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CAS No. : | 203436-45-7 | MDL No. : | MFCD11047295 |
Formula : | C8H8Cl2N4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GKEFDRUWUYSFGW-UHFFFAOYSA-N |
M.W : | 231.08 | Pubchem ID : | 11218490 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 56.22 |
TPSA : | 43.6 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) : | -5.81 cm/s |
Log Po/w (iLOGP) : | 2.46 |
Log Po/w (XLOGP3) : | 2.68 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 1.15 |
Log Po/w (SILICOS-IT) : | 2.15 |
Consensus Log Po/w : | 2.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.37 |
Solubility : | 0.0984 mg/ml ; 0.000426 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.25 |
Solubility : | 0.131 mg/ml ; 0.000565 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.4 |
Solubility : | 0.0914 mg/ml ; 0.000395 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.91 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
With triethylamine; In propan-1-ol; at 90℃; for 4h;Inert atmosphere; | General procedure: 2,6-Dichloro-9-isopropylpurine (0.05 mol), appropriate substituted benzylamine (0.05 mol), n-propanol (230 ml) and triethylamine (0.15 mol) were placed into a reaction bulb, under nitrogen. The reaction mixture was warmed up to 90 C, and stirred for a period of 4 h. The contents of the bulb were then evaporated on rotary vacuum evaporator to give a semisolid residue, which was then treated with water (200 ml) for 20 min. The precipitate was filtered off, washed with water (3 × 20 ml) and dried in the vacuum oven to constant weight. Yield: 75-90%, according to the type of benzylamine used. The purity (HPLC): min. 97%. The crude product can be purified by crystallization from isopropyl alcohol if required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.02% | With potassium carbonate; In dimethyl sulfoxide; at 15℃; | 2,6-dichloro-9-isopropyl-9H-purine (2a). 2,6-dichloro-9H-purine (1.0g, 5.29mmol), and potassium carbonate (K2CO3) (2.193g, 15.87mmol) were dissolved in 20ml anhydrous DMSO. Iodopropane (2.64mL, 26.45mmol) was added dropwise at 15C. The reaction mixture was stirred at 15C overnight. Upon completion of the reaction, the reaction solution was poured into ice water, and a white solid precipitated. The solution was filtered and dried under a vacuum to give 1.1g of light yellow solid. Yield: 90.02%. 1H NMR (400MHz, DMSO-d6) δ 8.86 (s, 1H), 4.83 (p, J=6.8Hz, 1H), 1.56 (d, J=6.8Hz, 6H). |
90.02% | With potassium carbonate; In dimethyl sulfoxide; at 15℃; | 2,6-Dichloropurine (1.0g, 5.29mmol), potassium carbonate (2.193g, 15.87mmol), iodopropane (2.64ml, 26.45mmol) was added to anhydrous DMSO (20ml),The reaction solution was stirred at 15 C overnight.After the reaction was monitored by TCL, the reaction solution was poured into ice water, and a white solid precipitated.Filter and dry in vacuo to obtain the target compound 2,6-dichloro-9-isopropyl-9H-purine.Light yellow solid 1.1g, yield: 90.02%. |
90.02% | With potassium carbonate; In dimethyl sulfoxide; at 15℃; | General procedure: 2,6-dichloro-9-isopropyl-9H-purine (2a). 2,6-dichloro-9H-purine (1.0 g, 5.29 mmol), and potassium carbonate (K2CO3) (2.193 g, 15.87 mmol) were dissolved in 20 mL anhydrous DMSO. Iodopropane (2.64 mL, 26.45 mmol) was added dropwise at 15 C. The reaction mixture was stirred at 15 C overnight. Upon completion of the reaction, the reaction solution was poured into ice water, and a white solid precipitated. The solution was filtered and dried under a vacuum to give 1.1 g of light yellow solid. Yield: 90.02%. 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 4.83 (p, J = 6.8 Hz, 1H), 1.56 (d, J = 6.8 Hz, 6H). |
70% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 120h; | General procedure: To a solution of 2,6-dichloro-9H-purine (12.5 g, 66.1 mmol) in 75 mL of DMSO were added potassium carbonate (27.4 g, 198 mmol), and 2-iodopropane (33 mL, 330 mmol) at rt. The reaction mixture was stirred at rt for 5 days, quenched with water, and extracted with EtOAc (4 x 500 mL). The combined organic layers were washed with water and brine, dried (MgSO4), concentrated, and purified by automated flash column chromatography (hexane-EtOAc: 20-60% gradient) to give the title compound (10.6 g, 70%) as a white solid. mp 153 - 156 C; 1H NMR (399 MHz, CDCl3) δ 8.16 (s, 1H), 4.91 (hept, J = 6.8 Hz, 1H), 1.65 (dd, J = 6.8, 1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 152.7, 152.6, 151.6, 143.5, 131.0, 48.4, 22.5; HRMS (ESI) m/z calcd for C8H8Cl2N4 (M + H)+ 231.0199; found, 231.0199. |
70% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 120h; | To a solution of 2,6-dichloro-9H-purine (12.5 g, 66.1 mmol) in 75 mL of DMSO were added potassium carbonate (27.4 g, 198 mmol), and 2- iodopropane (33 mL, 330 mmol) at rt. The reaction mixture was stirred at rt for 5 days, quenched with water, and extracted with EtOAc (4 x 500 mL). The combined organic layers were washed with water and brine, dried (MgSO4), concentrated, and purified by automated flash column chromatography (hexaneEtOAc: 20-60% gradient) to give the title compound (10.6 g, 70%) as a white solid. mp 153- 156 C; 1H NMR (399 MHz, CDCl3) δ 8.16 (s, 1H), 4.91 (hept, J = 6.8 Hz, 1H), 1.65 (dd, J = 6.8, 1 Hz, 8H); 13C NMR (75 MHz, CDCl3) δ 152.7, 152.6, 151.6, 143.5, 131.0, 48.4, 22.5; HRMS (ESI) m/z calcd for C8H8Cl2N4 (M + H)+ 231.0199; found, 231.0199. |
68% | With potassium carbonate; In dimethyl sulfoxide; at 15 - 20℃; | 2,6-Dichloro-9-isopropyl-9H-purine (15c). To a solution of 2,6-dichloro-9H-purine (0.500 g, 2.65 mmol) in anhydrous DMSO (3.0 mL) cooled to 15 C was added K2CO3 (1.10 g, 7.96 mmol) followed by 2-iodopropane (1.35 mL, 13.4 mmol). The mixture was stirred overnight at room temperature, quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried (MgS04), concentrated, and purified by chromatography on S1O2 (hexanes, 100%, to hexanes/EtOAc, 1 : 1) to yield 15c (0.415 g, 1.80 mmol, 68%) as a colorless solid: Mp 149-151 C; IR (ATR, neat) 1587, 1554, 1356, 1214 cm 1 ; NMR (CDCb, 600 MHz) δ 8.18 (s, 1 H), 4.92 (hept, 1 H, / = 6.6 Hz), 1.65 (d, 6 H, / = 6.6 Hz); 13C NMR (CDCb, 150 MHz) δ 152.7, 152.6, 151.6, 143.5, 131.0, 48.3, 22.5 ; HRMS (EI) m/z calcd for C8H8CbN4 230.0126, found 230.0120. |
