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CAS No. : | 90914-41-3 | MDL No. : | MFCD08276165 |
Formula : | C5H2BrClN4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MDFHFCAMBZNSLV-UHFFFAOYSA-N |
M.W : | 233.45 | Pubchem ID : | 340228 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.39 |
TPSA : | 54.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.2 cm/s |
Log Po/w (iLOGP) : | 0.93 |
Log Po/w (XLOGP3) : | 2.15 |
Log Po/w (WLOGP) : | 1.77 |
Log Po/w (MLOGP) : | 1.18 |
Log Po/w (SILICOS-IT) : | 2.49 |
Consensus Log Po/w : | 1.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.25 |
Solubility : | 0.132 mg/ml ; 0.000566 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.93 |
Solubility : | 0.277 mg/ml ; 0.00119 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.64 |
Solubility : | 0.0532 mg/ml ; 0.000228 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | 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. ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With triethylamine; In 1,4-dioxane; at 85℃; for 0.5h; | To 3-bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (200 mg, 0.86 mmol, T. Y.H. Wu, P. G. Schultz, S. Ding, Org. Lett. 2003, 5, 3587-3590) in anhydrous dioxane (5 mL) was added triethylamine ( 0.17 mL, 1.20mmol) and 1-(5-chloro-2-methylphenyl)- piperazine (254 mg, 1.20 mmol). The reaction mixture was stirred at 85 C for 30 min, concentrated, and the solid residue was suspended in 2-propanol. The solid was filtered, washed with water and 2-propanol, and dried to provide 3-bromo-4-[4-(5-chloro-2- methylphenyl)piperazin-1-yl]-lH-pyrazolo[3,4-d]pyrimidine (150 mg, 43% yield) as a white solid. ¹H NMR (400 MHz, d6-DMSO) 8 8.37 (s, 1H), 7.22 (d, 1H), 7.08-7.03 (m, 2H), 3.94 (m, 4H), 3.05 (m, 4H), 2.29 (s, 3H); MS (ESI) for C16H16BrClN61 407 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; In tetrahydrofuran; n-heptane; ethyl acetate; | 3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate W) To a solution of <strong>[90914-41-3]3-bromo-4-chloropyrazolo[3,4-d]pyrimidine</strong> (Intermediate B) (7.5 g, 32 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (15.17 g, 96 mmol), triphenylphosphine (16.86 g, 64 mmol) in THF (275 mL) was added diethylazodicarboxylate (11.14 g, 64 mmol) in THF (50 mL) at 0 C. under nitrogen. The reaction mixture was stirred at 0 C. for 1 hour, warmed to room temperature and then stirred at room temperature for 3 hrs. The reaction mixtures was concentrated in vacuo and dissolved in hot heptane/EtOAc/DCM (5:1:5). Flash silica gel column chromatography using heptane, heptane/EtOAc (5/1) then heptane/EtOAc (4/1) gave a solid which was triturated with heptane and the solids removed by filtration to furnish 8.2 g of 3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (69%) [Rf in 1:1 heptane:EtOAc 0.5] 1H NMR (400 MHz, d6-DMSO): 8.89 (1H, s), 4.92 (1H, m), 3.90 (4H, m), 2.16 (2H, m), 1.96 (2H, m), 1.81 (6H, m) HPLC: Tr=17.11 mins, 96.6% | |
With triphenylphosphine; In tetrahydrofuran; n-heptane; ethyl acetate; | 3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate W) To a solution of <strong>[90914-41-3]3-bromo-4-chloropyrazolo[3,4-d]pyrimidine</strong> (Intermediate B) (7.5 g, 32 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (15.17 g, 96 mmol), triphenylphosphine (16.86 g, 64 mmol) in THF (275 mL) was added diethylazodicarboxylate (11.14 g, 64 mmol) in THF (50 mL) at 0 C. under nitrogen. The reaction mixture was stirred at 0 C. for 1 hour, warmed to room temperature and then stirred at room temperature for 3 hrs. The reaction mixtures was concentrated in vacuo and dissolved in hot heptane/EtOAc/DCM (5:1:5). Flash silica gel column chromatography using heptane, heptane/EtOAc (5/1) then heptane/EtOAc (4/1) gave a solid which was triturated with heptane and the solids removed by filtration to furnish 8.2 g of 3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (69%) [Rf in 1:1 heptane:EtOAc=0.5]1H NMR (400 MHz, d6-DMSO): 8.89 (1H, s), 4.92 (1H, m), 3.90 (4H, m), 2.16 (2H, m), 1.96 (2H, m), 1.81 (6H, m) HPLC: Tr=17.11 mins, 96.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; In tetrahydrofuran; dichloromethane; ethyl acetate; | 1-(1-benzyl-4-piperidinyl)-<strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (Intermediate C) <strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (Intermediate B) (5.0 g, 21.42 mmol), 1-benzyl-4-piperidinol (8.2 g, 42.83 mmol) and triphenylphosphine (11.23 g, 42.83 mmol)were suspended in 250 ml of tetrahydrofuran. The reaction mixture was cooled in an ice-water bath and diethyl azodicarboxylate (6.8 ml, 42.83 mmol) was added dropwise. 10 minutes later, the reaction mixture was allowed to warm up to room temperature. After stirring for 2 hours, solvent was removed and the residue was taking into ethyl acetate. The organic layer was washed, dried and evaporated. The crude product was passed through Biotage flash column using dichloromethane/ethyl acetate (90:10) as the mobile phase to yield 10.56 g of 1-(1-benzyl-4-piperidinyl)-<strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong>. The product was 61% pure with a HPLC retention time of 12.46 min. (HPLC condition: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min., the column size is 3.9*150 mm, 300 A). | |
