29 g, 83%) as a light yellow solid. 1H NMR (400.13 MHz, DMSO-d6) delta14.52 (br. s, 1H), 8.83 (s, 1H), 8.45 (s, 1H). MS m/z 155 [M+1]+.
71%
With triethylamine; hydrazine; In methanol; at -60 - 20℃;
Hydrazine hydrate (2.0 ml, 41 mmol) was slowly added to a solution of 4,6- dichloropyrimidine-5-carbaldehyde (7.2 g, 41 mmol) in MeOH (150 ml) -60 0C (nitromethane-dry ice bath) followed by triethylamine (6.8 mL, 49 mmol). The mixture was allowed to warm to rt and stirred for 2 h. MeOH was removed in vacuo and water <n="65"/>(150 mL) was added. The mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered through a glass funnel. Removal of solvent gave 4-chloro-lH-pyrazolo[3,4-d]pyrimidine (4.45 g, 71%). MS (ESI, pos. ion) m/z: 155 [M+H]+
68.9%
With hydrazine hydrate; triethylamine; In methanol; at -65 - 20℃;
To the solution of 4,6-dichloropyrimidine-5-carbaldehyde(1.0 g, 0.006 mol) in methanol (20 mL) at -65 C, triethylamine (0.97 mL,1.2 equivalents (eq.)) wasadded. A solution of hydrazine monohydrate (0.274 mL 1.0 eq.) in methanol (10 mL) was slowlydripped into above stirred solution by using a constant-pressure dropping funnel. The mixture wasallowed to warm to room temperature and stirred for 2-3 h. The reaction mixture was concentratedin vacuo and crude product was diluted with water (20 mL), and extracted with EtOAc (60 mL x 3).The combined organic layer was washed with saturated solution of NaCl (60 mL x 3), dried overMgSO4 and concentrated to give compound 2. Yield: 68.9%. 1H-NMR (400 MHz, deuteriated dimethylsulfoxide (DMSO-d6)) delta 14.51 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H). ESI-MS m/z: 153.00 [M - H]-.
68.9%
With hydrazine hydrate; triethylamine; In methanol; at -65 - 20℃;
In a 100 mL three-necked flask, 1.0 g of 4,6-dichloro-5-pyrimidinecarboxaldehyde and 20 mL of methanol were added and dissolved with stirring. The temperature was lowered to -65 C and 0.97 mL (1.2 eq) of triethylamine was added dropwise. 0.274 mL (1.0 eq) of hydrazine monohydrate was diluted with 10 mL of methanol and dropped slowly using a dropping funnel. Recovery was completed to room temperature, the reaction 2 ~ 3h, TLC monitoring. After the reaction was completed, the solvent was evaporated to dryness. The solid was dissolved with ethyl acetate (30 mL x 3), filtered, and combined, washed with saturated NaCl solution (60 mL x 3). Dried over anhydrous MgSO4, the solvent was removed by rotary evaporation and dried to give a pale yellow solid in a yield of 68.9%.
68.9%
With hydrazine hydrate; triethylamine; In methanol; at -65 - 20℃;
In a 100 mL three-necked flask, 4,6-dichloro-5-pyrimidine formaldehyde (1.0 g, 5.68 mmol) was added.Methanol (20 mL) was dissolved by stirring, cooled to -65[deg.] C., and triethylamine (0.97 mL, 6.81 mmol) was added dropwise. Hydrazine monohydrate (0.274 mL, 5.68 mmol) was diluted with methanol (10 mL) and slowly dropped using a dropping funnel. After the completion of the addition, the reaction was allowed to return to room temperature for 2 to 3 h and monitored by TLC. The reaction is over,The solvent was evaporated and dried. The solid was dissolved in ethyl acetate (30 mL x 3), filtered and combined and washed with saturated NaCl solution (60 mL)×3). Dry over anhydrous MgSO4, evaporate the solvent, and dry to give a pale yellow solid (0.60 g, 68.9% yield)
68.9%
With triethylamine; hydrazine; In methanol; at -65 - 20℃; for 4h;
General procedure: To the solution of 4,6-dichloropyrimidine-5-carbaldehyde 2 (1.0g, 5.6mmol) in methanol (20mL) at-65C, triethylamine (0.97mL) was added. A solution of hydrazine monohydrate (0.274mL 1.0 eq.) in methanol (10mL) was slowly dripped into above stirred solution by using a constant-pressure dropping funnel. The mixture was allowed to warm to room temperature and stirred for 2-3h. The reaction mixture was concentrated in vacuo and crude product was diluted with water (20mL), and extracted with EtOAc (60mL×3). The combined organic layer was washed with saturated solution of NaCl (60mL×3), dried over MgSO4 and concentrated to give compound 3 (0.602g, yield: 68.9%.) 1H NMR (400MHz, deuteriated dimethyl sulfoxide (DMSO-d6)) delta 14.51 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H). ESI-MS m/z: 153.00 [M- H]-.
27%
With triethylamine; hydrazine; In tetrahydrofuran; at 160℃; for 0.333333h;Molecular sieve; microwave irradiation;
A suspension of 4,6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (lOmL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 mu, 5.650 mmol). The reaction was allowed to stir at RT for 10 minutes before being heated to 160C for 20 minutes in the microwave. The mixture was diluted with EtOAc/water and the organic layer washed with saturated NaCl, dried (MgSC ), and concentrated in vacuo. This was purified by column chromatography (ISCO Companion, 40g column, MeOH / DCM) to give the required product (117mg, 27% Yield).JH NMR (DMSO, 400 MHz) delta 8.45 (IH, s), 8.84 (IH, s), 14.54 (IH, br s) ppm; MS (ES*) 154.96
27%
With triethylamine; hydrazine; In tetrahydrofuran; at 20 - 160℃; for 0.5h;Molecular sieve; Microwave irradiation;
A suspension of 4,6-dichloropyrimidine-5-carbaldehyde (500 mg, 2.825 mmol) in THF (10 mL) was allowed to stir at RT and treated with 3A sieves and hydrazine (3.461 g, 3.390 mL of 1M in THF, 3.390 mmol) followed by triethylamine (571.7 mg, 787.5 muL, 5.650 mmol). The reaction was allowed to stir at RT for 10 minutes before being heated to 160 C. for 20 minutes in the microwave. The mixture was diluted with EtOAc/water and the organic layer washed with saturated NaCl, dried (MgSO4), and concentrated in vacuo. This was purified by column chromatography (ISCO Companion, 40 g column, MeOH/DCM) to give the required product (117 mg, 27% Yield). 1H NMR (DMSO, 400 MHz) delta 8.45 (1H, s), 8.84 (1H, s), 14.54 (1H, br s) ppm; MS (ES+) 154.96
With hydrazine; In tetrahydrofuran; 1,4-dioxane; at -78 - 20℃; for 16h;
Preparation of 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine: 4,6-Dichloro-pyrimidine-5-carbaldehyde hydrazine (10 mL, excess), and dioxane (90 mL) are combined at -78 C. in THF. The reaction solution is warmed to rt and stirred for 16 hr. The solvent is evaporated in vacuo to provide a crude residue which is diluted with dichloromethane (600 mL). The organic solution is washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The solvent is removed in vacuo to provide 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine as a yellow powder which is used without further purification.
