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CAS No. : | 84905-80-6 | MDL No. : | MFCD06658411 |
Formula : | C6H4ClN3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZGJDDWOXVGDTSP-UHFFFAOYSA-N |
M.W : | 153.57 | Pubchem ID : | 5370695 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 38.9 |
TPSA : | 41.57 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) : | -6.26 cm/s |
Log Po/w (iLOGP) : | 1.4 |
Log Po/w (XLOGP3) : | 1.38 |
Log Po/w (WLOGP) : | 1.61 |
Log Po/w (MLOGP) : | 0.37 |
Log Po/w (SILICOS-IT) : | 2.24 |
Consensus Log Po/w : | 1.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.33 |
Solubility : | 0.722 mg/ml ; 0.0047 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.86 |
Solubility : | 2.14 mg/ml ; 0.0139 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.14 |
Solubility : | 0.112 mg/ml ; 0.000728 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | 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 |
---|---|---|
89% | for 1 h; Inert atmosphere; Reflux | Step 4: Preparation of 4-Chloropyrrolo[3,2-d]Pyrimidine (32e) To a sample of 3H,5H-Pyrrolo[3,2-d]pyrimidin-4-one (32d) (31.08 g, 230 mmol) under N2 was added phosphorus oxy chloride (60 mL, 644 mol). The mixture was heated at reflux for 1 h during which time the reaction became black homogenous. The reaction was cooled in an ice-water bath and then poured into chipped ice (775 mL) with stirring. The pH of the aqueous solution was slowly adjusted to ~ pH 8 with concentrated NH4OH (225 mL) with continued cooling of the mixture. The resulting precipitate was collected by vacuum filtration and washed with water. The solid was transferred to a drying tray and dried in vacuum at 110 °C to furnish 4-Chloropyrrolo[3,2-d]Pyrimidine (32e) (31.48 g, 89percent) as a dark gray solid. An analytical sample was obtained by column chromatography (Silica gel, EtOAc-hexanes, 35:65) followed by evaporation of the relevant fractions. Trituration of the solid with EtOAc-MeOH afforded 4-Chloropyrrolo[3,2-d]Pyrimidine (32e) as an off-white solid, MP >150 °C (dec); 1H NMR (DMSO-< 5) δ 12.43 (s, D20 exchangeable, 1H), 8.61 (s, 1H), 7.97 (dd, J = 2.8, 2.8 Hz; D20 exchange collapse to d, 1H), 6.72 (dd, J = 1.7, 3.5 Hz; D20 exchange collapse to d, 1H). 13C-NMR (DMSO-d6) 151.30, 149.58, 142.12, 134.83, 124.32, 102.70; IR (neat) 3128, 3078, 2979, 1621 cm"1; MS (ES+) 154.01 (100percent, M+l) and 156.01 (33percent); Analysis calculated for C6H4N3C1: C, 46.93; H, 2.63; N, 27.36; CI, 23.09; Found: C, 47.10; H, 2.79; N, 27.15; CI, 22.93. |
57% | Stage #1: for 2 h; Heating / reflux Stage #2: With potassium carbonate In water at 20℃; |
A mixture of 3,5-dihydropyrrolo[3,2-]pyrimidin-4-one, (1.8 g, 13.5 mmol, 1 equiv.) and 50 mL of POCI3 was warmed at reflux for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue was then diluted with 200 mL of water, made basic with solid potassium carbonate and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 1.18 g (57percent) of 4-chloro-5H-pyrrolo[3,2-]pyrimidine as a yellow solid which was used without further purification. |
36% | Stage #1: for 1 h; Reflux Stage #2: With sodium hydrogencarbonate In water; ethyl acetate |
Step 4: Into a 50-mL round-bottom flask was placed a solution of 3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (5 g, 35.52 mmol, 1.00 equiv, 96percent) in trichlorophosphate (20 mL). The resulting solution was stirred at reflux for 1 h, concentrated under vacuum, dissolved in 100 mL of ethyl acetate, washed with 2.x.100 mL of 10percent aqueous sodium bicarbonate and 1.x.100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:8) to afford 2 g (36percent) of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With trichlorophosphate; for 1h;Inert atmosphere; Reflux; | Step 4: Preparation of 4-Chloropyrrolo[3,2-d]Pyrimidine (32e) To a sample of 3H,5H-Pyrrolo[3,2-d]pyrimidin-4-one (32d) (31.08 g, 230 mmol) under N2 was added phosphorus oxy chloride (60 mL, 644 mol). The mixture was heated at reflux for 1 h during which time the reaction became black homogenous. The reaction was cooled in an ice-water bath and then poured into chipped ice (775 mL) with stirring. The pH of the aqueous solution was slowly adjusted to ~ pH 8 with concentrated NH4OH (225 mL) with continued cooling of the mixture. The resulting precipitate was collected by vacuum filtration and washed with water. The solid was transferred to a drying tray and dried in vacuum at 110 C to furnish 4-Chloropyrrolo[3,2-d]Pyrimidine (32e) (31.48 g, 89%) as a dark gray solid. An analytical sample was obtained by column chromatography (Silica gel, EtOAc-hexanes, 35:65) followed by evaporation of the relevant fractions. Trituration of the solid with EtOAc-MeOH afforded 4-Chloropyrrolo[3,2-d]Pyrimidine (32e) as an off-white solid, MP >150 C (dec); 1H NMR (DMSO-< 5) delta 12.43 (s, D20 exchangeable, 1H), 8.61 (s, 1H), 7.97 (dd, J = 2.8, 2.8 Hz; D20 exchange collapse to d, 1H), 6.72 (dd, J = 1.7, 3.5 Hz; D20 exchange collapse to d, 1H). 