With triphenylphosphine; In tetrahydrofuran; dichloromethane; ethyl acetate; | 1-(1-benzyl-4-piperidinyl)-<strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (Intermediate C) <strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (Intermediate B) (5.0 g, 21.42 mmol), 1-benzyl-4-piperidinol (8.2 g, 42.83 mmol) and triphenylphosphine (11.23 g, 42.83 mmol)were suspended in 250 ml of tetrahydrofuran. The reaction mixture was cooled in an ice-water bath and diethyl azodicarboxylate (6.8 ml, 42.83 mmol) was added dropwise. 10 minutes later, the reaction mixture was allowed to warm up to room temperature. After stirring for 2 hours, solvent was removed and the residue was taking into ethyl acetate. The organic layer was washed, dried and evaporated. The crude product was passed through Biotage flash column using dichloromethane/ethyl acetate (90:10) as the mobile phase to yield 10.56 g of 1-(1-benzyl-4-piperidinyl)-<strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong>. The product was 61% pure with a HPLC retention time of 12.46 min. (HPLC condition: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min., the column size is 3.9*150 mm, 300 A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N-diethylaniline; In hypochloric acid; | 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate A) (15.08 g, 70.5 mmol) was suspended in 189 ml of phosphous oxychloride. Diethylaniline (19 ml, 119.4 mmol) was added and the resulting reaction mixture was heated to 106 C. for 2 hours. After cooling to room temperature, the solvent was removed and the resulting amber syrup was poured to 300 ml of ice-water. 20 minutes later, the aqueous layer was extracted with diethyl ether (500 ml*4). The combined organic layer was washed, dried and evaporated to give 6.87 g of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine as light yellow solid. 1H NMR (DMSO) 8.857 (s 1H), 14.84 (bs, 1H); LC/MS (MH+=233). | |
With N,N-diethylaniline; In hypochloric acid; | 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate A) (15.08 g, 70.5 mmol) was suspended in 189 ml of phosphous oxychloride. Diethylaniline (19 ml, 119.4 mmol) was added and the resulting reaction mixture was heated to 106 C. for 2 hours. After cooling to room temperature, the solvent was removed and the resulting amber syrup was poured to 300 ml of ice-water. 20 minutes later, the aqueous layer was extracted with diethyl ether (500 ml*4). The combined organic layer was washed, dried and evaporated to give 6.87 g of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine as light yellow solid. 1H NMR (DMSO) 8.857 (s 1H), 14.84 (bs, 1H); LC/MS (MH+=233). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With triethylamine; In tetrahydrofuran; at 65℃; for 30h; | To a round bottom flask, 52.7 mg (0.153 mmol) of 6, 3 mL of THF and 88.5 muL (0.635 mmol) OfNEt3 were added. To this suspension, 29.8 mg (0.127 mmol) of 7 were added and stirred at 65 0C for 30 minutes. The crude reaction was concentrated. Ethyl acetate and distilled water were added and the organic layer was washed with water twice and brine once. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude material was purified by preparative HPLC to afford 16.4 mg of final product 8 (25%).Observed M+H: 508.1 EPO <DP n="99"/>NMR, DMSO-d6, HCl salt: delta 10.43 (br. s, IH), 8.30 (s, IH), 7.22 (d, 2H), 7.03 (d, 2H), 4.60 (d, 2H), 4.01 (m, IH), 3.63 (m, 2H), 3.29 (m, 2H), 3.14 (m, 4H), 3.02 (m, 2H), 1.84 (m, 4H), 1.19 (t, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 65℃; for 0.5h; | The resulting de- boc'ed residue was dissolved in TEtaF (5mL), and Et3N (0.1 mL) before adding 3-Bromo-4- Chloro-lH-pyrazolo[3,4- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In 1,4-dioxane; at 70℃; for 1h; | To a mixture of N-Boc-4-(4-chlorobenzoyl)piperidine (300 mg, 0.92 mmol) and 2-(diethylamino)ethylamine (215 mg, 1.85 mmol) at rt was added Ti(O1Pr)4 (1.05 g, 3.70 mmol). The stirring was continued for 12 h. MeOH (3 mL) and AcOH (1 mL) were then added. Followed by careful addition of NaBH4 (70 mg, 1.85 mmol) as small portions. The reaction mixture was then stirred for another 1 h and filtered through Celite. The Celite pad was washed with EtOAc. TheEtOAc