With hydrazine hydrate; triethylamine; In 1,4-dioxane; at 20℃; for 1h;
Hydrazine hydrate (1 1.5 mL, 23.7 mmol) was slowly added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol) and triethylamine (30 mL, 22 mmol) in 1 ,4-dioxane (600 mL) with cooling to maintain an internal temperature below 20 C. After the addition was completed, the reaction was warmed to rt. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford the title intermediate (29 g, 83 %) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 14.52 (br. s, 1 H), 8.83 (s, 1 H), 8.45 (s, 1 H). MS m/z 155 [M+l]+.
N-[4-methyl-3-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-phenyl]-3-trifluoromethyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In <i>tert</i>-butyl alcohol at 150℃; for 0.333333h; Microwave irradiation;
27
Example 27: N-f4-Methyl-3-(1 H-pyrazolor3.4-dlpyrimidin-4-ylamino)-phenvn-3- trifluoromethyl-benzamide4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (0.60 g, 3.9 mmol) and N-(3-amino-4-methyl-phenyl)- 3-trifluoromethyl-benzamide (0.92 g, 3.9 mmol) are heated in tert. -butanol in the microwave oven to 150 C for 20 minutes. The reaction is cooled down and solvent is removed under reduced pressure. The product is purified by automated column chromatography and is dried at the high vacuum pump. The title compound is obtained as a white solid. HPLC: tR = 8.38 min ; MS-ES+: (M+H)+ = 413 ; TLC**: RpO.22
With dmap; In acetonitrile; at 20℃; for 0.166667h;
To a solution of 4-chloro-1 /-/-pyrazolo[3,4-c/]pyriiotatauiotaidine (0.5 g, 3.2 mmol) in CH3CN (2 mL) was added Boc2O (0.84 g, 3.8 mmol) and DMAP (~2 mg). After the mixture was stirred at RT for 10 min, it was concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 3:1) to give the title compound (0.74 g, 90%) as a white solid: LC-MS (ES) m/z = 255 (M+H)+.
1.65 g
With triethylamine; In dichloromethane; at 20℃; for 6h;
4-Chloro-1 H-pyrazolo[3,4-d]pyrimidine was dissolved in DCM, Boc anhydride (16.2 mL, 71 mmol) was added followed by addition of TEA (15 mL, 108 mmol). The reaction mixture was stirred at room temperature for 6 hrs. After completion of the reaction, as judged by TLC, water (125 mL) was added and the aqueous was extracted with DCM (25 mL x 3). The organic layer was washed with water (10mL), brine (10 mL), was separated off and dried over Na2S04. The organic layer was concentrated in vacuo at 40C to afford the crude title product. The crude product was adsorbed onto silica gel and was purified by column chromatography on silica eluting with a gradient of 0-1 % methanol in DCM to afford the title product (1.65 g, 18%).
With toluene-4-sulfonic acid; In tetrahydrofuran; for 2h;Reflux;
Example l.A.2. Intermediate 2: 4-chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-d]- pyrimidine [0186] To a solution of 4-chloro-lH-pyrazolo[3,4-d]pyrimidine (35 g, 226 mmol) in THF (1 L) was added dihydropyran (31 mL, 340 mmol) and p-TsOH.H20 (4.3 g, 22.6 mmol). The solution was heated to reflux. After stirring for lh, another batch of dihydropyran (16 mL, 175 mmol) was added. After stirring for additional lh, the solution was concentrated and purified by column chromatography over silica gel (DCM/EtOAc = 2%~10%) to afford the title compound as a white powder (50 g, 90%). MS (ESI) calcd for Ci0HnClN4O: 238; found: 239 [M+H]. 1H NMR (400 MHz, CDC13) delta 8.80 (s, 1H), 8.20 (s, 1H), 6.11 - 5.99 (m, 1H), 4.16 - 4.05 (m, 1H), 3.85 - 3.74 (m, 1H), 2.69 - 2.57 (m, 1H), 2.24 - 2.11 (m, 1H), 2.05 - 1.94 (m, 1H), 1.87 - 1.71 (m, 2H), 1.71 - 1.59 (m, 1H).
90%
With toluene-4-sulfonic acid; In tetrahydrofuran; for 2h;Reflux;
[0150] To a solution of <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (35 g, 226 mmol) in THF (1 L) was added dihydropyran (31 mL, 340 mmol) and p-T5OH?H20 (4.3 g, 22.6 mmol). The solution was heated to reflux. After stirring for lh, another batch of dihydropyran (16 mL, 175 mmol) was added. After stirred for additional lh, the solution was concentrated and purified by column chromatography over silica gel (DCM/EtOAc: 2%?lO%) to afford the title compound as a white powder (50 g, 90%). MS (ESl) calcd for C10H11C1N40: 238; found: 239 [M+H]. 1H NMR (400 MHz, CDCI3) 6 8.80 (s, 1H), 8.20 (s, 1H), 6.11-5.99 (m, 1H), 4.16-4.05 (m, 1H), 3.85-3.74 (m, 1H), 2.69-2.57 (m, 1H), 2.24-2.11 (m, 1H), 2.05-1.94 (m, 1H), 1.87-1.71 (m, 2H), 1.71-1.59 (m, 1H).
80%
Step 1: 4-Chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine; 3,4-Dihydro-2H-pyran (10 mL) and 10-camphorsulfonic acid (200 mg, 0.86 mmol) were added to a solution of <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (Intermediate 30; 2.1 g, 13.6 mmol) in ethyl acetate (80 mL). The mixture was stirred at room temperature for 70 h, poured into saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography eluting with 20% ethyl acetate/hexanes to give 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (2.61 g, 80%) as a lavender-colored crystalline solid.
80%
With toluene-4-sulfonic acid; In ethyl acetate; for 3h;Reflux;
<strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (678mg, 4.39 mmol) and p-toluenesolfonic acid monohydrate (16mg, 0.09 mmol) were suspended in ethyl acetate (25 mL), 3,4-Dihydro-2H-pyran was added and the reaction mixture was heated under reflux for 3 hours. Once all suspended solids had gone intosolution, the solvent was removed in vacuo and the crude product deposited onto silica. The product was purified by flash column chromatography (12g column, 0 to 100% EtOAc in Heptane)to furnish 4-chloro-l -tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine (840mg, 3.52 mmol, 80% yield) as a pink solid. 1H NMR (400MHz, CDCI3) O/ppm: 8.80 (s, 1H), 8.22 (s, 1H), 6.05 (dd, 1H, J = 10.4, 2.5 Hz), 4.15-4.10 (m, 1H), 3.85-3.77 (m, 1H), 2.68-2.57 (m, 1H), 2.21-2.12 (m, 1H), 2.03-1.95 (m, 1H), 1.95-1.77(m, 2H), 1.69-1.63 (m, 1H).