13C-NMR (DMSO-d6) 151.30, 149.58, 142.12, 134.83, 124.32, 102.70; IR (neat) 3128, 3078, 2979, 1621 cm"1; MS (ES+) 154.01 (100%, M+l) and 156.01 (33%); Analysis calculated for C6H4N3C1: C, 46.93; H, 2.63; N, 27.36; CI, 23.09; Found: C, 47.10; H, 2.79; N, 27.15; CI, 22.93. |
57% | A mixture of 3,5-dihydropyrrolo[3,2-</]pyrimidin-4-one, (1.8 g, 13.5 mmol, 1 equiv.) and 50 mL of POCI3 was warmed at reflux for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue was then diluted with 200 mL of water, made basic with solid potassium carbonate and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 1.18 g (57%) of 4-chloro-5H-pyrrolo[3,2-</]pyrimidine as a yellow solid which was used without further purification. | |
36% | Step 4: Into a 50-mL round-bottom flask was placed a solution of 3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (5 g, 35.52 mmol, 1.00 equiv, 96%) in trichlorophosphate (20 mL). The resulting solution was stirred at reflux for 1 h, concentrated under vacuum, dissolved in 100 mL of ethyl acetate, washed with 2×100 mL of 10% aqueous sodium bicarbonate and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:8) to afford 2 g (36%) of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine as a yellow solid. |
Step 4-2) 4-chloro-5H-pyrrolo[3,2-^pyrimidineTo 3,5-dihydropyrrolo[3,2-c ]pyrimidin-4-one (1.8 g), POCl3 (5 mL) was added, and refluxed while stirring. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove POCl3. Then, the reaction mixture was mixed with ethyl acetate, washed with saturated sodium bicarbonate and washed with a saline solution. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound. 1H NMR (300 MHz, DMSO- 6): delta 12.43 (s, 1 H), 8.61 (s, 1 H), 7.97 (dd, 1 H), 6.72 (dd, 1 H). to obtain the title compound as a yellowish solid (160 mg). | ||
With trichlorophosphate;Reflux; | To 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (1.8 g), POCl3 (5 mL) was added, and refluxed while stirring. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove POCl3. Then, the reaction mixture was mixed with ethyl acetate, washed with saturated sodium bicarbonate and washed with a saline solution. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound. [0208] 1H NMR (300 MHz, DMSO-d6): delta 12.43 (s, 1H), 8.61 (s, 1H), 7.97 (dd, 1H), 6.72 (dd, 1H), to obtain the title compound as a yellowish solid (160 mg). | |
With trichlorophosphate; for 1h;Reflux; | Step 2: Preparation of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine POCl3 (5 mL) was added to 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (1.8 g) and the mixture thus formed was stirred under reflux. Upon completion of the reaction, the mixture was distilled under reduced pressure to remove POCl3. The resulting mixture, to which ethyl acetate was added, was washed with sodium carbonate, and then washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): delta 12.43 (s, 1 H), 8.61 (s, 1 H), 7.97 (dd, 1 H), 6.72 (dd, 1 H). | |
With trichlorophosphate;Reflux; | POCl3 (5 mL) was added to 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (1.8 g) and the mixture thus formed was stirred under reflux. Upon completion of the reaction, the mixture was distilled under reduced pressure to remove POCl3. The resulting mixture, to which ethyl acetate was added, was washed with sodium carbonate, and then washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound. [0133] 1H NMR (300 MHz, DMSO-d6): delta 12.43 (s, 1H), 8.61 (s, 1H), 7.97 (dd, 1H), 6.72 (dd, 1H). | |