solution was washed with 5% NaOH, brine and dried over Na2SO4. Removal of the solvent gave the crude product (200 mg, 50%), which was used in the next step. The crude product obtained above was treated with excess TFA in CH2Cl2 for 30 min. The mixture was concentrated, diluted with EtOAc, washed with 10% NaOH, dried over Na2SO4 and concentrated.The residue was dissolved in 1,4-dioxane (4 mL). To this solution was added Et3N (0.33 mL, 2.35 mmol) and 3-Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (87 mg, 0.37 mmol). The reaction mixture was heated to 7O0C and the stirring was continued for 1 h.Purification by preparation HPLC gave 3 (127 mg, 52%). The free-based product was converted to the HCl salt.LC-MS (M+l): 522.5 (100%), 520.5 (80%).1H NMR (400 MHz, DMSO-d6) delta 14.07 (br s, 1 H), 10.81 (br s, 1 H), 10.05 (br s, 1 H), 8.30 (s, 1 H),7.69 (d, J = 8.6 Hz, 2 H), 7.56 (d, J = 8.6 Hz, 2 H), 4.54-4.37 (m, 2 H), 3.60-3.40 (m, 5 H), 3.20-2.90(m, 8 H), 2.24-2.21 (m, 1 H), (m, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 70℃; for 1h; | The crude product (about 0.34 mmol) was then reacted with 3-Bromo-4-chloro-lH- pyrazolo[3,4-d]pyrimidine (55 mg, 0.23 mmol) in the presence Of Et3N (172 mg, 1.7 mmol) in 1,4-dioxane (2 mL) at 70 0C for 1 h. The reaction mixture was then diluted with EtOAc. The organic phase was washed with sat. aqueous NaHCO3, dried over Na2SO4, and concentrated. The residue was triturated with ether and further purified by column chromatography (CH2Cl2 : MeOH = IOO : 10).LC-MS (M+l): 537.5 (100%), 535.4 (80%).1H NMR (400 MHz, DMSO-d6) delta 8.25 (s, 1 H), 7.36 (d, J = 8.6 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 8.7 Hz, 1 H), 5.83 (t, J = 5.3 Hz, 1 H), 4.55-4.47 (m, 3 H), 3.20-2.80 (m, 5 H), 2.20 (t, J = 6.1 Hz, 2 H), 2.09 (s, 6 H), 1.80-1.70 (m, 1 H), 1.48-1.30 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 70℃; for 1h; | To a solution of the crude carboxylic acid (76 mg, 0.21 mmol) and 2- (dimethylamio)ethylamine (75 mg, 0.85 mmol) in CH2Cl2 (4 mL) was added DIEA (110 mg, 0.85 mmol) and HATU (155 mg, 0.41 mmol). The mixture was stirred at rt for 2 h and diluted with EtOAc. The organic phase was washed with 5% NaOH, brine and dried over Na2SO4. Upon removal of solvents, the residue was treated with excess TFA in CH2Cl2. The crude product was then reacted with 3-Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (30 mg, 0.14 mmol) in the presence Of Et3N (101 mg, 1.0 mmol) in 1,4-dioxane (2 mL) at 70 C for 1 h. The mixture was then concentrated. Purification by preparation HPLC gave 6 (25 mg, 34%). LC-MS (M+l): 523.4 (100%), 521.4 (80%).1H NMR (400 MHz, DMSO-d6) delta 8.31 (s, 1 H), 8.17 (t, J - 5.7 Hz, 1 H), 7.45-7.40 (m, 4 H), 3.95 (s, 1 H), 3.81 (br s, 4 H), 3.16 (q, J = 5.9 Hz, 2 H), 2.60-2.52 (m, 2 H), 2.50-2.44 (m, 2 H), 2.28 (t, J - 6.6 Hz, 2 H), 2.14 (s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 70℃; for 1h; | To a -78 0C solution of l-N-Boc-4-piperidinecarboxylic acid methyl ester (2.0 g, 8.22 mmol) in THF (30 mL) was added LiHMDS (1.0 M in THF, 12 mL, 12.3 mmol) dropwise. The stirring was continued for 45 min. Then 4-chlorobenzyl chloride (1.59 g, 9.86) was added as a solution in THF (3 mL). The mixture was stirred for 5 h while it was warmed slowly to rt. H2O was added to quench the reaction. It was then extracted with EtOAc. The organic phase was washed with brine, and dried over Na2SO4. Removal of EtOAc gave the crude product. EPO <DP n="85"/>The crude methyl ester (1.0 g, 2.72 mmol) was mixed with KOH (440 mg, 10.8 mmol) inMeOH (5 mL) and H2O (5 niL). The mixture was stirred for 10 h at 80 0C. MeOH was removed; the residue was diluted with 20 mL OfH2O. The aqueous solution was washed with. ether and acidified with 4 N HCl. The product was extracted with EtOAc, washed with brine, and dried over Na2SO4. Removal of EtOAc gave desired carboxylic acid with above 90% purity. The carboxylic acid (250 mg, 0.71 mmol) was mixed with 2-(dimethylamio)propylamine (275 mg, 2.11 mmol), HATU (535 mg, 1.41 mmol), and DIEA(361 mg, 2.8 mmol) in DCM (6 mL). The stirring was continued for 2h. CH2Cl2 was removed and the residue was dissolved in EtOAc. The organic phase was washed with sat. NaHCO3 and brine. Removal of solvent gave the crude product.The crude product (about 0.7 mmol) obtained above was treated with excess TFA in DCM for30 min. Upon removal of excess TFA and DCM, the residue was free-based and then reacted with 3-Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (98 mg, 0.42 mmol) in the presence ofEt3N (354 mg, 3.5 mmol) in 1,4-dioxane (2 mL) at 70 0C for1 h. The mixture was concentrated. The crude product was purified by preparation HPLC.HCL salt:LC-MS (M+l): 564.4 (100%), 562.4 (80%).1H NMR (400 