77%
With toluene-4-sulfonic acid; In ethyl acetate; at 50℃; for 1.16667h;
To a round bottom flask equipped with a magnetic stir bar was added 4-chloro-lH-pyrazolo[3,4- d]pyrimidine (2.0 g, 12.9 mmol, 1.0 eq.) and ethyl acetate. The mixture was heated to 50 C. After 10 minutes /j-toluenesulfonic acid (50 mg) was added, followed by the addition of 2,3- dihydropurane (1.09 g, 15.5mmol, 1.2eq). The resulting reaction mixture was heated at 5O0C with stirring for 1 hour and was then cooled to room temperature at which time aqueous ammonia was added. After 5 minutes the organic layer was separated, and washed twice with water (100 ml) and once with brine (100 ml). The ethyl acetate was removed and petroleum ether was added. The mixture was heated and filtered thru cotton. Removal of the petroleum ether in vacuo afforded 4-chloro-l-(tetrahydro-pyran-2-yl)-lH-pyrazolo[3,4-d]pyrimidine as a light yellow colored solid (2.35g, 77%). 1H NMR (400 MHz, CDCl3): 8.8 l(s, IH), 8.22 (s, IH), 6.05 (dd, IH), 4.14 (m, IH), 3.81 (m, IH), 2.61 (m, IH), 2.14 (m, IH), 1.99 (m, IH), 1.81 (m, 2H), 1.64 (m, IH); MS (ESI) for C10HnClN4O: 239 (MH+).
76.5%
With pyridinium p-toluenesulfonate; In ethyl acetate; at 50℃;
Compound 2 (1.88 g, 0.012 mol)was dissolved in EtOAc (50 mL) and heated to 50 C. After 10 min pyridinium 4-toluenesulfonate(PPTs) (50 mg) were added, followed by the addition of 3,4-dihydro-2H-pyran. The resulting reactionmixture was at stirred 50 C. After the reaction was complete according to the TLC detection, themixture was cooled to room temperature, washed with water (60 mL x 1), and a saturated solution ofNaCl (50 mL x 2), and dried over MgSO4. The ethyl acetate was removed and petroleum ether (60 mL x 2) was added. The mixture was heated and filtered through cotton. Removal of petroleum ether invacuo gives compound 3 as light yellow colored solid. Yield: 76.5%. 1H-NMR (400 MHz, DMSO-d6) delta 8.92 (s, 1H), 8.55 (s, 1H), 6.02 (dd, J = 10.4, 2.4 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.76-3.70 (m, 1H),2.49-2.42 (m, 1H), 2.07-2.08 (m, 1H), 1.98-1.94 (m, 1H), 1.85-1.73 (m, 1H), 1.64-1.58 (m, 2H). ESI-MSm/z: 239.06 [M + H]+.
76.5%
With pyridinium p-toluenesulfonate; In ethyl acetate; at 50℃;
In a 100 mL three-necked flask, 1.88 g of 4-chloro-1H-pyrazolo [3,4-d] pyrimidine and 50 mL of ethyl acetate were added and the temperature was raised to 50 C. 50 mg of PPTs (pyridinium p-toluenesulfonate, catalyst amount) and 1.37 mL of 3,4-dihydro-2H-pyran (1.2 eq) were sequentially charged. 50 C incubation reaction 20-22h, TLC monitoring. The reaction was completed and the temperature was lowered to room temperature. The mixture was washed with water (60 mL × 1) and saturated NaCl solution (50 mL × 2), respectively. Dried over anhydrous MgSO4, the solvent was removed by rotary evaporation and dried. The resulting solid was extracted with petroleum ether (60 mL x 2). The solvent was evaporated to dryness and dried to give a pale yellow oily solid in 76.5% yield.
62%
With camphor-10-sulfonic acid; In ethyl acetate; at 20℃; for 24h;
To a solution of 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (2 g, 12.9 mmol) and D-10-Camphor sulphonic acid (0.324 g, 1.39 mmol) in anhydrous ethyl acetate (20 mL) was slowly added 3,4-dihydropyrane (6 mL, 5.53 g, 65.8 mmol) at room temperature. The reaction mixture was then allowed to stir at room temperature for 24 h. After completion of reaction, as judged by TLC, the reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford the title product (1.92 g, 62%).
29%
With toluene-4-sulfonic acid; In ethyl acetate; for 3h;Reflux;
Step 1 : 4-chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-d]pyrimidineTo a solution of 4-chloro-lH-pyrazolo[3,4-d]pyrimidine (2.00 g, 12.9 mmol) in EtOAc (30 mL) was added 3,4-dihydro-2H-pyran (3.29 g, 39.1 mmol), followed by 4-methylbenzenesulfonic acid (1%) and the resulting reaction mixture was heated to refluxing for 3 hrs. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (petrol ether: EtOAc = 6: 1 to 4: 1) to afford the desired product (0.85 g, 29%).1H NMR (DMSO-^): ? 8.62 (1H, s), 7.93 (1H, s), 5.53-5.56 (1H, m), 3.92-3.95 (1H, m), 3.64-3.67 (1H, m), 2.08-2.14 (1H, m), 1.89-1.99 (3H, m), 1.60-1.75 (2H, m).
29%
With toluene-4-sulfonic acid; In ethyl acetate; for 3h;Reflux;
To a solution of <strong>[5399-92-8]4-chloro-1H-pyrrolo[3,4-d]pyrimidine</strong> (2.00 g, 12.9 mmol) in ethyl acetate (30 mL) was added 3,4-dihydropyran (3.29 g, 39 mmol) And the catalytic amount of p-toluenesulfonic acid (1%). The reaction solution was heated under reflux for 3 hours. Water was added thereto, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether:Ethyl acetate = 4: 1) to give the title compound (0.85 g, 29%).
4-[(tert-butyloxycarbonyl)amino]-4-(methoxycarbonyl)piperidine[ No CAS ]
[ 5399-92-8 ]
[ 1035391-26-4 ]
Yield
Reaction Conditions
Operation in experiment
72.6%
With triethylamine; In ethanol; at 20 - 50℃; for 0.666667h;
EXAMPLE 107; <n="227"/>4-(7-(benzyloxy)-lH-benzordlimidazol-2-yl)-l-(lH-pyrazolor3,4-dlpyrimidin-4- yl)piperidin-4-amine107 A. Methyl 4-(tert-butoxycarbonylamino)-l-(lH-pyrazolor3,4-dlpyrimidin-4- yl)piperidine-4-carboxylateTriethylamine (25.3 mL, 181.81 mmol) was added in one portion to a stirred suspension of methyl 4-(t°t-butoxycarbonylamino)piperidine-4-carboxylate (10.80 g, 41.82 mmol) and 4-chloro-lH-pyrazolo[3,4-d]pyrimidine (5.62 g, 36.36 mmol)** in ethanol (175 mL) at 2O0C under nitrogen. The resulting solution was stirred at 2O0C for 30 minutes and at 5O0C for 10 minutes. The solution was filtered and the filtrate was evaporated. The crude product was purified by flash silica chromatography, elution gradient 2 to 8% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(tert- butoxycarbonylamino)- 1 -( 1 H-pyrazo Io [3 ,4-d]pyrimidin-4-yl)piperidine-4-carboxylate (9.94 g, 72.6 %) as a cream dry film, m/z (ESI+) M+ = 377; HPLC tR = 1.24 min; IH NMR (399.9 MHz, DMSO-d6) delta 1.41 (9H, s), 1.92 - 1.97 (2H, m), 2.07 - 2.10 (2H, m), 3.57 (2H, m), 3.63 (3H, s), 4.34 (IH, s), 7.53 (IH, s), 8.24 (IH, s), 8.30 (IH, s), 13.52 (IH, s).H= * Commercially available from Chontech (catalogue number: 07044)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 4h;
The starting material B-Cl(1a-n) (12.94 mmol) was weighed and dissolved in DMF (10 mL).DIEA (51.76mmol),1-Boc piperazine (15.53 mmol) was added to the reaction flask and reacted at 90 C for 4 h.The reaction was completely detected by TLC, and the reaction solution was poured into 10 times of ice water.A large amount of white solid was precipitated, filtered, and the cake was washed with water (20 ml × 3) and dried.Intermediate 2 was obtained. In the above preparation, la is <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong>, which gives 2a as a white solid, yield 89%
89%
In N,N-dimethyl-formamide; at 90℃;Microwave irradiation;
General procedure: 3-substituted-1H-pyrazolo[3,4-d]pyrimidine(10 mmol) was dissolved in DMF (15 mL).1-tert-butoxycarbonylpiperazine (10.5 mmol), microwave reaction at 90 C for 20-30 min, the reaction is completed, the reaction solution is quenched with ice water (150 mL).The organic phase was extracted with aq. EtOAc (3×30 mL). In addition to solvents,Purification by column chromatography (petroleum ether: ethyl acetate = 1:3) gave Intermediate 2
84%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 80℃;
The 4-clzloro-1B-pyrazolo [3, 4-d] pylimidine (500 mg, 3.24 mmol) and piperazine-1-carboxylic acid tert-butyl ester (603 mg, 3.24 mmol) were dissolved in 11.0 mL of NMP then treated with diisopropylethyl amine (845 muL, 4.85 mmol). The yellow solution was heated to 80C overnight to completion and was allowed to cool to room temperature. The solution was diluted with ethyl acetate, poured into diluted NaHC03 solution, and extracted with ethyl acetate. The combined organic was washed with water, brine, separated, dried over MgS04, filtered, and concentrated in vacuo to afford the crude material as a tan solid. The material was triturated with DCM/hexanes to afford the 4-(1H-pyrazolo [3, 4-d] pyrimidin-4-yl)- piperazine-1-carboxylic acid tert-butyl ester as a cream-colored solid (824 mg, 84%). 1H NMR (CDC13, 400 MHz) 8 8.48 (s, 1H), 8.06 (s, 1H), 4.05 (m, 4H), 3.67 (m, 4H). LCMS (APCI+) nl/z 305 [M+H] + ; Rt = 2.14 min.
