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Structure of 315-30-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
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
2
[ 315-30-0 ]
[ 2380-63-4 ]
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
[ 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
4
[ 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
3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate A) 1H-pyrazolo[3,4-d]pyrimidin-4-ol (10 g, 73.5 mmol) was suspended in 700 ml of water. Bromine (10 ml, 194 mmol) was added and the resulting reaction mixture was heated to 91 C. overnight. After cooling on ice-water, the solid was collected by filtration to give 1.508 g of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol as light yellow solid. 1H NMR (DMSO) 8.06 (s 1H), 12.25(bs, 1H), 14.06 (bs, 1H).
EXAMPLE 29 1-(N-Butylcarbamoyl)allopurinol STR57 A mixture of allopurinol (2.7 g, 20 mmole), triethylamine (0.2 ml), butylisocyanate (3 g, 30 mmole) in N,N-dimethylformamide was stirred at 90 C. for 2 hours. Upon cooling 1.05 g of the title compound precipitated. The crude product was recrystallized from N,N-dimethylformamide-ethanol, m.p.>270 C.
EXAMPLE 1 1-(Acetyl)allopurinol STR34 A suspension of allopurinol (500 mg, 3.67 mmole) in acetic acid anhydride (8 ml) was heated in an oil bath at 130 C. for five hours. After cooling, water (10 ml) was added and the mixture was stirred at room temperature for three hours. The precipitate was collected and washed with water and dried, yielding 375 mg (57%). Recrystallization from ethanol-N,N-dimethylformamide gave an analytically pure compound, m.p. 251-254 C. (dec.).
EXAMPLE 2 1-(Propionyl)allopurinol STR35 The compound was prepared from allopurinol and propionic acid anhydride by the procedure described in Example 1. The yield was 60%. Recrystallization from ethanol-N,N-dimethylformamide gave an analytically pure product, m.p. 259-263 C.
EXAMPLE 3 1-(Butyryl)allopurinol STR36 The compound was prepared from allopurinol and butyric acid anhydride by the procedure described in Example 1. The yield was 52%. Recrystallization from ethanol gave an analytically pure product, m.p. 222-225 C.
EXAMPLE 4 1-(Chloroacetyl)allopurinol STR37 A mixture of allopurinol (2.7 g; 20 mmole) and chloroacetic acid anhydride (6.8 g; 40 mmole) in N,N-dimethylformamide (20 ml) was heated to 80 C. and a clear solution was obtained. After 1 hour, the solution was cooled and the precipitate was collected and washed with acetone. Yield: 2.6 g (61%), m.p. 233-236 C. (dec.).
EXAMPLE 20 1-(N,N-Dimethylglycyl)allopurinol (hydrochloride) R1 =(CH3)2 NCH2 CO--; R5 =H [Method (a)] To a suspension of allopurinol (778 mg, 5.7 mmole) in 5 ml of N,N-dimethylformamide was added a solution of N,N-dimethylglycinyl chloride hydrochloride (5.7 mmole) in 10 ml of N,N-dimethylformamide. The mixture was heated to 80 C. for 1 hour. After cooling the precipitate was collected and washed with ethanol. Yield: 209 mg, m.p. 192-196 C. (dec.).
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