MHz, DMSO-d6) delta 14.17 (br s, 1 H), 10.34 (br s, 1 H), 8.33 (s, 1 H), 8.11 (br s,1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.10 (d, J = 7.7 Hz, 2 H), 4.27 (br d, J = 13.4 Hz, 2 H), 3.28-3.27 (m, 2 H), 3.20-3.10 (m, 2 H), 3.10-3.00 (m, 4 H), 3.00-2.90 (m, 2 H), 2.85 (s, 2 H), 2.17(br d, J = 13.0 Hz, 2 H), 1.82 (br s, 2 H), 1.64 (br s, 2 H), 1.21-1.18 (m, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 70℃; for 1h; | To a solution of N-Boc-4-(p-chlorophenyl)-piperidine-4-carbamide (135 mg, 0.40 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 20 mg, 0.5 mmol). The stirring was continued for 30 min. Then 3-(diethylamino)propyl chloride (90 mg, 0.60) was added. The mixture was then warmed to 90 0C. The stirring was continued for another 3 h. To the cooled mixture was added H2O. It was then extracted with EtOAc. The organic phase was washed with brine, and dried over Na2SO4. Removal of EtOAc gave the crude product. The crude product (about 0.4 mmol) obtained above was treated with excess TFA in DCM for 30 min. Upon removal of excess TFA and DCM, the residue was free-based and then reacted with 3-Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (40 mg, 0.17 mmol) in the presence of Et3N (152 mg, 1.5 mmol) in 1,4-dioxane (2 mL) at 70 0C for 1 h. The mixture was concentrated. The crude product was purified by preparation EtaPLC. LC-MS (M+l): 550.4 (100%), 548.4 (80%).1H NMR (400 MHz, DMSO-d6) delta 8.31 (s, 1 H), 7.83 (t, J = 5.5 Hz, 1 H), 7.41 (s, 4 H), 4.25 (br d, J = 13.4 Hz, 2 H), 3.37 (br t, J = 11.9 Hz, 2 H), 3.08 (q, J = 6.4 Hz, 2 H), 2.63 (br d, J = 13.7 Hz, 2 H), 2.34 (q, J = 7.2 Hz, 4 H), 2.23-2.19 (m, 2 H), 1.99-1.92 (m, 2 H), 1.49-1.41 (m, 2 H), 0.85 (t, J = 7.2 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 70℃; for 1h; | To a solution of 4-Boc piperazinone (240 mg, 1.2 mmol) in DMF (3 mL) was added NaH (58 mg, 1.44 mmol, 60% in mineral oil). The resulting solution was stirred for 30 min at rt. 2- Bromo-(p-chlorophenyl)-acetic acid methyl ester (315 mg, 1.2 mmol) was then added. The reaction mixture was stirred for additional 3 h at rt. It was diluted with EtOAc, and washed with brine, dried over Na2SO4. Removal of EtOAc gave the desired product, which was then treated with NaOH (102 mg, 2.56 mmol) in MeOH (2 mL) and H2O (1 mL) for 3 h. MeOH was removed under reduced pressure. The residue was dissolved in H2O (5 mL), and washed EPO <DP n="84"/>with ether. The aqueous phase was acidified with 1 N HCl. The solid was filtered, washed with H2O, and dried under vacuum. The crude carboxylic acid (165 mg, 0.44 mmol) was mixed with 2-(dimethylamio)ethylamine (157 mg, 1.79 mmol), HATU (680 mg, 1.79 mmol), and DIEA (231 mg, 1.79 mmol) in DCM (2 mL). The stirring was continued for 2h. The mixture was concentrated and the residue was dissolved in EtOAc. The organic phase was washed with sat. NaHCO3 and brine. Removal of solvent gave the crude coupling product. The crude product obtained above was treated with excess TFA in DCM for 30 min. Upon removal of excess TFA and DCM, the residue (about 0.4 mmol) was free-based and then reacted with 3-Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (25 mg, 0.11 mmol) in the presence OfEt3N (126 mg, 2.5 mmol) in 1,4-dioxane (2 mL) at 70 0C for 1 h. The mixture was concentrated. The crude product was purified by preparation HPLC. LC-MS (M+l): 537.4 (100%), 535.4 (80%).1H NMR (400 MHz, DMSO-d6) delta 8.33-8.31 (m, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 6.21 (s, 1 H), 4.55-4.42 (m, 2 H), 4.05-4.00 (m, 3 H), 3.74-3.68 (m, 1 H), 3.32-3.22 (m, 1 H), 3.20-3.10 (m, 1 H), 3.08-3.00 (m, 1 H), 2.28 (t, J = 6.5 Hz, 2 H), 2.13 (s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine; In tetrahydrofuran; for 1.5h;Heating / reflux; | Bromopyrazolopyrimidine (8) To a 25 mL recovery flask were added 6 (230 mg, 0.708 mmol, 1.05 eq.), THF (10 mL), Et3N (470 muL, 3.37 mmol, 5.0 eq.), and chloropyrazolopyrimidine 7 EPO <DP n="88"/>(157 mg, 0.674 mmol, 1.0 eq.). The reaction mixture was stirred at reflux for 1.5h. The reaction was concentrated and diluted with EtOAc (50 mL) and NaHCO3 (sat'd aq., 50 niL). The organic layer was washed with H2O (50 mL) and brine (50 mL). The combined aqueous layers were extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a light-brown oil that slowly solidified to a white solid (308 mg crude). The crude material was purified via flash chromatography (10% to 20% CH3OH/CH2C12) to give a colorless oil (205 mg, 58%).Observed M+H: 523.1 (Br isotope)NMR, DMSO-d6, HCl salt : deltaltheta.40 (s, IH), 8.30 (s, IH), 7.49 (d, 2H), 7.26 (d, 2H), 4.88 (s, IH), 4.59 (m, 2H), 4.50 (obs m, 2H), 3.34-3.23 (m, 4H), 3.07-3.03 (m, 2H), 2.73 (s, 6H), 1.94 (d, 2H), 1.38-1.34 