Stage #1: tert-butyl 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate With methanol; acetyl chloride at 5 - 20℃;
Stage #2: With triethylamine In dimethyl sulfoxide for 0.5h;
Stage #3: 4-chloro-1H-pyrazolo[3,4-d]pyrimidine In dimethyl sulfoxide at 20℃;
57
Prepare an anhydrous HCl solution by slow addition of acetyl chloride (193.14 mL; 2.71 moles, 4.00 eq) to methanol (1160 mL) over 45 minutes at < 5°C. Add the resulting solution to a separate flask containing a solution of 4-[4-(4-fluoro-3- trifluoromethyl-phenyl)- 1 -methyl- IH- imidazol-2-yl]-piperidine- 1 -carboxylic acid tert- butyl ester (290 g; 678.46 mmoles) in methanol (2320 mL) over 90 minutes at 20 0C. Stir the reaction mixture at 20 0C overnight. Concentrate the reaction mixture under vacuum at 30 0C. Add dimethyl sulfoxide (1080 mL; 15.20 moles; 1.08 L; 1.19 kg) and the distillation continues until the internal temperature reaches 50 0C at a pressure of 20 mm Hg. Add DMSO until the total volume is 2030 mL. Then add triethylamine (473 mL; 3.39 moles, 5 eq) via addition funnel over 30 minutes. Charge solid 4-chloro-lH- pyrazolo[3,4-0C overnight. Heat the slurry to 80 0C. Add water (229 mL) to afford a clear solution. Seed the reaction and add more water (1273 mL) slowly over 4 hours to fully crystallize the product. Cool the slurry to 50 0C and filter the solid. Wash the cake with 30% water in DMSO (2 x 29OmL), then water (290 mL). Dry the solids under vacuum at 60 0C to afford 4-{4-[4-(4-fluoro-3- trifluoromethyl-phenyl)- 1 -methyl- IH- imidazol-2-yl]-piperidin- 1 -yl} - lH-pyrazolo[3,4-
92.66%
Stage #1: tert-butyl 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate With hydrogenchloride In dichloromethane at 20℃; for 1h;
Stage #2: 4-chloro-1H-pyrazolo[3,4-d]pyrimidine With triethylamine In isopropyl alcohol for 1h; Heating / reflux;
55
Add hydrogen chloride ( 4.00 equiv; 81.41 mmoles; 20.35 mL) to a solution of 4- [4-(4-Fluoro-3-trifluoromethyl-phenyl)-l-methyl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid tert-butyl ester (8.7 g; 1.00 equiv; 20.35 mmoles) in dichloromethane (101.77 mL), at room temperature. Stir the solution at room temperature for 1 hour. Remove the solvent under reduced pressure, and dissolve the crude in isopropyl alcohol (101.77 mL). Add 4-chloro-lH-pyrazolo[3,4-
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; for 1h;microwave irradiation;
EXAMPLE 34; 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-lH-imidazol-2-yl]-piperazin-l-yl}-lH- pyrazolo[3 ,4-<f|pyrimidine hydrochloride; Combine 1 -[5-(4-Fluoro-3-trifluoromethyl-phenyl)- lH-imidazol-2-yl]-piperazine (195 mg, 1.00 equiv; 0.620 mmoles); 4-Chloro-lH-pyrazolo[3,4-(/]pyrimidine (1.00 equiv; 0.620 mmoles; 96 mg); isopropyl alcohol (3 mL); diisopropylethylamine (1 mL) and heat in a microwave reactor at 800C for 60 min. Evaporate the reaction mixture and purify on silica gel with 5% MeOeta/DCM. Combine the fractions to give 213.2 mg <n="50"/>(0.494mmol, 80%) of 4-{4-[5-(4-Fluoro-3-trifluoromethyl-phenyl)-lH-imidazol-2-yl]- piperazin-l-yl}-lH-pyrazolo[3,4-(/]pyrimidine. Dissolve the free base in DCM/MeOeta and add 1.0 eq IM HCl in ether. Concentrate the mixture to give 237.2 mg 4-{4-[5-(4- Fluoro-3-trifluoromethyl-phenyl)-lH-imidazol-2-yl]-piperazin-l-yl}-lH-pyrazolo[3,4- <i]pyrimidine hydrochloride. MS (ES): m/z = 443 [M + H].