57% | With potassium carbonate; In dimethyl sulfoxide; for 8h; | To a solution of 2,6-dichloro-9H-purine (20.0 g, 106 mmol) in DMSO (111 mL) was added K2CO3 (44.0 g, 318.8 mmol, 3 equiv) and 2-iodopropane (54 mL, 541 mmol, 5 equiv). After 8 h stirring, water was added and the solution was extracted with AcOEt (3x100 mL). The organic layers were assembled, washed with brine, dried (Na2S04), concentrated, and chromatographed on a silica gel column (hexane/AcOEt 1 : 1, long column). The upper spot was collected, then the rest of the material was washed with EtOAc, and purified again to give a white solid. M= 7.69+6.19 g. Yield = 57%; 1H MR (CDC13): δ 1.65 (d, 6H, J= 6.8 Hz), 4.91 (hept, 1H, J= 6.8 Hz), 8.17 (s, 1H) |
45% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 24h;Inert atmosphere; | To a solution of 2,6-dichloro-9H-purine (1.00 g, 5.29 mmol) dissolved in 40 mL of DMSO was added 2-iodopropane (1.62 g, 9.52 mmol) and K2C03 (1.32 g, 9.52 mmol). The solution was stirred at room temperature under a nitrogen atmosphere for 1 day. The reaction mixture was diluted in H20 and ethyl acetate, the organic layer was separated and the aqueous layer extracted twice with ethyl acetate. Purification by flush column chromatography (silica gel, hexane/ethyl acetate 1 :3) afforded 2,6-dichloro-9-/'sopropyl-9H-purine (45% yield) as a white solid. 1H NMR CDCI3 (ppm): 8.17 (d, 1H), 4.86-4.97 (septet, 1 H),1.64-1.66 (d, 6H). m/z: 231 [MH+] |
39% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 24h;Inert atmosphere; | [0308] Synthesis of 9-/so-Propyl-2,6-dichloro-9H-purine; [0309] 2,6-Dichloro-9H-purine (4.00 g, 2.12 mmol) was dissolved in DMSO (240 ml). Then potassium carbonate (5.27 g, 3.81 mmol, 1.8 eq) was added followed by addition of 2-iodopropane (3.80 ml, 3.81 mmol, 1.8 eq). A milky white solution was observed. The solution was stirred at room temperature under an atmosphere of nitrogen for 24 hours. The solution was extracted with ethyl acetate and washed with water. The solvent of the organic phase was evaporated to obtain a concentrated yellow solution. Purification was carried out by flash column chromatography on silica gel (eluent hexane/ethyl acetate 1 :3) to deliver the desired compound (1.57 g, 39% yield). 1H-NMR (CDCI3): δ 8.16 (s, 1H), 4.91 (sep, 1H), 1.65 (d, 6H). m/z: 231.36 [MH]+. |
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 10h; | General procedure: 2,6-dichloro-9H-purine (18.9 g, 0.1 mol) and K2CO3(27.6 g, 0.2 mol) was dissolved in 150 mL DMF,iodoalkanes (0.2 mol) were subsequently added under ice bath. The resulting mixture was stirred at room temperature for 10 h. Then the mixture was added into 400 mL water and the precipitate was collected by filtration and dried under vacuum to obtaincorresponding product2. | |
2.53 g | With potassium carbonate; In dimethyl sulfoxide; at 20℃;Cooling with ice; | 2-Iodopropane (7.9 mL) was added to a stirred, ice-cooled suspension of 2,6- dichloro-9H-purine (3.0 g) and potassium carbonate (6.58 g) in DMSO (15 mL) then the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with water and brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with 0-20 % acetone in DCM to give the title compound as a white solid (2.53 g). H NMR (400 MHz, CDCl3) d 8.17 (1H, s), 4.96 - 4.88 (1H, m), 1.66 (6H, d, J=6.8 Hz); LCMS (Method 3) Rt 1.11 min m/z 231/233/235 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24.5h; | Example 1 Synthesis of the compound of the invention Synthesis of 2,6-dichloro-9-/sopropyl-9H-purine; 2,6-Dichloropurine (2 mmol), /sopropanol (8 mmol) and triphenylphosphine (4 mmol) were taken up in 40 ml anhydrous tetrahydrofuran and di/soproplyazidodicarboxylate (4 mmol) was added drop wise at room temperature over a period of 30 min. The reaction mixture was then stirred at room temperature for a further 24 h. The reaction was periodically monitored by TLC or LC-MS. The reaction mixture was poured in to a beaker containing ice- cold water. Extraction of the aqueous layer, using 3x100 ml portions of ethyl acetate, afforded the crude product. This was purified by chromatography on a silica gel column (10-80% ethyl acetate in petroleum ether, gradient elution), to give 2,6-dichloro-9-/sopropyl-9H-purine in a yield of 77%. |
77% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h; | 2,6-Dichloropurine (2 mmol), isopropanol (8 mmol) and triphenylphosphine (4 mmol) were taken up in 40 ml anhydrous tetrahydrofuran and diisoproplyazidodicarboxylate (4 mmol) was added drop wise at room temperature over a period of 30 min. The reaction mixture was then stirred at room temperature for a further 24 h. The reaction was periodically monitored by TLC or LC-MS. The reaction mixture was poured in to a beaker containing ice-cold water. Extraction of the aqueous layer, using 3×100 ml portions of ethyl acetate, afforded the crude product. This was purified by chromatography on a silica gel column (10-80% ethyl acetate in petroleum ether, gradient elution), to give 2,6-dichloro-9-isopropyl-9H-purine in a yield of 77%. |