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5% | With triethylamine; In isopropyl alcohol; for 1.5h;Heating / reflux; | To a 25 mL recovery flask were added H (563 mg, 1.26 mmol, 2.0 eq.), /-PrOH (10 mL), Et3N (660 muL, 3.78 mmol, 6.0 eq.), and chloropyrazolopyrimidine 7 (147 mg, 0.630 mmol, 1.0 eq.). The reaction mixture was stirred at reflux for 1.5h. The reaction was concentrated and diluted with EtOAc (50 mL) and NaHCO3 (sat'd aq., 50 mL). The organic layer was washed with H2O (50 mL) and brine (50 mL). The combined aqueous layers were extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a light- brown solid that was purified via reverse-phase, preparative HPLC. The fractions containing desired product were collected, neutralized with NaHCO3 (sat'd aq.), and extracted with EPO <DP n="92"/>EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give an off-white solid (54 mg, 7.5%).Observed M+H: 572.1NMR, DMSO-d6, HCl salt: delta 10.51 (br s, IH), 8.89 (s, IH), 7.52 (d, 2H), 7.39 (d, 2H), 4.78- 4.75 (m, 2H), 4.50 (d, 2H), 4.33 (m, IH), 3.86 (m, 2H), 3.41 (m, 2H), 3.26-3.18 (m, 6H), 2.12 (d, 2H), 1.42 (m, 2H), 1.24-1.14 (m, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.7% | With triethylamine; In tetrahydrofuran; at 65℃; for 0.5h; | To a round bottom flask, 354 mg (0.957 mmol) of 4, 10 niL of THF and 0.8 niL (5.74 mmol) OfNEt3 were added. To this suspension, 223.4 mg (0.957 mmol) of 5_ was added and stirred at 65 0C for 30 minutes. The crude reaction was concentrated. Ethyl acetate and distilled water were added and the organic layer was washed with water twice and brine once. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude material was purified by preparative HPLC to afford 50.5 mg of 6 (0.102 mmol, 10.7 %).Observed M+H: 495.0NMR, DMSO-d6, HCl salt: delta 8.30 (s, IH), 7.50 (d, 2H), 7.39 (d, 2H), 4.45 (m, 2H), 4.20 (d, IH), 3.71 (m, 2H), 3.43 (m, IH), 3.23 (m, 2H), 3.03 (m, 2H), 2.80 (d, 3H), 2.75 (d, 3H), 2.13- 1.90 (m, 2H), 1.51-1.23 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.69% | EXAMPLE 46; (4-(lH-benzordlimidazol-2-yl)-l-(3-bromo-lH-pyrazolor3,4-dlpyrimidin-4-yl)piperidin-4- vDmethanamineN-Ethyldiisopropylamine (0.046 ml, 0.26 mmol) was added to l-(4-(lH-benzo[d]imidazol- 2-yl)piperidin-4-yl)-N-(diphenylmethylene)methanamine (86mg, 0.22 mmol) (Example 45A) and 3-bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (50.9 mg, 0.22 mmol) in butan- l-ol (4 ml). The resulting solution was stirred at 20 0C for 4 hours. Hydrogen chloride 6N in isopropanol (0.363 ml, 2.18 mmol) and water (1 ml) were added and the reaction stirred for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The crude product was eluted from the column using 7M NH3/MeOH. The crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford desired product as a yellow gum. The product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM with ammonia. Pure fractions were evaporated to dryness to afford (4-(lH-benzo[d]imidazol-2- <n="149"/>yl)-l-(3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methanamine (23.00 mg,24.69 %) as a white solid.1H NMR (400.13 MHz, DMSO-d6) delta 1.85 - 1.91 (2H, m), 2.84 (2H, s), 3.37 (2H, s), 4.28 -4.32 (2H, m), 7.13 - 7.16 (2H, m), 7.52 - 7.55 (2H, m), 8.29 (IH, s)MS m/e MH+ 427 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.70% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 20℃; for 3h; | EXAMPLE 25N-(( 1 H-Indo 1-2- yl)methyl)-4-(amino methyl)- 1 -(3 -bromo- 1 H-pyrazo Io [3 ,4-d1pyrimidin-4- yl)piperidine-4-carboxamide; <n="140"/>N-Ethyldiisopropylamine (0.066 ml, 0.38 mmol) was added to 3-bromo-4-chloro-lH- pyrazolo[3,4-d]pyrimidine (73.4 mg, 0.31 mmol) and N-((lH-indol-2-yl)methyl)-4- (aminomethyl)piperidine-4-carboxamide (90mg, 0.31 mmol) in butan-1-ol (2ml). The resulting solution was stirred at 20 0C for 3 hours. The reaction mixture was evaporated and the crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents then repeated using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents . Fractions containing the desired compound were evaporated to dryness to afford N-((lH-indol-2-yl)methyl)-4- (aminomethyl)-l-(3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-yl)piperidine-4-carboxamide (36.0 mg, 23.70 %) as a white solid. IH NMR (400.13 MHz, DMSO-d6) delta 1.57 - 1.64 (2H, m), 2.22 (2H, d), 2.78 (2H, s), 3.47 (2H, d), 4.15 (2H, d), 4.52 (2H, d), 6.24 (IH, s), 6.91 - 6.95 (IH, m), 6.99 - 7.03 (IH, m), 7.32 - 7.35 (IH, m), 7.43 (IH, d), 8.29 (IH, s), 8.58 (IH, t), 11.15 (IH, s) MS m/e MH+ 483 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.0% | EXAMPLE 31 ( 1 -(3 -Bromo- 1 H-pyrazo Io [3 ,4-dlpyrimidin-4- yl)-4-(3 -( 1 -methyl- 1 H-pyrazo 1-4- yl)phenyl)piperidin-4-yl)methanamine; N-Ethyldiisopropylamine (0.120 ml, 0.69 mmol) was