With triethylamine; In methanol; at 50℃; for 0.5h;
Charge 4-Chloro-lH-pyrazolo[3,4-<i]pyrimidine (93.3 g; 1.00 equiv; 603.66 mmoles; 93.30 g), (4-[4-(3-Trifluoromethyl-phenyl)-lH-imidazol-2-yl]-piperidine)-, Hydrochloride (1 : 1) (200.1 g; 1.00 equiv; 603.13 mmoles), and Methanol (1800 mL) to a 5000 mL 4-necked round bottom flask (fitted with nitrogen blanket, rubber septum, mechanical stirrer, heating mantle, condenser and thermocouple probe). Add Triethylamine (280 mL; 2.01 moles) via addition funnel over approximately 15 min. Heat the resulting clear orange solution to 50 0C and hold at 50 0C for 15 min. When reaction is deemed complete by HPLC, add Water (2000 mL) via an addition funnel at 500C. Add seed crystals during this water addition and the product crystallizes. On completion of addition, heat the slurry to reflux for 1 hour. Cool to room temperature then filter and wash solids with 20% MeOH in water (2x250 mL). Dry the solids in a <n="60"/>vacuum oven at 45C overnight to afford 4-{4-[4-(3-Trifruoromethyl-phenyl)-lH- imidazol-2-yl]-piperidin-l-yl}-lH-pyrazolo[3,4-(i]pyrimidine as a tan solid (211.5g, 0.603 mol, 85%). m.p. = 281 0C; MS m/z = 414 [M + eta]
EXAMPLE 1; 4-(4-(5-('2,4-Dichlorophenyl)-lH-imidazol-2-yl)piperidin-l-yl)-lH-pyrazolor3,4-fi?- pyrimidine hydrochloride; Heat a mixture of 4-(4-(2,4-dichlorophenyl)-lH-imidazol-2-yl)piperidine (270 mg, 0.91 mmol), 4-chloro-lH-pyrazolo[3,4-(/]pyrimidine (280 mg, 1.82 mmol), EtsN (0.63 mL, 4.5 mmol), and 2-propanol (10 mL) at 90 0C overnight under N2. Cool the mixture to room temperature and pour into water (100 mL). Extract the mixture with Ceta2CI2 (2x200 mL), combine the organic layers, and wash with water (50 mL). Dry (Na2SO4) the organic layer, filter the mixture, and concentrate the filtrate in vacuo. Purify the residue by silica gel chromatography (25 g of SiO2, elute with CH2C12/CMA 4: 1, 1000 mL) to provide 4-(4-(5-(2,4-dichlorophenyl)-lH-imidazol-2-yl)piperidin-l-yl)- lH-pyrazolo[3,4-<i]pyrimidine (304 mg, 80%). Add hydrochloric acid (2.0 M aqueous, 0.36 mL, 0.72 mmol) to a suspension of 4-(4-(5-(2,4-dichlorophenyl)-lH-imidazol-2- yl)piperidin-l-yl)-lH-pyrazolo[3,4-<i]pyrimidine (300 mg, 0.72 mmol) in methanol (7 mL). Concentrate the mixture in vacuo to dryness. Dissolve the residue in methanol (2 mL) and add diethyl ether (50 mL) to form a precipitate. Filter the precipitate, and wash the filter cake with Et2O. Dissolve the solid in methanol (10 mL) and remove the solvent in vacuo to dryness to provide 4-(4-(5-(2,4-dichlorophenyl)-lH-imidazol-2-yl)piperidin- l-yl)-lH-pyrazolo[3,4-<i]pyrimidine hydrochloride (210 mg, 65%) as an off-white solid. MS (APCI): m/z = 414 [M + H].
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at -20℃; for 1h;
Synthesis of Compound 4.2. Diisopropylethylamine (35 mL, 0.20 mol) was added to a solution of compound 4.1 (25 g, 0.16 mol), [beta-(trimethylsilyl)ethoxy]methyl chloride (36 mL, 0.20 mol) in THF (200 mL, 2 mol) and DMF (100 mL, 1 mol) at -20 C. After 1 hr, the reaction mixture was warmed to RT. The reaction mixture was diluted dichloromethane, washed with 0.5 N HCl, and then concentrated. The residue was purified by flash chromatography using hexane/EtOAc (SiO2, 100/0 to 0/100) to afford compound 4.2 (26 g, 56%) as a clear oil. 1H NMR (400.13 MHz, CDCl3) 8.84, (s, 1H), 8.24 (s, 1H), 5.86, (s, 2H), 3.68 (m, 2H), 0.95 (m, 2 H), 0.03 (s, 9H). MS m/z 285 [M+1]+.
56%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at -20℃; for 1h;
Diisopropylethylamine (35 mL, 0.20 mol) was added to a solution of 4-chloro- 1 H-pyrazolo [3, 4- d]pyrimidine (25 g, 0.16 mol) and [ -(trimethylsilyl)ethoxy]methyl chloride (36 mL, 0.20 mol) in THF (200 mL, 2 mol) and DMF (100 mL, 1 mol) at -20 C. After 1 h, the reaction mixture was warmed to rt. The reaction mixture was diluted with CH2CI2, washed with 0.5 N C1 , and concentrated under reduced pressure. The residue was purified by flash chromatography using hexane/EtOAc (Si02, 100/0 to 0/100) to afford the title intermediate (26 g, 56%) as a clear oil. 1H NMR (400 MHz, CDC13) 8.84, (s, 1 H), 8.24 (s, 1 H), 5.86, (s, 2 H), 3.68 (m, 2 H), 0.95 (m, 2 H), 0.03 (s, 9 H). MS m/z 285 [M+l]+.
32.6%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at -20℃; for 3h;
Slowly add a solution of DIPEA (63g, 0.488mol, Chinese name: N, N-diisopropylethylamine) in THF (50mL) at -20 C to SM (50g, 0.324mol) and 2- (trimethyl In a mixed solution of silyl) ethoxymethyl chloride (62 g, 0.39 mol, SEMCl) in DMF (50 mL) and THF (200 mL), after stirring at -20 C for 3 hours, water was added to quench it, and ethyl acetate Ester extraction, drying the organic phase, filtering, and concentrating to obtain the crude product, which was purified by flash column using petroleum ether and ethyl acetate (v / v = 1/1) as eluent to obtain pale yellow oil A-1 (45g, 0.158 mol, yield: 32.6%).
With sodium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; at 70.0℃;Inert atmosphere;
A solution of 4-chloro-lH-pyrazolo[3,4-d]pyrimidine (110 mg, 0.7117 mmol) in dioxane (20 mL) was treated with l-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]cyclopropanecarbonitrile (230.7 mg, 0.7715 mmol) and then 2M sodium carbonate (1.068 mL of 2 M, 2.135 mmol). The reaction mixture was degassed (vacuum/nitrogen cycles) and then treated with Pd[P(tBu)3]2 (36.37 mg, 0.07117 mmol) and the reaction heated at 70C overnight. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc H20. The organics were separated, washed with saturated NaCl, dried (MgS04), passed through a short silica pad and concentrated to give an oil. This was purified by column chromatography (ISCO Companion, 80g column, 0-10% MeOH / DCM) to give the required product (2.8mg, 2% Yield). NMR (DMSO, 400 MHz) delta 1.65 - 1.69 (m, 2H), 1.84 - 1.87 (m, 2H), 7.57 (d, J = 8.2 Hz, IH), 7.67 (t, J = 8.0 Hz, IH), 8.24 - 8.26 (m, 2H), 8.69 (s, IH), 9.09 (s, IH) and 14.27 (brs, IH) ppm; MS (ES+) 261.0
2%
With sodium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 70.0℃;
A solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (110 mg, 0.7117 mmol) in dioxane (20 mL) was treated with <strong>[1346264-25-2]1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitrile</strong> (230.7 mg, 0.7715 mmol) and then 2M sodium carbonate (1.068 mL of 2 M, 2.135 mmol). The reaction mixture was degassed (vacuum/nitrogen cycles) and then treated with Pd[P(tBu)3]2 (36.37 mg, 0.07117 mmol) and the reaction heated at 70 C. overnight. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc/H2O. The organics were separated, washed with saturated NaCl, dried (MgSO4), passed through a short silica pad and concentrated to give an oil. This was purified by column chromatography (ISCO Companion, 80 g column, 0-10% MeOH/DCM) to give the required product (2.8 mg, 2% Yield). 1H NMR (DMSO, 400 MHz) delta 1.65-1.69 (m, 2H), 1.84-1.87 (m, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 8.24-8.26 (m, 2H), 8.69 (s, 1H), 9.09 (s, 1H) and 14.27 (brs, 1H) ppm; MS (ES+) 261.0
1-(2-(azepan-1-yl)ethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
Step 1.- 1-(2-(azepan-1-yl)ethyl)- -chloro-1 H-pyrazolo[3,4-d]pyrimidine. 1-(2-(azepan-1-yl)ethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.65 mmol) anh. DMF (2 mL) was added to a suspension of NaH (91 mg, 60percent dispersion mineral oil) in anh. DMF (3 mL) at 0 5C. The mixture was stirred at room temperature for 45 min. Then, 1 -(2-chloroethyl)azepane hydrochloride (192 mg, 0.97 mmol) in portions at -15 5C and was kept at this temperature for 3 h. The solvent was evaporated to dryness and the residue was diluted in ethyl ether, filtered and the solvent was removed under reduced pressure. The crude was purified by flash chromatography to give 1 -(2-(azepan-1 -yl)ethyl)-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (40 mg, 0.14 mmol, 22percent) as an oil.