66% | With N-ethyl-N,N-diisopropylamine; triphenylphosphine; In tetrahydrofuran;Heating; | 2, 6-Dichloro-9-isopropyl-9H-purine (SB1-E-14-4) To a solution of SM-14-2 ( 3.0 g, 15.3 mmol) and 2-propanol (2.75 g, 45.9 mmol) in THF (30 mL), PPh3 (8.02 g, 30.6 mmol) was added. The mixture was stirred at room temperature for lOmin. Then DIEA (6.18 g, 30.6 mmol) was added. The final mixture was stirred at 70C for 3h. after completion, concentrated to remove the solvent, water (30 mL) was added, the resulting mixture was extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over sodium sulfate, filtered through Celite, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/acetone = 20 / 1 to 10 /l) to afford SB1-E-14-4 (off-white solid, 2.34 g, 66% yield). |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; | A mixture of 2,6-dichloro-9H-purine (5 g, 26.45 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) was added propan-2-ol (8 g, 133.12 mmol, 5.03 equiv) and PPh3 (13.9 g, 52.99 mmol, 2.00 equiv). This was followed by the addition of DIAD (10.7 g, 52.92 mmol, 2.00 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 12 h at room temperature then was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/10) to afford 7.5 g (crude) of 2,6-dichloro-9-(propan-2-yl)- 9H-purine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 110℃; | General procedure: DIPEA (1.8 mmol) and the respective benzylamine (0.9 mmol) were added to a solution of the corresponding 9-alkyl-2,6-dichloro-9H-purine (2a-2f, 1.00 mmol) in 1-butanol (5 mL) and the reaction mixture was heated at 110 C overnight. Then, the solvent was removed under vacuum and the crude product was purified by column chromatographic on silica gel using as eluent a mixture 4:1 of chloroform/acetone for all derivatives. |
With triethylamine; | Scheme A, step b: 2-Chloro-6-(benzylamino)-9-(2-propyl)purine 2-Chloro-6-(benzylamino)-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 15 for preparation), benzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | EXAMPLE 30 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2.3-dimethoxybenzyl)amino]-9-(2-propyl)purine dihydrochloride Scheme A, step b: 2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine 2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 for preparation), <strong>[4393-09-3]2,3-dimethoxybenzylamine</strong>, and triethylamine essentially as described above in Example 1, Scheme A, step b. Scheme A, step c: 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine dihydrochloride 2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine dihydrochloride is prepared from 2-chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine essentially as described in Example 1, Scheme A, step c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 90℃; for 12h;Combinatorial reaction / High throughput screening (HTS); | To a solution of dichloro-heterocycle (S) (15.0 mmol) in n-butanol (200 mL) was added PAL-resin-bound amine 1 (10.0 mmol), followed by addition of diisopropylethylamine (5.2 mL, 30.0 mmol). The suspension was heated to 90[deg.] C. under argon. After 12 hours, the resin was washed by methanol (200 mL*4) and dichloromethane (200 mL*4) and dried under vacuum. The complete conversion of secondary amine (PAL-amine) to tertiary amine was confirmed by bromophenol blue test. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine In butan-1-ol at 100℃; for 2h; | |
56% | With triethylamine In butan-1-ol at 100℃; for 2h; | 4.5. Preparation of 2-chloro-9-isopropyl-N-[[4-(2-pyridyl)phenyl]methyl]purin-6-amine (7) To a solution of 6 (2.31 g, 10 mmol) in n-BuOH was added the primary amine (12 mmol) and NEt3 (2.20 mL, 16 mmol). After heating at 100 °C for 2 h, n-BuOH was evaporated in vacuo. After dilution with H2O (10 mL), the mixture was extracted with AcOEt (3 x 20 mL). The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The residue was chromatographied on a silica gel column using CH2Cl2/AcOEt, 2:1 to 1:1 as eluent. Yield 56%, mp: 176-179 C. 1H NMR (CDCl3) δ: 1.58 (d, 6H, J = 6.8 Hz, CH(CH3)2), 4.79 (hept, 1H, CH(CH3)2), 4.85 (bs, 2H, NHCH2), 6.59 (bs, 1H, NHCH2), 7.20-7.23 (m, 1H, Hpyridyl), 7.49 (d, 2H, J = 8 Hz, Hphenyl), 7.73-7.71 (m, 2H, Hpyridyl), 7.79 (s, 1H, H-8), 7.98 (d, 2H, Hphenyl), 8.71 (d, 1H, J = 4.8 Hz, Hpyridyl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In butan-1-ol; at 120℃; for 0.333333h;Microwave irradiation; | 2-Chloro-9-isopropyl-A^-(pyridin-3-ylmethyl)-9H-puriii-6-amine (16r). To a solution of 15c (99.0 mg, 0.423 mmol) in n-BuOH (1.5 mL) were added 3-pyridinemethanamine (55.6 mg, 0.514 mmol) and Et3N (70.1 mg, 0.685 mmol). The reaction mixture was heated under microwave irradiation at 120 C for 20 min. n-BuOH was evaporated in vacuo. The residue was diluted with water (5.0 mL) and extracted with EtOAc (3 x 7.0 mL). The combined organic extracts were dried (MgS04), filtered, and concentrated to yield a pale yellow solid. The solid residue was resuspended (hexanes/Et20, 2: 1), filtered, and the solid was rinsed (hexanes/Et20, 3: 1). The filtered solid was dried under high-vacuum to yield 16r (112.0 mg, 0.389 mmol, 86%) as a pale yellow solid: NMR (CDC13, 300 MHz) δ 8.65 (s, 1 H), 8.54 (dd, 2 H, / = 1.2, 4.5 Hz), 7.73-7.70 (m, 1 H), 7.28-7.23 (m, 1 H), 6.62 (bs, 1 H), 5.00-4.75 (m, 2 H), 4.83 (hept, 1 H, / = 6.9 Hz), 1.57 (d, 6 H, / = 6.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine In butan-1-ol at 100℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In butan-1-ol; at 120℃; for 0.333333h;Microwave irradiation; | A^-(Biphenyl-4-ylmethyl)-2-chloro-9-isopropyl-9H-purin-6-amine (16s). To a solution of 15c (150.0 mg, 0.649 mmol) in n-BuOH (1.5 mL) were added 4-phenylbenzylamine (0.125 0.682 mmol) and triethylamine (108.0 mg, 1.06 mmol) under an N2 atmosphere. The reaction mixture was heated under microwave irradiation at 120 C for 20 min. n-BuOH was evaporated, and the residue was dissolved in EtOAc and washed with water. The aqueous phase was further extracted with EtOAC, and the combined organic extracts were dried (MgS04) and concentrated to yield a colorless solid. The solid was resuspended (hexanes/Et20, 3: 1), filtered, and rinsed (hexanes/Et20, 3:1). The solid was dried under high-vacuum to yield 16s (187.0 mg, 0.495 mmol, 76%) as an off- white solid: Mp 98-100 C; IR (ATR, neat) 1615, 1571, 1350, 1308 cm 1; NMR (CDCb, 600 MHz) δ 7.68 (bs, 1 H), 7.61-7.57 (rm 4 H), 7.487.42 (m, 4 H), 7.36 (L 1 H / = 7.8 Hz), 6.55 (bs, 1 H), 4.88 (bs, 2 H), 4.82 (hept, 1 H, / = 6.6 Hz), 1.56 (d, 6 H, / = 6.6 Hz); 13C NMR (CDCb, 150 MHz) δ 155.1, 154.3, 149.8, 140.6, 137.7, 137.0, 128.8, 128.4, 127.4, 127.3, 127.1, 118.9, 46.9, 44.3, 22.8; HRMS (ES) m/z calcd for C21H20CIN5 [M+Na]+ 400.1305, found 400.1308. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In dimethyl sulfoxide; at 15 - 18℃; | General procedure: To a solution of 2,6-dichloro-9H-purine or 2-amino-6-chloro-9H-purine (1.0 eq.) in DMSO (5.5 mL for 1 mmol of purine) at 15 C were added K2CO3 (3.0 eq.) and 2-bromopropane (5.0 eq.). After 2-3 days stirring at 15-18 C, water was added and the solution was extracted with EtOAc. The organic layer, once combined, was washed with brine, dried (Na2SO4), concentrated and purified by chromatography on silica gel columns (eluant: cyclohexane/EtOAc 1:9) to yield white solids (60%-75%). |
41% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 48h; | To a stirred solution of 2,6-dichloropurine [0952] (1 g, 5.291 mmol) and 2-bromopropane [0953] (1.952 g, 15.873 mmol) in dimethylsulfoxide (10 mL) was added potassium carbonate (2.194 g, 15.873 mmol). The reaction mixture was stirred at rt for 48 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (20 mL), brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 2% methanol in chloroform as eluent to afford 2,6-dichloro-9-isopropyl-9H-purine [0954] as off-white solid (0.5 g, 41%). MS(M+1)+=231.1. |
13.9% | With potassium carbonate; In dimethyl sulfoxide; at 25℃; for 12h; | To a solution of 2,6-dichloro-9H-purine (20 g, 105.82 mmol, 1 eq) in DMSO (160 mL) was added K2CO3 (73.13 g, 529.09 mmol, 5 eq) and 2-bromopropane (65.07 g, 529.09 mmol, 49.67 mL, 5 eq). The mixture was stirred at 25 C for 12 h. TLC (PE/EtOAc = 1/1, Rf = 0.45) indicated starting material was consumed completely and one major new spot was detected. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (80 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel column chromatography (from PE/EtOAc = 5/1 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.45) to yield 2,6-dichloro-9-isopropyl- purine (3.52 g, 14.75 mmol, 13.9% yield, 96.8% purity) as a white solid. MR (400 MHz, CD3OD) δ ppm 8.66 (s, 1H), 4.97-4.89 (m, 1H), 1.65 (d, J = 6.8 Hz, 6H); ES-LCMS m/z 231.0, 232.9 [M+H]. |
With potassium carbonate; In dimethyl sulfoxide; at 15 - 18℃; for 49h; | Step a): Alkylation of 2,6-chloropurine (10g, 52.9 mmol) in 200 mL of DMSO in the presence of K2CO3 (21.9 g, 158.7 mmol) was achieved upon adding slowly (within 1 hour) 2-bromopropane (32.5 g 264.5 mmol) at 15-18 C. The temperature should be carefully adjusted between 15 and 18C to avoid excessive formation of the 7-regiosiomer. After 2 days stirring, 1000 mL of water was added and the mixture was extracted with AcOEt (5x20 mL). The organic layer was washed with water dried and evaporated. The residue was purified by column chromatography using (cyclohexane:AcOEt 7:3) for elution. | |
With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 0.866667h; | In an alternative embodiment, compound [2] is prepared by treating compound [6] with 2-bromopropane to form compound [8] using similar conditions and reagents to those described above. Compound [8] is then reacted with compound [9] in the presence of n- butanol and DIEA using similar conditions to those described above to form compound [2]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | [0310] Synthesis of 5-(2-chloro-9-/sopropyl-9H-purin-6-yl)-pyrimidin-2-ylamine; [0311] To a solution of 2,6-dichloro-9-/sopropyl-9H-purine (5.21 mmol), 5-(4,4,5,5- tetramethyl -[1 ,3,2]dioxaborolan-2-ylamine (5.21 mmol) and 1 ,1'- bis(diphenylphosphino)ferrocene palladium (II) chloride complexed with dichloromethane (0.26 mmol) in peroxide free dioxane (40 ml) was added a 2M aqueous solution of sodium carbonate (15.6 mmol). The resulting mixture was degassed and purged with nitrogen. This reaction mixture was then stirred while being heated on an oil bath maintained at 8O0C for 3h. The reaction was monitored by LC-MS for the disappearance of the starting purine. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was taken up in a mixture of ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3x100 ml portions of ethyl acetate. The organics were dried over sodium sulfate and the solvents removed under vacuum to give 5-(2-chloro-9-/sopropyl-9H-purin-6-yl)-pyrimidin-2-ylamine in 55% yield. |
55% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | Synthesis of 5-(2-chloro-9-/sopropyl-9H-purin-6-yl)-pyrimidin-2-ylamine; To a solution of 2,6-dichloro-9-/sopropyl-9H-purine (5.21 mmol), 5-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-ylamine (5.21 mmol) and 1 ,1'-bis(diphenylphosphino) ferrocene palladium (II) chloride complexed with dichloromethane (0.26 mmol) in peroxide free dioxane (40 ml) was added a 2M aqueous solution of sodium carbonate (15.6 mmol). The resulting mixture was degassed and purged with nitrogen. This reaction mixture was then stirred while being heated on an oil bath maintained at 8O0C for 3h. The reaction was monitored by LC-MS for the disappearance of the starting purine.The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was taken up in a mixture of ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3x100 ml portions of ethyl acetate. The organics were dried over sodium sulfate and the solvents removed under vacuum to give 5-(2-chloro-9-/sopropyl-9H-purin-6-yl)-pyrimidin-2-ylamine in 55% yield. |
55% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; dichloromethane; water; at 80℃; for 3h;Inert atmosphere; | To a solution of 2,6-dichloro-9-isopropyl-9H-purine (5.21 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylamine (5.21 mmol) and 1,1'-bis(diphenylphosphino) ferrocene palladium (II) chloride complexed with dichloromethane (0.26 mmol) in peroxide free dioxane (40 ml) was added a 2M aqueous solution of sodium carbonate (15.6 mmol). The resulting mixture was degassed and purged with nitrogen. This reaction mixture was then stirred while being heated on an oil bath maintained at 80 C. for 3 h. The reaction was monitored by LC-MS for the disappearance of the starting purine.The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was taken up in a mixture of ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3×100 ml portions of ethyl acetate. The organics were dried over sodium sulfate and the solvents removed under vacuum to give 5-(2-chloro-9-isopropyl-9H-purin-6-yl)-pyrimidin-2-ylamine in 55% yield. |
55% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 80℃; for 3h;Inert atmosphere; | 2,6-dichloro-9-isopropyl-9H-purine (5.21 mmol),5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-ylamine (5.21 mmol),To a solution of 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride complexed with dichloromethane (0.26 mmol) in dioxane without peroxide (40 mL)A 2 M aqueous solution of sodium carbonate (15.6 mmol) was added.The resulting mixture was degassed,And purged with nitrogen.Then,While heating in an oil bath maintained at 80 C. for 3 hours,The reaction mixture was stirred.Regarding the disappearance of the starting pudding,The reaction was monitored by LC-MS |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In ethyl acetate; at 78℃; for 5h; | General Procedure: <strong>[203436-45-7]2,6-dichloro-9-isopropylpurine</strong> (L1) was prepared from 2,6-dichloropurine according to the previously reported general preparation of 2,6-dihalogen-9-alkylpurine derivatives [20]. The synthesis of 4 and 5 follows the published procedure of C2,N9-substituted 6-benzylaminopurine derivatives [21] (see Scheme 3), where a mixture of L1 and the corresponding benzylamine derivative (in a molar ratio of 1:1) was stirred in 150 ml of ethyl acetate at the temperature of 78 C for 5 h. Then, the products were filtered off, washed with ethanol and diethyl ether, and dried at 40 C. The yields ranged from 76% to 88%. The single crystals were prepared by slow evaporation of the isopropanol/acetone mixture (1:1) at laboratory temperature. |
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h; | General procedure: To a solution of2(5 mmol,1equiv) in DMF (10 mL) was added 3-bromobenzylamine (5 mmol, 1equiv) and K2CO3(5 mmol, 1equiv).Then the reaction mixture was stirred for 4 h at 90C. Then the mixture was quenched with water (50ml) and extracted with ethyl acetate (2×50 mL).The combined organic layers werewashed with saturated NaCl solution anddried overanhydrous Na2SO4and concentrated under vacuumto give the corresponding target product3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In butan-1-ol; at 120℃; for 0.5h;Inert atmosphere; | 2-Chloro-9-isopropyl-^-((5-methylthiophen-2-yl)methyl)-9H-purin-6-amine (16u). To a solution of 15c (74.4 mg, 0.322 mmol) in n-BuOH (1.25 mL) was added (5-methylthien-2- yl)methylamineHCl (55.7 mg, 0.340 mmol) and freshly distilled Et3N (98.0 mg, 0.969 mmol) under an N2 atmosphere. The reaction mixture was subjected to microwave irradiation at 120 C for 30 min. White crystals were observed upon completion of the heating. n-BuOH was evaporated in vacuo, and the residue was dissolved in EtOAc (20.0 mL) and deionized water (10.0 mL). The aqueous phase was further extracted with EtOAc (3 x 10.0 mL), and the combined organic layers were dried (MgS04), filtered, and concentrated to yield a light yellow solid. The solid was resuspended (hexanes/Et20, 3: 1), and the precipitated solid was filtered through a fritted funnel and dried under high- vacuum overnight to obtain 16u (96.9 mg, 0.301 mmol, 94%) as light yellow amorphous solid: IR (ATR, neat) 3340, 3256, 3213, 3184, 3137, 3120, 3064, 2977, 2967, 2921, 1705, 1676, 1620, 1569, 1538, 1463, 1351, 1310, 1290, 1256, 1224, 1200, 1159, 1098, 1070, 1036, 1010, 969, 956, 798, 787, 761, 736, 725, 695, 678, 658 cm 1 ; NMR (300 MHz, CDCb) δ 7.77 (bs, 1 H), 6.85 (d, 1 H, / = 3.3 Hz), 6.60 (d, 1 H, / = 3.3 Hz), 6.25 (bs, 1 H), 4.89 (bs, 2 H), 4.83 (sept, 1 H, / = 6.7 Hz), 2.45 (s, 3 H), 1.58 (d, 6 H, / = 6.6 Hz); 13C NMR (75 MHz, CDCb) δ 154.8, 154.2, 149.9, 139.9, 138.5, 137.8, 126.0, 124.7, 118.8, 46.9, 39.6, 22.8, 15.4; HRMS (ES) m/z calcd for Ci4Hi6N5SCl 321.0850, found 321.0813. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In butan-1-ol; at 120℃; for 0.5h;Microwave irradiation; Inert atmosphere; | 2-Chloro-9-isopropyl-A^-(3-(trifluoromethyl)benzyl)-9H-purin-6-amine (16v). To a solution of 15c (65.8 mg, 0.273 mmol) in n-BuOH (1.0 mL) were added 3-(trifluoromethyl)benzylamine (52.4 mg, 0.300 mmol) and Et3N (46.1 mg, 0.456 mmol) under a nitrogen atmosphere. The reaction mixture was heated with microwave irradiation at 120 C for 30 min. The n-BuOH was evaporated, and the residue was dissolved in EtOAc (20.0 mL) and washed with water (10.0 mL). The aqueous phase was further extracted with EtOAc (2 x 10.0 mL), and the combined organic extracts were dried (MgS04), filtered, and concentrated to yield a colorless solid. The solid was resuspended (hexanes/Et20, 3: 1), filtered, washed (hexanes/Et20, 3: 1), and dried under high- vacuum to yield 16v (63.0 mg, 0.170 mmol, 60%) as a colorless amorphous solid: IR (ATR, neat) 3250, 3150, 2990, 2925, 1625, 1446, 1313, 1230, 1159, 1140, 1099, 980, 930, 700 cm"1; NMR (300 MHz, CDC13) delta 7.77 (s, 1 H), 7.63 (s, 1 H), 7.59 (d, 1 H, / = 7.5 Hz), 7.56 (d, 1 H, / = 7.8 Hz), 7.47 (t, 1 H, / = 7.5 Hz), 6.33 (bs, 1 H), 4.90 (bs, 2 H), 4.83 (sept, 1 H, / = 6.8 Hz), 1.58 (d, 6 H, / = 6.9 Hz); 13C NMR (75 MHz, CDCb) delta 155.1, 154.2, 150.0, 139.4, 137.8, 131.2, 130.9 (q, J = 32.2 Hz), 129.3, 124.4, 124.3, 124.0 (q, J = 270.1 Hz), 118.8, 47.0, 43.9, 22.7; HRMS [EI] m/z calcd for [C16H15CIF3N5] 369.0968, found 369.9640. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24.5h; | Synthesis of 2,6-dichloro-9-isopropyl-9H-purine2,6-dichloropurine (2 mmol),Isopropanol (8 mmol)And triphenylphosphine (4 mmol)Was taken up in 40 mL of anhydrous tetrahydrofuran,Then,Diisopropyl azidodicarboxylate (4 mmol)Was added dropwise over 30 minutes at room temperature.Then,The reaction mixture was stirred for a further 24 hours at room temperature.The reaction was monitored periodically by TLC or LC-MS.The reaction mixture was poured into a beaker containing ice cold water.The aqueous layer was extracted three times with 100 mL portions of ethyl acetate,A crude product was obtained.Chromatography on a silica gel column (10 to 80% ethyl acetate in petroleum ether,Gradient elution) to afford2,6-Dichloro-9-isopropyl-9H-purine was obtained with a yield of 77% |
52% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; for 2h;Inert atmosphere; | 2,6-Dichloropurine (1.89 g; 0.01 mol) was dissolved under a nitrogen atmosphere in a mixture of tetrahydrofuran (40 ml) and isopropanol (4 ml; 0.06 mol), and then triphenyl phosphine (3.14 g; 0.012 mol) and DIAD (2.4 ml; 0.012 mol; dropwise) were added. The temperature of reaction mixture was maintained at 20-25 C during addition of DIAD. The reaction mixture was the stirred for 2 h at 20-25 C. TLC (mobile phase: ethyl acetate - toluene; 1:1) after 2 h indicated that the reaction had gone to completion. The reaction mixture was then evaporated to a thick yellow residue, which was dissolved in hot (60 C) methanol (30 ml). After crystallization in a refrigerator (-18 C) overnight, the crystalline mass was collected by filtration, washed with cold (-10 C) methanol (2 × 5 ml) and dried in the vacuum drying oven (60 C) to constant weight. Yield: 1.20 g of almost white crystalline powder (52%). The purity (HPLC): >98%. (0022) M.p. = 149-152 C. Physico-chemical data including 1H NMR were in accordance with those published [21-24]. The second crop (up to 10%) of product of lower purity could be obtained from mother liquor. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 110.0℃; | General procedure: DIPEA (1.8 mmol) and the respective benzylamine (0.9 mmol) were added to a solution of the corresponding 9-alkyl-2,6-dichloro-9H-purine (2a-2f, 1.00 mmol) in 1-butanol (5 mL) and the reaction mixture was heated at 110 C overnight. Then, the solvent was removed under vacuum and the crude product was purified by column chromatographic on silica gel using as eluent a mixture 4:1 of chloroform/acetone for all derivatives. |
With triethylamine; In propan-1-ol; at 90.0℃; for 4.0h;Inert atmosphere; | General procedure: 2,6-Dichloro-9-isopropylpurine (0.05 mol), appropriate substituted benzylamine (0.05 mol), n-propanol (230 ml) and triethylamine (0.15 mol) were placed into a reaction bulb, under nitrogen. The reaction mixture was warmed up to 90 C, and stirred for a period of 4 h. The contents of the bulb were then evaporated on rotary vacuum evaporator to give a semisolid residue, which was then treated with water (200 ml) for 20 min. The precipitate was filtered off, washed with water (3 × 20 ml) and dried in the vacuum oven to constant weight. Yield: 75-90%, according to the type of benzylamine used. The purity (HPLC): min. 97%. The crude product can be purified by crystallization from isopropyl alcohol if required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 90℃; for 4h;Inert atmosphere; | General procedure: 2,6-Dichloro-9-isopropylpurine (0.05 mol), appropriate substituted benzylamine (0.05 mol), n-propanol (230 ml) and triethylamine (0.15 mol) were placed into a reaction bulb, under nitrogen. The reaction mixture was warmed up to 90 C, and stirred for a period of 4 h. The contents of the bulb were then evaporated on rotary vacuum evaporator to give a semisolid residue, which was then treated with water (200 ml) for 20 min. The precipitate was filtered off, washed with water (3 × 20 ml) and dried in the vacuum oven to constant weight. Yield: 75-90%, according to the type of benzylamine used. The purity (HPLC): min. 97%. The crude product can be purified by crystallization from isopropyl alcohol if required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: A solution of Pd(OAc)2 and BINAP in dry toluene was warmed at 45 C for 5 min. The leaving group-containing purine was then added under N2 bubbling; the mixture was kept at 45 C for 10 min. and KOtBu was added. After 10 min, the appropriate nucleophile was added. The mixture was heated at 100 C under N2 until reaction completion (3 h to 2 days depending upon the nucleophile used). After cooling to room temperature,the mixture was filtered through Celite, and concentrated. The residue was dissolved in CH2Cl2 (75 mL) and washed (1 × 10 mL) with water and brine (2 × 10 mL). The organic layer was dried and concentrated under vacuum. The residue was purified by chromatography on silica gel using various amounts of EtOAc/cyclohexane/ethanol as eluants. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 1h; | 2,6-Dichloro-9-isopropyl-9H-purine (1.16 g, 5 mmol), as prepared in step 1 of Example 1, was mixed with 4-amino-1-methylpyrazole (1.02 g, 10 mmol) and DIPEA (1.74 mL, 10 mmol) in nBuOH (33 mL) and was stirred and heated at 100 C. (block temperature) for 1 hr. The reaction was cooled, and the volatiles were removed under vacuum to give a dark residue. Ethyl acetate (120 mL) was added and the mixture was washed with sat. aq. NaHCO3 (3×30 mL), dried over Na2SO4 and evaporated to give a dark residue. This residue was dissolved in ethyl acetate, passed through a thin pad of silica gel, and eluted with 90% ethyl acetate-10% ammonia (7 N in methanol). The eluent was evaporated to afford the title compound as a dark solid (1.43 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.41 (br. s., 1H) 8.38 (s, 1H) 8.00 (s, 1H) 7.68 (s, 1H) 4.71 (quin, J=6.72 Hz, 1H) 3.84 (s, 3H) 1.52 (d, J=6.72 Hz, 6H). m/z (APCI+) for C12H14ClN7 292.1 with Cl isotope pattern (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 5h;Inert atmosphere; | Step 1: synthesis of 3-(2-chloro-9-isopropyl-9H-purin-6-yl)phenol (5a)To a pre-stirred of solution of <strong>[203436-45-7]2,6-dichloro-9-isopropyl-9H-purine</strong> 3a (230 mg, 1.0 mmol), (3- hydroxyphenyl)boronic acid 4c (152 mg, 1.1 mmol) in dioxane (10 mL), were added a solution of K2C03 (345 mg, 2.5 mmol) in deionized water (1.0 mL). The mixture was degassed for 30 mm then added Pd(dppf)C12.CH2C12 (41 mg), and the resulting mixture was heated at 70C for 5 hours. LC-MS showed the reaction completed. After a simple workup, the product 5a (215 mg, 75%) was obtained by flash chromatography (silica, 20% to 50% ethyl acetate in hexanes). |