added to 3-bromo-4-chloro-lH- pyrazolo[3,4-d]pyrimidine (134 mg, 0.58 mmol) and N-(diphenylmethylene)-l-(4-(3-(l- methyl-1 H-pyrazo l-4-yl)phenyl)piperidin-4-yl)methanamine (250mg, 0.58 mmol) (Example 28D) in butan-1-ol (4 ml). The resulting solution was stirred at 20 0C for 4 hours. HCl 6N in isopropanol (1 mL, 0.41 mmol) and water (0.5 ml) were added and the reaction stirred for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The crude product was eluted from the column using 7M NH3/MeOH. The crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford impure product as a yellow gum. The crude product was purified by flash silica chromatography, elution gradient 5% MeOH in DCM with ammonia. Pure fractions were evaporated to <n="156"/>dryness. Trituration with diethyl ether gave (l-(3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4- yl)-4-(3-(l-methyl-lH-pyrazol-4-yl)phenyl)piperidin-4-yl)methanamine (78 mg, 29.0 %) as a white solid.IH NMR (400.13 MHz, DMSO-d6) delta 1.96 - 2.02 (2H, m), 2.32 (2H, d), 2.74 (2H, s), 3.44 (2H, d), 3.87 (3H, s), 4.06 - 4.10 (2H, m), 7.24 (IH, d), 7.36 (IH, t), 7.42 (IH, d), 7.57 (IH, s), 7.88 (IH, s), 8.17 (IH, s), 8.28 (IH, s) MS m/e MH+ 467 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | a) 3-bromo-4-chloro-1-(phenylsulfon -1 H-pyrazolo[3,4-c ]pyrimidineTo a dry 500 mL flask was added 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (4 g, 17.13 mmol) in THF (160 mL). DMF (10 mL) was added and the stirred contents were cooled to 0 C. NaH (60% dispersion in oil, 0.82 g, 20 mmol) was added portionwise and the mixture was stirred for 15 min. Benzene sulfonyl chloride (2.4 mL, 18.8 mmol) was added dropwise via syringe. After stirring for 15 min, the reaction vessel was removed from an ice bath. After 2 h, the contents were poured onto ice-water (50 mL), and stirred for 30 min. The white precipitate was filtered and washed with water to afford 4.38 g of a white solid. The mother liquor was concentrated down, extracted thrice with EtOAc and evaporated to dryness. The residue was triturated with EtOAc to afford an additional 1.3 g of the title compound. A total weight of 5.68 g of title compound was obtained (89%). LCMS(ES) m/e 373, 375 (M, M+2); 1H NMR (400 MHz, DMSO-d6) delta ppm 9.1 1 (s, 1 H), 8.1 1 (dd, J = 1.14, 8.46 Hz, 2H), 7.84 (s, 1 H), 7.71 (d, J = 8.34 Hz, 2H). | |
88% | To a solution of 3-Bromo-4-chloro-lH-pyrazolo [3,4-d] pyrimidine (1.3 g, 5.5 mmol) in DMF (42 mL) at 0 C was added NaH (180 mg, 7.7 mmol) in portions. The reaction mixture was stirred at 0 C for 5 minutes, then stirred at room temperature for 1.5 hours, after which it was cooled back to 0 C. Neat PhSO2Cl (0.7 mL, 5.6 mmol) was added and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NILCl and diluted further with H20. The resulting precipitate was isolated by vacuum filtration to give 1-Benzenesulfonyl-3-bromo-4-chloro-1H- pyrazolo [3,4-d] pyrimidine (1.8g, 88%.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 50℃; for 24h; | Step 2: To a slurry of 182 in tetrahydrofuran (10 ml) and triethylamine (0.3 ml) was added <strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (63 mg). The mixture was shaken at 50 C. for 24 hours. After cooling to room temperature the mixture was poured into ethyl acetate (150 ml) washed with water (2×200 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow solid which was purified by silica gel chromatography eluting with 60-100% ethyl acetate in hexanes to 1% methanol in ethyl acetate yielding N1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N3-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)propane-1,3-diamine 183 as a yellow powder (43 mg). M.p.=145-148 C. 1H NMR (DMSO-d6) 400 MHz delta 8.26 (s, 1H), 7.84-7.8 (m, 2H), 7.63-7.52 (m, 1H), 7.22-7.0 (m, 5H), 7.15-7.12 (m, 1H), 5.16 (m, 1H), 4.56-4.53 (m, 2H), 3.9 (s, 3H), 3.75 (m, 2H), 3.52-3.4 (m, 2H), 2.87-2.86 (m, 3H), 2.11 (m, 2H), LCMS m/e 534 and 536 (M+) Calculated for C24H24BrN9O.0.72 H2O-0.32 C4H8O2: C 52.75, H 4.9, N 21.9; found C, 52.76; H, 4.44; N, 21.92. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 50℃; for 24h; | Step 5: Synthesis of 4-(4-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)amino)-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (144): To a solution of 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (143) (196 mg, 0.43 mmol) and triethylamine (0.5 ml) in anhydrous tetrahydrofuran (8 ml) was added <strong>[90914-41-3]3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine</strong> (122 mg, 0.52 mmol). The mixture was stirred at 50 C. for 24 hours before being poured into ethyl acetate (150 ml) washed with water (300 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow foam that was crystallized from dichloromethane and ethyl acetate to give 4-(4-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)amino)-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (144) as a yellow solid (145 mg) M.p.