4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 4℃;
Step 1.- Synthesis of 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1 H-pyrazolo[3,4- djpyrimidine. To a stirred solution of 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (0.2 g, 1 .29 mmol) in anh THF (10ml_) were sequentially added 2-(piperidin-1 -yl)ethanol (0.258 mL, 1 .94 mmol) and triphenylphosphine (0.51 g ,1 .94 mmol). The reaction mixture was cooled to 0 5C and diisopropylazodicarboxylate (0.38 mL ,1 .94mmol) was added dropwise and the mixture was stirred for 30 min. at 0 5C and kept overnight at 4 5C. The solvent was removed at reduced pressure and the residue was dissolved in DCM and washed with diluted HCI 1 N. The aqueous phase was separated, basified and extracted with DCM. The organic phase was separated, dried and the solvent was removed under reduced pressure to give a residue that was purified by flash chromatography eluting with (EtOAc/Petroleum ether, 8:2) to yield 4-chloro-1 -(2-(piperidin-1 -yl)ethyl)-1 H- pyrazolo[3,4-d]pyrimidine (146 mg, 55 mmol, 42 %) as an oil that solidifies "on standing".
42%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 4℃;
To a stirred solution of <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (0.2 g, 1.29 mmol) in anh THF (10 mL), 2-(piperidin-1-yl)ethanol (0.258 mL, 1.94 mmol) and triphenylphosphine (0.51 g ,1.94 mmol) were sequentially added. The reaction mixture was cooled to 0 C and diisopropylazodicarboxylate (0.38 mL ,1.94mmol) was added dropwise. The mixture was stirred for 30 min. at 0 C and kept overnight at 4 C. The solvent was removed at reduced pressure and the residue was dissolved in DCM and washed with diluted HCl 1N. The aqueous phase was separated, basified and extracted with DCM. The organic phase was separated, dried and the solvent was removed under reduced pressure to give a residue that was purified by flash chromatography eluting with (EtOAc/Petroleum ether, 8:2) to yield 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (146 mg, 55 mmol, 42 %) as an oil that solidifies "on standing".
42%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 4℃;
General procedure: To a stirred solution of 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (0.2 g, 1 .29 mmol) in anh THF (10 ml_), 2-(piperidin-1 -yl)ethanol (0.258 ml_, 1 .94 mmol) and triphenylphosphine (0.51 g ,1 .94 mmol) were sequentially added. The reaction mixture was cooled to 0 5C and diisopropylazodicarboxylate (0.38 ml_ ,1 .94mmol) was added dropwise. The mixture was stirred for 30 min. at 0 5C and kept overnight at 4 5C. The solvent was removed at reduced pressure and the residue was dissolved in DCM and washed with diluted HCI 1 N. The aqueous phase was separated, basified and extracted with DCM. The organic phase was separated, dried and the solvent was removed under reduced pressure to give a residue that was purified by flash chromatography eluting with (EtOAc/Petroleum ether, 8:2) to yield 4-chloro-1 -(2-(piperidin-1 -yl)ethyl)-1 H- pyrazolo[3,4-d]pyrimidine (146 mg, 55 mmol, 42 %) as an oil that solidifies "on standing".
Example 2 Preparation of 4-(1H-pyrazolo-4-phenoxy)aniline (3a-1) P-aminophenol (0.55g, 5.5mmol) and sodium hydroxide (0.20g, 5.5mmol) were added to 10mL water; potassium carbonate (0.76g, 5.5mmol) was added after resulting mixture was stirred for 30 minutes at normal temperature; the temperature was increased to 60C, and tetrahydrofuran solution of 4-chloro-1H-pyrazolopyrimidine (intermediate 2) (0.94g, 6.6mmol) was slowly added to the reaction solution; after one hour, reaction was stopped; after the tetrahydrofuran of the reaction system was distilled to dryness, the remaining system was extracted with ethyl acetate and water twice; the ethyl acetate layer was dried with anhydrous magnesium sulfate and then spun dry, and then introduced into a column for purification to obtain 0.77g 4-(1H-pyrazolo-4-phenoxy)aniline (3a-1) at a yield of 62.1%. 1H NMR (400 MHz, DMSO-d6): delta 14.07(s, 1H), 8.50(s, 1H), 7.67(s, 1H), 6.96(d, J=8.8 Hz, 2H), 6.64(d, J=8.8 Hz, 2H), 5.20(s, 2H) ppm. LCMS m/z: 228.1 [M + H].
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃;Inert atmosphere;
General procedure: Compound 2 (1 eq.) was dissolved in dryTHF (10 mL) at r.t. and TBAF 2.0 M in THF solution (2 eq.) was added. Theopportune 2-bromoacetophenone was added to the solution and the reactionmixture was stirred at r.t. for 24 hours. The reaction mixture was filtered ona Celite pad, diluted with EtOAc (100 mL) and washed with water. The organicphase was dried over anhydrous Na2SO4and concentrated under reduced pressure. The brown solid was purified by flashchromatography on silica gel (eluent CH2Cl2/MeOH = 99/1).
General procedure: To a 20 mL vial was added 1 (97%, 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(74%);
4-[4-(2-methoxyphenyl)piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 120℃; for 3h;
Intermediate I 9A4-[4-(2-methoxyphenyl)piperazin-1 -yI]-IH-pyrazolo[3,4-d]pyrimidine 6.0 g (38.8 mmo[) 4-ch[oro-1H-pyrazo[o[3,4-d]pyrimidine, 7.464 g (38.8 mmo[) 1-(2-methoxypheny[)piperazine and 17.38 mL (116.5 mmo[) DBU in 54 mL anhydrous DMF were stirred three h at 120CC. The reaction was a[[owed to reach rt and was concentrated on a rotavap. Water was added to the residue and the reaction mixture was poured into di[uted aqueous sodium hydrogencarbonate so[ution. It was stirred 30 minutes and the so[id was fi[tered off under suction. The so[id was washed fivetimes with water and dried 48 hat 45CC under vacuum yie[ding 11 g (91%) product.LC-MS (ana[ytica[ method 3): R = 0.82 mm, MS (ESipos): mlz = 311 (M+H).1H-NMR (300MHz, DMSO-d6): 6 [ppm]= 3.02 - 3.11 (m, 4H), 3.79 (5, 3H), 3.98 - 4.09(m, 4H), 6.81 - 7.01 (m, 5H), 8.22 (5, 1H), 8.30 (5, 1H).