75% | To a pre-stirred of solution of 2,6-dichloro-9-isopropyl-9Hpurine13a (230 mg, 1.0 mmol), (3-hydroxyphenyl)boronic acid 14a(152 mg, 1.1 mmol) in dioxane (10 mL), were added a solution of K2CO3 (345 mg, 2.5 mmol) in deionized water (1.0 mL). The mixturewas degassed for 30 min then added Pd(dppf)Cl2·CH2Cl2 (41 mg), andthe resulting mixture was heated at 70 C for 5 h. LC-MS showed the reaction completed. After a simple workup, the product 15a (215 mg,75%) was obtained by flash chromatography (silica, 20% to 50% ethylacetate in hexanes). LC-MS m/z (relative intensity): [M + H]+ 289.3(100%), 291.3 (33.5%). 1H NMR (400 MHz, CDCl3) δ 8.33 (dt, J = 7.8and 1.2 Hz, 1H), 8.24 (dd, J = 2.5 and 1.6 Hz, 1H), 8.18 (s, 1H), 7.43(t, J = 8.0 Hz, 1H), 7.04 (ddd, J = 8.1, 2.6, and 0.9 Hz, 1H), 5.92 (s,1H), 4.97 (septet, J = 6.8 Hz, 1H), 1.66 (d, J = 6.8 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100.0℃; for 2.0h; | A mixture of l-benzyl- lH-pyrazol-4-amine hydrochloride (2.43 g, 11.59 mmol, 1.20 equiv), 2,6-dichloro-9-(propan-2-yl)-9H-purine (2.23 g, 9.65 mmol, 1.00 equiv) and DIEA (1.24 g, 9.59 mmol, 0.99 equiv) in propan-2-ol (30 mL) was stirred for 2 h at 100 C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/1) to afford 2.3 g (65%) of N-(l -benzyl- 1H- pyrazol-4-yl)-2-chloro-9-(propan-2-yl)-9H-purin-6-amine as a dark red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 8h; | A suspension of 2,6-dichloro-9-isopropyl-9H-purine (3.0 g, 12 mmol) and <strong>[33786-89-9]5-chlorobenzene-1,3-diamine</strong> (1.8 g, 12 mmol) in n-butanol (21 mL) was stirred at rt as DIPEA (4.1 mL, 24 mmol) was added drop-wise. The resulting suspension was allowed to stir at 100 C and the suspension became a clear solution. After 8 h heating, the solution became a suspension. This suspension was allowed to cool to rt and filtered. The solids were washed with EtOAc (2x10 mL) and dried under vacuum. The title compound (3.6 g) was recovered as solid in 83% yield. 1H NMR (399 MHz, DMSO-d6) delta 10.08 (s, 1H), 8.42 (s, 1H), 7.10 (t, J = 1.9 Hz, 1H), 6.96 (t, J = 1.9 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 5.41 (s, 2H), 4.71 (p, J = 6.8 Hz, 1H), 1.51 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) delta 152.7, 152.3, 150.7, 150.6, 141.0, 140.9, 133.4, 119.6, 109.2, 108.9, 105.4, 47.4, 22.6, 22.5; HRMS (ESI) m/z calcd for C14H14Cl2N6 (M + H)+, 337.0730; found, 337.0727. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; | Example 11. N-(3-(2-((lr,4r)-4-(Dimethylamino)cyclohexylamino)-9-isopropyl-9H-purin- 6-ylamino)cyclohexyl)acrylamide (SB1-E-15) Synthetic Scheme 11 tert-butyl 3-(2-Chloro-9-isopropyl-9 -purin-6-ylamino)cyclohexylcarbamate (SBl-E-15-2) The mixture of SB1-E-15-1 (520 mg, 2.25 mmol), SM-15-2 (490 mg, 2.29 mmol), n-BuOH (15 mL) and DIPEA (1 mL) was stirred at 100C overnight, after completion, concentrated to remove the solvent, the residue was purified by silica gel (PE/ethyl acetate = 2/1) to obtain SBl-E-15-2 (light broen solid, 380 mg, yield 41%). LCMS (m/z): 409 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 90℃; | Example 12. N-(3-(2-((lr,4r)-4-(Dimethylamino)cyclohexylamino)-9-isopropyl-9H-purin- 6-ylamino)benzyl)acrylamide (SB1-E-16) Synthetic Scheme 12 tert-butyl 3-(2-Chloro- o)benzylcarbamate (SB1 The mixture of SB1-E-16-2 (500 mg, 2.16 mmol), SB1-E-16-1 (490 mg, 2.20 mmol), n-BuOH (20 mL) and DIPEA (1 mL) was stirred at 90C overnight, after completion, concentrated to remove the solvent, the residue was purified by silica gel (PE/ethyl acetate = 2/1) to obtain SBl-E-16-3 (off-white solid, 360 mg, yield 40%). LCMS (m/z): 417 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
280 mg | With hydrogenchloride; N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 50℃; for 5.0h; | To a solution of 2,6-dichloro-9-isopropyl -purine (200 mg, 827.24 umol, 1 eq) in isopropanol (10 mL) was added DIEA (427.65 mg, 3.31 mmol, 576.35 uL, 4.0 eq) and 3-(2-aminoethyl)-1H- benzimidazol-2-one (265.13 mg, 1.24 mmol, 1.5 eq, HCl). The mixture was stirred at 50 C for 5 h. LC-MS showed most of starting material was consumed. The reaction mixture was concentrated under reduced pressure to remove isopropanol. The residue was diluted with H20 (20 mL) and extracted with DCM/isopropanol (20 mL x 3, v/v = 3/1). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified on silica gel column chromatography (from DCM/MeOH = 1/0 to 10/1, TLC: DCM/MeOH = 10/1, Rf = 0.15) to give 3-[2-[(2-chloro-9-isopropyl-purin-6-yl)amino]ethyl]-lH- benzimidazol-2-one (280 mg, 730.45 umol, 88.3% yield, 97% purity) as a white solid; NMR (400 MHz, CD3OD) delta ppm 8.14 (s, 1H), 7.28 (d, J= 7.2 Hz, 1H), 7.06-6.97 (m, 3H), 4.78-4.75(m, 1H), 4.22 (t, J = 6.0 Hz, 2H), 3.97(t, J = 6.0 Hz, 2H), 1.62 (d, J = 6.4 Hz, 6H); ES-LCMS m/z 372.1, 374.0 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 50℃; for 12.0h; | To a solution of 2,6-dichloro-9-isopropyl-purine (148.07 mg, 620.33 umol, 1 eq) in z-PrOH (10 mL) was added DIEA (400.86 mg, 3.10 mmol, 540.24 uL, 5.0 eq) and 2-(lH-pyrrolo[3,2- c]pyridin-3-yl)ethanamine (100 mg, 620.33 umol, 1 eq). The mixture was stirred at 50 C for 12 h. LC-MS showed starting material was consumed completely and 33% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (from DCM/MeOH = 100/1 to 5/1, TLC: DCM/MeOH = 10/1, Rf = 0.68) to yield 2-chloro-9-isopropyl-N-[2-(lH-pyrrolo[3,2-c]pyridin-3- yl)ethyl]purin-6-amine (74.5 mg, 33.8% yield, crude) as a yellow solid; ES-LCMS m/z 356.0, 357.