=167-172 C. 1H NMR (DMSO-d6) 400 MHz delta 8.4-8.33 (m, 2H), 7.9-7.8 (m, 2H), 7.52 (m, 2H), 7.24-7.2 (m, 1H), 7.15-7.12 (m, 1H), 5.9-5.74 (m, 1H), 4.56-4.53 (m, 2H), 3.95 (s, 1H), 3.9 (s, 3H), 3.41-3.26 (m, 2H), 3.22 (s, 6H), 2.28-2.25 (m, 2H), 1.97-1.75 (m, 2H), LCMS m/e 574 and 576 (M+) Calculated for C27H28BrN9O.CH2Cl2: C, 51.00; H, 4.59; N, 19.12; found C 51.00, H 4.39, N 18.85. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.5% | With silver trifluoromethanesulfonate; In 1,4-dioxane; at 80℃;Sealed tube; | EXAMPLE 10 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-//-methyl-4- (methyloxy)benzenesulfonamideTo a solution of 3-amino-/V-methyl-4-(methyloxy)benzenesulfonamide (189 mg,0.87 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (170 mg, 0.73 mmol) in 1 ,4-dioxane (10 mL) was added AgOTf (262 mg, 1 .02 mmol). The reaction mixture was stirred at 80 C in a sealed tube overnight. The reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (1 16 mg, 38.5%) as an off white solid. LCMS (ES) m/e 413, 415 (M, M+2); 1H NMR (400 MHz, DMSO-d6) delta ppm 14.21 (br. s, 1 H), 9.15 (d, J = 2.27 Hz, 1 H), 8.86 (s, 1 H), 8.55 (s, 1 H), 7.55 (dd, J = 2.40, 8.46 Hz, 1 H), 7.41 (d, J = 5.05 Hz, 1 H), 7.34 (d, J = 8.59 Hz, 1 H), 4.07 (s, 3H), 2.44 (d, J = 5.05 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With acetic acid; In 1,4-dioxane; at 100℃; for 18h;Sealed tube; | EXAMPLE 753-[(3-bromo-1 H-pyrazolo[3,4-c/]pyrimidin-4-yl)amino]-/V-methyl-4-[(2,2,2- trifluoroethyl)oxy]benzenesulfonamidea) 3-[(3-bromo-1 H-pyrazolo[3,4-(^pyrimidin-4-yl)amino]-4-fluoro-//- methylbenzenesulfonamideA solution of 3-amino-4-fluoro-//-methylbenzenesulfonamide (1.5 g, 7.34 mmol), 3- bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (1.715 g, 7.34 mmol), and AcOH (2.63 mL, 36.7 mmol) in 1 ,4-dioxane (25 mL) was heated at 100 C for 18 h in a sealed tube. A white precipitate formed which was filtered and washed with EtOAc to afford the title compound (2.6 g, 88%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.6% | With silver trifluoromethanesulfonate; In 1,4-dioxane; at 80℃;Sealed tube; | EXAMPLE 9 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-//- methylbenzenesulfonamideTo a solution of 3-amino-4-(dimethylamino)-/V-methylbenzenesulfonamide (200 mg, 0.87 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (170 mg, 0.73 mmol) in 1 ,4-dioxane (10 mL) was added AgOTf (262 mg, 1.02 mmol). The reaction mixture was stirred at 80 C in a sealed tube overnight. The reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCIs) / CHCI3 as eluent to afford the title compound (98 mg, 31.6%) as an off white solid. LCMS (ES) m/e 426,428 (M, M+2); 1H NMR (400 MHz, DMSO-d6) delta ppm 14.19 (s, 1 H), 9.44 (s, 1 H), 9.17 (s, 1 H), 8.56 (s, 1 H), 7.51 (s, 2H), 7.45 (d, J = 5.05 Hz, 1 H), 2.77 (s, 6H), 2.46 (d, J = 5.05 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.8% | With silver trifluoromethanesulfonate; In 1,4-dioxane; at 80℃;Sealed flask; | EXAMPLE 8 3-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-//-methyl-4-(4- morpholinyl)benzenesulfonamideTo 3-amino-/V-methyl-4-(4-morpholinyl)benzenesulfonamide (1.39 g, 5.14 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (1.0 g, 4.28 mmol) in 1 ,4-dioxane (60 mL) was added AgOTf (1.32 g, 5.14 mmol), and the reaction mixture was stirred at 80 C in a sealed flask overnight. The reaction material was concentrated onto silica gel and purified by flash column chromatography using 0-50% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (1 .5 g, 74.8%) as an off white solid. LCMS (ES) m/e 468,470 (M, M+2); 1H NMR (400 MHz, DMSO-d6) delta ppm 14.22 (s, 1 H), 9.15 (s, 1 H), 9.1 1 (d, J = 1 .77 Hz, 1 H), 8.54 (s, 1 H), 7.52 - 7.59 (m, 2H), 7.49 (d, J = 5.05 Hz, 1 H), 3.82 - 3.92 (m, 4H), 2.90 - 3.01 (m, 4H), 2.47 (d, J = 5.05 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With acetic acid; In 1,4-dioxane; at 100℃; for 18h;Sealed tube; | EXAMPLE 773-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[(1 ,2-dimethylpropyl)oxy]-//- methylbenzenesulfonamideA solution of 3-amino-4-[(1 ,2-dimethylpropyl)oxy]-//-methylbenzenesulfonamide (100 mg, 0.367 mmol), 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (86 mg, 0.367 mmol), and AcOH (0.131 mL, 1.836 mmol) in 1 ,4-dioxane (3 mL) was heated at 100 C for 18 h in a sealed tube. The reaction mixture was adsorbed onto silica gel, concentrated to dryness and purified by flash column chromatography [40-70%: (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3]. The resulting solid was