With hydrogenchloride; In 1,4-dioxane; ethanol; at 110℃; for 10h;
General procedure: A mixture comprising 60.0 mg (307 mumol) 4-chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate exampLe 1a), 51 mg <strong>[56354-98-4]6-amino-1,3-benzothiazol-2(3H)-one</strong> (CAS-No: 56354-98-4), 1.75 mL ethanol and 16.9 muL hydrochloric acid (4M in dioxane) was reacted at 110C for 10 hours. The residue was digested in a mixture of diethyl ether and ethanol and dried to give 85.3 mg (85%) of the title compound.
With hydrogenchloride; In 1,4-dioxane; ethanol; at 150℃; for 4h;Microwave irradiation;
A mixture comprising 250 mg (1 .57 mmol) 4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (CAS-No: 5399-92-8), 292 mg 1 H-indazol-5-amine, 10.9 mL ethanol and 78 mu hydrochloric acid (4M in dioxane) was reacted at 150 C under microwave irradiation for 4 hours. The mixture was poured into water, neutralized and the precipitate filtered and dried to give 368 mg (92%) of the title compound. 1 H-N R (DMSO-d6): delta= 7.53 ( 1 H), 7.58 (1 H), 7.87-8.21 (1 H), 8.05 (1 H), 8.24 (1 H), 8.32 (1 H), 9.95 (1 H), 13.01 (1 H), 13.52 (1 H) ppm.
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride[ No CAS ]
[ 5399-92-8 ]
3-(1-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)-4-phenyl-1H-isochromen-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 80℃; for 3h;
3 -(1 -aminoethyl)-4-phenyl- 1 H-isochromen- 1-one hydrochloride (Intermediate El,141mg, 0.136 mmol), <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (42.0 mg, 0.272 mmol) and DIEA (95 jiL, 0.543 mmol) were stirred at 80C for 3hrs in tert-butanol (800 jiL). The reaction was quenched by the addition of lmL of 1M HClaqueous and the resulting crude was straightforward purified via reverse phase chromatography using a BiotageCl 8 30g SNAP with a gradient of water and acetonitrile to give the title compound (29 mg, 56 %).1H NMR (400 MHz, DMSO-d6) oe ppm 13.10 - 13.60 (bs, 1 H), 8.46 - 8.70 (m, 1 H), 8.15 - 8.30 (m, 2 H), 8.05 - 8.13 (m, 1 H), 7.68 - 7.85 (m, 1 H), 7.47 - 7.65 (m, 5 H), 7.32 - 7.43 (m, 1 H), 6.85 - 7.06 (m, 1 H), 4.92 - 5.13 (m, 1 H), 1.42 - 1.63 (m, 3 H).UPLC-MS: 4.69 mm, 384.1 [M+H]+, method 3.
56%
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 80℃; for 3h;
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (Intermediate E1, 141 mg, 0.136 mmol), <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (42.0 mg, 0.272 mmol) and DIEA (95 muL, 0.543 mmol) were stirred at 80 C. for 3 hrs in tert-butanol (800 muL). The reaction was quenched by the addition of 1 mL of 1M HClaqueous and the resulting crude was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (29 mg, 56%).1H NMR (400 MHz, DMSO-d6) delta ppm 13.10-13.60 (bs, 1H), 8.46-8.70 (m, 1H), 8.15-8.30 (m, 2H), 8.05-8.13 (m, 1H), 7.68-7.85 (m, 1H), 7.47-7.65 (m, 5H), 7.32-7.43 (m, 1H), 6.85-7.06 (m, 1H), 4.92-5.13 (m, 1H), 1.42-1.63 (m, 3H). UPLC-MS: 4.69 min, 384.1 [M+H]+, method 3.
Example 70 Preparation of 1-(3-(1H-pyrazolopyrimidine-4-phenoxy)phenyl)-3-(3-chloro-4-(fluorophenyl)urea (4b-1) After 60mL n-butyl alcohol was added to 1-(3-aminophenyl)-3-(3-chloro-4(fluorophenyl)urea (1.4g), catalytic amount of hydrochloric acids was added and stirred at normal temperature for 20 minutes; 780mg 4-chloro-1H-pyrazolopyrimidine (intermediate 2) was added; the temperature was increased to 100C for reacting for 2.5 hours, after which, solvents were spun dry; after potassium carbonate was added for proper adjustment of pH value, ethyl acetate was used to extract twice; after the ethyl acetate layer was spun dry and stirred, the reaction product was introduced into a column for purification with dichloromethane and methanol at a ratio of 24:1, thus obtaining 1.71g solid at a yield of 86.6%. 1H NMR(400 MHz, DMSO-d6): delta 13.65(s, 1H), 10.02(s, 1H), 8.88(d, J=11.2Hz,1H), 8.40(s, 1H), 8.31(s, 2H), 8.03(m, 6H), 7.83(t, J=6.4Hz, 1H), 7.57(d, J=7.6Hz, 1H), 7.37-7.27(m, 3H), 7.19(d, J=7.6Hz, 1H) ppm.
5-([4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl]methyl)-2-methyl-1,3-benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
498 5-([4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl]methyl)-2-methyl-1,3-benzothiazole
5-([4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl]methyl)-2-methyl-1,3-benzothiazoleInto a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed (2-methyl-1,3-benzothiazol-5-yl)methanol (500 mg, 2.79 mmol, 1.00 equiv)(Example 497), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (462 mg, 2.99 mmol, 1.07 equiv), triphenyl phosphine (954 mg, 3.64 mmol, 1.30 equiv) and tetrahydrofuran (30 mL) with stirring at 0° C. This was followed by the addition of DEAD (633 mg, 3.63 mmol, 1.30 equiv) dropwise with stirring at 0° C. The resulted solution was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was diluted with 100 mL of water and extracted with 3×50 mL of ethyl acetate. The organic phase was washed with 2×100 mL of water and 1×100 mL of brine and dried over anhydrous sodium sulfate. The crude was purified by silica gel column with ethyl acetate/petroleum ether (1:4-1:1). This resulted in 220 mg (25%) of 5-([4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl]methyl)-2-methyl-1,3-benzothiazole as a off-white solid. MS (ESI) m/z 316 [M+H]+.
methyl 3-((4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90 mg
With diisopropyl (E)-azodicarboxylate In dichloromethane for 14h;
652 methyl 3-((4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate
methyl 3-((4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate4-chloro-1H-pyrazolo[3,4-d]pyrimidine (240.00 mg; 1.55 mmol; 1.00 eq.)(Example 651) was suspended in DCM (15 ml) containing methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (363.78 mg; 2.33 mmol; 1.50 eq.) The mixture was cooled in an ice bath and triphenylphosphine resin (1.04 g; 3 mmol/g; 3.11 mmol; 2 eq.) was added followed by slow addition of diisopropyl -1,2-diazenedicarboxylate (914.54 ul; 4.66 mmol; 3.00 eq.) After 14 h, the mixture was filtered, the resin rinsed w/ DCM and the solution evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give methyl 3-((4-chloro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate as a white solid (90 mg). MS (M+H)+ found for C13H13ClN4O2: 293.1.