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.52% | With triethylamine; In ethanol; at 80℃; for 6h;Reflux; | 3-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one (3a). 2,6-dichloro-9-isopropyl-9H-purine (2a) (540mg, 2.34mmol), <strong>[771579-27-2]3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one</strong> (427mg, 2.81mmol, obtained following the reference procedure [40]), and triethylamine (1.626mL, 11.7mmol) were added to ethanol (10mL), and the reaction solution was reacted under reflux at 80C for 6h. A white solid precipitated during the reaction. After the reaction was completed, the suspension obtained was filtered and washed with cold ethanol (10mL) to afford a solid product. The crude product was purified by silica gel column chromatography to afford target compounds as white solid with yield 50.52%, mp 141-143C.1H NMR (400MHz, DMSO-d6) delta 11.52 (s, 1H), 8.24 (s, 1H), 7.73 (t, J=5.7Hz, 1H), 5.87 (s, 1H), 4.66 (m, J=6.7Hz, 1H), 4.45 (d, J=5.3Hz, 2H), 2.28 (s, 3H), 2.11 (s, 3H), 1.49 (d, J=6.8Hz, 6H). 13C NMR (101MHz, Chloroform-d) delta 165.35, 155.06, 154.13, 150.85, 149.71, 143.23, 137.16, 121.96, 119.10, 109.66, 46.77, 37.00, 22.80 (2C), 19.70, 18.87. HRMS (ESI): calcd. for C16H19ClN6O [M+Na]+: 369.1207, found: 369.1204. |
50.52% | With triethylamine; In ethanol; at 80℃; for 6h; | 2,6-dichloro-9-isopropyl-9H-purine (540mg, 2.34mmol<strong>[771579-27-2]3-(aminomethyl)-4,6-dimethylpyridine-2(1H)-one</strong> (427mg, 2.81mmol),Triethylamine (1.626ml, 11.7mmol) was added to ethanol,The reaction solution was reacted under reflux at 80 C for 6h.A white solid precipitated during the reaction. After the reaction was completed, the reaction liquid was cooled with ice water.Filtration gave 410 mg of white solid with a yield of 50.52%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: To a pre-stirred of solution of 2,6-dichloro-9-isopropyl-9Hpurine13a (230 mg, 1.0 mmol), (3-hydroxyphenyl)boronic acid 14a(152 mg, 1.1 mmol) in dioxane (10 mL), were added a solution of K2CO3 (345 mg, 2.5 mmol) in deionized water (1.0 mL). The mixturewas degassed for 30 min then added Pd(dppf)Cl2·CH2Cl2 (41 mg), andthe resulting mixture was heated at 70 C for 5 h. LC-MS showed the reaction completed. After a simple workup, the product 15a (215 mg,75%) was obtained by flash chromatography (silica, 20% to 50% ethylacetate in hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.23% | With triethylamine; In ethanol; at 80℃; for 5h; | General procedure: 3-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)-4-ethyl-6- methylpyridin -2(1H)-one (3a1). <strong>[203436-45-7]2,6-dichloro-9-isopropyl-9H-purine</strong> (2a) (300.00 mg, 1.30 mmol), 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one (258.95 mg, 1.56 mmol, obtained following the reference procedure [21]), and triethylamine (0.90 mL, 6.50 mmol) were added to ethanol (10 mL), and the reaction solution was reacted under reflux at 80 C for 5 h. After completion (monitored by TLC), the reaction mixture was removed under vacuum and extracted with DCM. The organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford target compounds as white solid with yield 91.23%, mp 215-217 C. 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.24 (s, 1H), 7.69 (t, J = 5.5 Hz, 1H), 5.92 (s, 1H), 4.71-4.62 (m, 1H), 4.49 (d, J = 5.2 Hz, 2H), 2.63 (q, J = 7.3 Hz, 2H), 2.13 (s, 3H), 1.49 (d, J = 6.8 Hz, 6H), 1.11 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.01, 155.01, 153.13, 149.73, 143.84, 139.90, 121.03, 118.96, 106.36, 47.22, 36.63, 25.90, 22.55 (2C), 18.78, 14.90. HRMS (ESI): calcd. for C17H21ClN6NaO [M+Na]+: 383.1363 found: 383.1355. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.32% | With triethylamine; In ethanol; at 80℃; for 5h; | General procedure: 3-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)-4-ethyl-6- methylpyridin -2(1H)-one (3a1). <strong>[203436-45-7]2,6-dichloro-9-isopropyl-9H-purine</strong> (2a) (300.00 mg, 1.30 mmol), 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one (258.95 mg, 1.56 mmol, obtained following the reference procedure [21]), and triethylamine (0.90 mL, 6.50 mmol) were added to ethanol (10 mL), and the reaction solution was reacted under reflux at 80 C for 5 h. After completion (monitored by TLC), the reaction mixture was removed under vacuum and extracted with DCM. The organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford target compounds as white solid with yield 91.23%, mp 215-217 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.1% | With triethylamine; In ethanol; at 80℃; for 5h; | General procedure: 3-(((2-chloro-9-isopropyl-9H-purin-6-yl)amino)methyl)-4-ethyl-6- methylpyridin -2(1H)-one (3a1). <strong>[203436-45-7]2,6-dichloro-9-isopropyl-9H-purine</strong> (2a) (300.00 mg, 1.30 mmol), 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one (258.95 mg, 1.56 mmol, obtained following the reference procedure [21]), and triethylamine (0.90 mL, 6.50 mmol) were added to ethanol (10 mL), and the reaction solution was reacted under reflux at 80 C for 5 h. After completion (monitored by TLC), the reaction mixture was removed under vacuum and extracted with DCM. The organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford target compounds as white solid with yield 91.23%, mp 215-217 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 90 °C 2: 160 °C / Inert atmosphere |
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