triturated with CH2CI2 to afford the title compound (80 mg, 46%) as a white solid. LCMS (ES) m/e 471 (M+H)+; 1 H NMR (400 MHz, DMSO-de) delta ppm 0.95 (d, J=6.82 Hz, 3H) 1 .00 (d, J=6.57 Hz, 3H) 1.31 (d, J=6.06 Hz, 3H) 2.04 (dq, J=13.23, 6.71 Hz, 1 H) 2.45 (d, J=5.05 Hz, 3H) 4.59 (q, J=6.13 Hz, 1 H) 7.31-7.43 (m, 2H) 7.51 (dd, J=8.59, 2.27 Hz, 1 H) 8.55 (s, 1 H) 8.77 (s, 1 H) 9.20 (d, J=2.27 Hz, 1 H) 14.23 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.2% | With silver trifluoromethanesulfonate; In 1,4-dioxane; at 80℃;Sealed tube; | EXAMPLE 803-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-//-methyl-4-(1- piperidinyl)benzenesulfonamideA mixture of 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (220 mg, 0.942 mmol), 3-amino-/V-methyl-4-(1-piperidinyl)benzenesulfonamide (267 mg, 0.989 mmol) and silver trifluoroacetate (271 mg, 1 .225 mmol) in 1 ,4-dioxane (10 mL) was stirred at 80 C in a sealed tube overnight. The reaction mixture was concentrated onto Celite and purified by flash column chromatography using 30-80% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (190 mg, 43.2%). LCMS(m/e):466,468(M, M+2); 1 H NMR (400 MHz, DMSO-d6) delta ppm 14.23 (br. s, 1 H), 9.19 (s, 1 H), 9.06 (s, 1 H), 8.54 (s, 1 H), 7.49 - 7.56 (m, 2H), 7.46 (q, J = 4.97 Hz, 1 H), 2.83 - 2.92 (m, 4H), 2.46 (d, J = 5.05 Hz, 3H), 1 .73 - 1 .83 (m, 4H), 1.58 (br. s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With silver trifluoromethanesulfonate; In 1,4-dioxane; at 80℃;Sealed tube; | EXAMPLE 163-[(3-bromo-1 /-/-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-{ethyl[2-(methyloxy)ethyl]amino}-//- methylbenzenesulfonamideTo 3-amino-4-{ethyl[2-(methyloxy)ethyl]amino}-//-methylbenzenesulfonamide (233 mg, 0.81 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (180 mg, 0.77 mmol) in 1 ,4-dioxane (10 mL) was added AgOTf (258 mg, 1.0 mmol). The reaction mixture was stirred at 80 C in a sealed tube overnight. The reaction materials were concentrated onto Celite and purified by flash column chromatography using 0-60% (1 % NH4OH / 9% MeOH / 90% CHCI3) / CHCI3 as eluent to afford the title compound (42 mg, 1 1 %) as an off-white solid. LCMS(ES) m/e 484,486 (M, M+2); 1H NMR (400 MHz, DMSO-d6) delta ppm 14.19 (s, 1 H), 9.87 (s, 1 H), 9.24 (d, J = 2.02 Hz, 1 H), 8.55 (s, 1 H), 7.62 (d, J = 8.34 Hz, 1 H), 7.43 - 7.54 (m, 2H), 3.30 - 3.33 (m, 2H), 3.1 1 - 3.24 (m, 4H), 3.05 (s, 3H), 2.48 (d, J = 5.05 Hz, 3H), 0.95 (t, J = 7.07 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With silver trifluoromethanesulfonate; In 1,4-dioxane; at 80℃;Sealed tube; | 15 3-[(3-bromo-1 H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-4-[ethyl(2-hydroxyethmethylbenzenesulfonamideTo 3-amino-4-[ethyl(2-hydroxyethyl)amino]-/V-methylbenzenesulfonamide (221 mg, 0.81 mmol) and 3-bromo-4-chloro-1 H-pyrazolo[3,4-d]pyrimidine (180 mg, 0.77 mmol) in 1 ,4-dioxane (10 ml.) was added AgOTf (258 mg, 1.0 mmol). The reaction mixture was stirred at 80 C in a sealed tube overnight. The reaction materials were concentrated onto silica gel and purified by flash column chromatography using 0-70% (1 % NH4OH / 9% MeOH / 90% CHCIs) / CHCI3 as eluent to afford the title compound (43 mg, 12%) as an off-white solid. LCMS(ES) m/e 470,472(M, M+2); 1H NMR (400 MHz, DMSO-d6) delta ppm 14.18 (br. s, 1 H), 9.83 (s, 1 H), 9.22 (d, J = 2.02 Hz, 1 H), 8.55 (s, 1 H), 7.57 - 7.63 (m, 1 H), 7.43 - 7.54 (m, 2H), 4.53 (t, J = 5.18 Hz, 1 H), 3.39 - 3.48 (m, 2H), 3.08 - 3.20 (m, 4H), 2.48 (d, J = 5.05 Hz, 3H), 0.95 (t, J = 7.07 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 5h; | 3-Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine (720 mg, 3.1 mmol) and 4-phenoxyphenol (1.73 g, 9.3 mmol) were dissolved in 20 mL NMP. To it was added powder cesium carbonate (2.02 g, 6.2 mmol). The mixture was then stirred at 100C for 5 h. It was diluted with ethyl acetate, washed with brine and IN NaOH, dried, concentrated in vacuo, subjected to flash column with 0-40% ethyl acetate in DCM to isolate 3-bromo-4-(4-phenoxyphenoxy)-lH-pyrazolo[3,4-d]pyrimidine (0.97 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; In isopropyl alcohol; at 95℃; | Intermediate 1-c' To a solution of intermediate 1-b' (6.0 g, 25.7 mmol) in 2-propanol (36.0 ml) was added ammonium hydroxide (50.0 ml). The reaction was heated in a pressure vessel at 95C overnight and 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, dried under vacuum to provide intermediate 1-c' as a white solid. |
Tags: 90914-41-3 synthesis path| 90914-41-3 SDS| 90914-41-3 COA| 90914-41-3 purity| 90914-41-3 application| 90914-41-3 NMR| 90914-41-3 COA| 90914-41-3 structure
[ 944902-17-4 ]
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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