4-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
To a solution of <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> 2 (0.1 g, 0.65 mmol) in anhydrous DMF(dimethylformamide, 5 mL ), TEA (trimethylamine, 0.20 g, 1.95 mmol) was firstly added, and mixturewas stirred at room temperature for 30 min. Then, bromoethane (0.084 g, 0.78 mmol) was addedand the mixture was stirred at room temperature for 1 h, and KI was then added. Then, the reactionmixture was diluted with water (15 mL), acidified with HCl and extracted with ethyl acetate. At last,the organic layer was washed with water and the organic phase was concentrated to dryness, and theresidue was purified by column chromatography on silica gel using 10:1 petroleum ether/ethyl acetateas eluent to give 3: white powder, 76% yield, mp 76-77 C; 1H-NMR (400 MHz, DMSO-d6) delta: 8.87(s, 1H, CH), 8.49 (s, 1H, CH), 4.51 (q, J = 7.24 Hz, 2H, CH2), 1.45(t, J = 7.26 Hz, 3H, CH3); 13C-NMR(100 MHz, DMSO-d6) 156.7, 150.8, 150.4, 134.4, 106.1, 42.4, 15.1; IR (KBr, nu, cm-1): 3466, 3094, 2924,2854, 1690, 1575, 1538, 1460, 1389, 1283, 1209, 1131, 1007, 956, 782, 680, 594, 533, 406. HRMS (ESI) calcd.for C7H8ClN4: [M + H]+ 183.0437, found 183.0535.
To a solution of <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> 2 (0.1 g, 0.65 mmol) in anhydrous DMF(5 mL ), TEA (0.22 g, 0.65 mmol) was firstly added and stirred at room temperature for 30 min. Then, asolution of benzyl bromide (0.11 g, 0.78 mmol) in anhydrous DMF (5 mL) was added and the mixturewas reacted for 1 h, then KI was added and continue reaction. The reaction mixture was at last dilutedwith water (15 mL), and extracted with ethyl acetate. The organic layer was washed with water andthe organic phase was dried over MgSO4 and concentrated, and the residue was purified by columnchromatography on silica gel using 10:1 petroleum ether/ethyl acetate as eluent to give 6: 65% yield,mp 62-63 C; 1H-NMR (400 MHz, DMSO-d6) delta: 8.91 (s, 1H, CH), 8.53 (s, 1H, CH), 7.26-7.33 (m, 5H,ArH), 5.70 (s, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6) 156.6, 151.3, 150.9, 137.2, 135.1, 129.0, 129.0,128.1, 128.1, 128.0, 106.3, 50.8; IR (KBr, delta, cm-1): 3441, 3090, 2935, 1897, 1756, 1585, 1547, 1479, 1410,1347, 1243, 1174, 1135, 950, 858, 783, 730, 698, 596, 534; HRMS (ESI) calcd. for C12H10ClN4: [M + H]+245.0594, found 245.0584.
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In toluene; at 85℃; for 2h;
[0149] To a suspension of allopurinol (2.0 g, 15 mmol) in toluene (20 mL) was added POCI3 (7 mL, 74 mmol) and DIPEA (6 mL, 32 mmol). The mixture was heated to 85C with stirring for 2hrs. The mixture was allowed to cool, concentrated to half of the volume and poured into 2M K2HPO4 (200 mL). The mixture was stirred overnight at room temperature and filtered. The filter mass was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to afford the title compound as pale orange powder (1.6 g, 70%). MS (ESl) calcd for C5H3CIN4: 154.0; found: 155 [M+H]. 1H NMR (400 MHz, dG-DMSO) 6 14.47 (brs, 1H), 8.82 (s, 1H), 8.43 (s, 1H).
With thionyl chloride; N,N-dimethyl-formamide; for 2h;Inert atmosphere; Reflux;
A suspension of 6a (0.5 g, 3.68 mmol) in thionyl chloride (15 mL) and DMF (1.5 mL) was refluxed for 2 h under argon. The solution was concentrated, and the contents were poured into crushed ice water (150 mL). The solution was extracted with ethylacetate (3x100 mL). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and concentrated to give 7a (64%) as a yellow solid.
64%
With thionyl chloride; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;
The compound 8a (0.5 g, 3.68 mmol)A solution of thionyl chloride (15 ml) was added dropwise under argonDMF (1.5 mL),After completion of the dropwise addition, the temperature was raised to 80 C and the reaction was refluxed for 2 hours.The reaction solution was cooled to room temperature, poured into 150 mL of ice water vigorously, and extracted three times with 100 mL of ethyl acetate. The organic phases were combined,Washed with saturated brine, dried over anhydrous magnesium sulfate,Spin to dry yellow powder 9a 367mg, yield 64%.
With N-Bromosuccinimide; In dichloromethane; at 0 - 20℃;
To a stirred solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 16.23 mmol, 1 equiv) in DCM (30 mL) was added NBS (3.4 g, 19.48 mmol, 1.2 equiv) at 000. The reaction mixture was warmed to room temperature and stirred for 0/N. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate evaporated to obtain crude which was purified over silica gel flash column chromatography. The compound eluted out in 15% ethyl acetate in n-hexane to afford 3-bromo-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, crude) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) O ppm - 8.02 (s, 1H), 12.18 (s, 1H), 14.00 (br.s, 1H)
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.
With caesium carbonate In N,N-dimethyl-formamide at 0℃;
4.1.2 General procedure A for the synthesis of compounds (4)
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.
tetraethyl 3-(2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-azapentane-1,5-diphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere;
General procedure: In a 60mL vial, triphenylphosphine (790mg, 3mmol), <strong>[5399-92-8]4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (310mg, 2mmol) and the corresponding alcohol (2mmol) were dissolved in dry THF (40mL) under argon atmosphere. The solution was cooled to 0C on an ice bath and DIAD (0,6mL, 3mmol) was added dropwise. The reaction mixture was stirred at 0C for 2h and then it was diluted with 10mL of methanol and evaporated. The residue was purified by column chromatography on silica gel using solvent gradient F to A. 4.5.1 103 Tetraethyl 3-(2-(4-chloropyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-azapentane-1,5-diphosphonate 5a (0051) Prepared by General Procedure D from alcohol 1a. Yield 816mg (78%). 1H NMR (400MHz, CDCl3) delta 8.63 (s, 1H, H-6), 8.04 (s, 1H, H-3), 4.47 (t, J=6.4Hz, 2H, ArCH2), 4.04-3.87 (m, 8H, POCH2), 2.91 (t, J=6.3Hz, 2H, ArCH2CH2), 2.73-2.62 (m, 4H, NCH2), 1.74-1.60 (m, 4H, PCH2), 1.20 (t, J=7.1Hz, 12H, POCH2CH3). 31P NMR (162MHz, CDCl3) delta 32.29. 13C NMR (101MHz, CDCl3) delta 154.6 (C-4), 154.3 (C-6), 153.4 (C-7a), 132.0 (C-3), 113.4 (C-3a), 61.6 (d, J=6.5Hz, POCH2), 51.5 (ArCH2CH2), 46.6 (PCH2CH2), 45.6 (ArCH2), 23.4 (d, J=137.4Hz, PCH2), 16.3 (d, J=6.0Hz, POCH2CH3). MS (ESI+) m/z=526 [M+ H]+.
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