With trichlorophosphate; In acetonitrile; at 110℃; for 0.0833333h;Microwave irradiation; | General procedure: A solution of 6,7-dimethoxyisoquinolin-1(2H)-one(200 mg, 0.97 mmol), phosphoryl trichloride (0.268 mL, 2.92 mmol) inacetonitrile (5 mL) was stirred at 110 C for 5 minutes under microwaveirradiation. The reaction was quenched with a saturated aqueous sodium bicarbonatesolution and stirred at ambient temperature for 1 h. It was filtered throughcelite and washed with ethyl acetate. The filtrate was concentrated to dryness.The crude material was purified by flash chromatography, eluting with heptanesand ethyl acetate (1:0 to 0:1) to give the desired product as a gum (99 mg,45.4 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 5 : Preparation of 6-Methoxy-N-(benzyloxymethyl)-9-deazahypoxanthine (32f) To the suspension of pre -washed NaH (20 g, 500 mmol, 60% oil dispersion, washed with hexanes 2 times) in anhydrous THF (1.0 L) cooled to 4 C was added portion wise solid 4- Chloropyrrolo[3,2-d]Pyrimidine (32e) (61.4 g, 400 mmol) cautiously with stirring under N2 in portions over 10-15 min such that H2 gas evolution was controlled. After about an hour gas evolution ceased and benzyl chloromethyl ether (61 mL, 440 mmol) was added drop wise over 45 min at 4C (additional gas evolution was observed). The resulting mixture was allowed to warm to ambient temperature and stir for 1 h. The reaction mixture was cooled to 4C and quenched carefully with sodium meth oxide (93 mL, 5.4 M solution in methanol, 500 mmol). The mixture was allowed to warm to ambient temperature overnight and neutralized with glacial acetic acid (30 mL, 500 mmol) to pH 6. The mixture was concentrated and the residue triturated with water (2 x 400 mL). The aqueous layer was decanted and the residue dried in vacuum. The residue was taken in ethyl acetate (250 mL) and boiled to reflux and filtered through a fluted filter paper. The residue was boiled with ethyl acetate (2 x 100 mL) and filtered (the residue left behind is unwanted compound and doesn't move in TLC analysis 50% ethyl acetate in hexane). The filtrates were combined concentrated in vacuum to 250 mL and kept in refrigerator overnight. The brown crystals obtained was collected by filtration washed with ice cold ethyl acetate/hexane (2 x 100 mL) and dried in vacuum to furnish 6-Methoxy-N-(benzyloxymethyl)-9-deazahypoxanthine (32f) (46.64 g, 43%) as a orange brown solid, an analytical sample was prepared by recrystallization from ethyl acetate; MP 123 - 127 C; 1H NMR (DMSO-<) delta 8.44 (s, 1H), 7.86 (d, J = 3.1 Hz, 1 H), 7.31 - 7.22 (m, 5 H), 6.62 (d, J = 3.6 Hz, 1 H), 5.75 (s, 2 H), 4.49 (s, 2 H), 4.05 (s, 3 H); 13C- NMR (DMSO-<) 156.11, 151.59, 150.09, 137.82, 134.80, 128.53, 127.87, 127.77, 114.99, 103.08, 77.55, 69.95, 53.73; IR (KBr) 1602 cm"1; MS (ES+) 269.97 (M+l); Analysis calculated for Ci5Hi5N302: C, 66.90; H, 5.61; N, 15.60; Found: C, 67.09; H, 5.60; N, 15.60. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium acetate; In water; at 95℃; for 12h; | To a suspension of crude (3R, [4R)-3-HYDROXY-4- (2-] phenylethyl) pyrrolidine hydrochloride 25 (194 [MG, 0.] 85 [MMOL)] and [6-CHLORO-9-] deazapurine (118 mg, 0.76 [MMOL)] in water (2.2 mL) was added 37 % aqueous [FORMALDEHYDE (70, UL,] 0.94 [MMOL)] and sodium acetate (70 mg, 0.85 [MMOL).] The mixture was heated to [95 C] in a sealed tube under stirring for 12 h. After cooling, the dark brown slurry was diluted with 1, 4-dioxan (3 mL) and the dark brown solution preabsorbed onto silica. Column chromatography afforded the title compound as a cream [COLOURED/BROWNISH] film (104 mg, 38 [%).'H] NMR (300 MHz, MeOH-d4): [8] ppm: 8.71 (s, [1H),] 8.12 (s, 1H), 7. [17] (s, 5H), 4.55 (s, 1H), 4.18 (m, [1H),] 3.56 (m, 2H), 3.31 (m, 1. H), 3.04 (dd, J = 11.6 and 7.7 Hz, [1H),] 2.64 (m, 2H), 2.21 (m, [1H),] 1.87 (m, [1H),] 1.61 (m, [1H).] [13C] NMR (300 MHz, MeOH-d4): 8 ppm: 151.62, 151.35, 145.02, 142.99, 138.11, 129.84, 129.82, 127. 46, 126.81, 107.73, 75.68, [61.] [00,] 58.48, 49.51, 47.56, 35. [26,] 34. [88.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 120℃; for 1.5h; | Example 60 Production of ethyl 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate A mixture of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (2.78 g), ethyl 3-aminobenzoate (4.49 g) and 1-methyl-2-pyrrolidone (20 mL) was stirred at 120C for 1.5 hrs. To the reaction mixture were added ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution. The insoluble material was filtered off, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, and the mixed ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtered insoluble material was suspended in methanol and ethyl acetate and saturated brine were added. The ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixed ethyl acetate layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate) and crystallized from methanol-acetone-diisopropyl ether to give the title compound (2.85 g) as a pale-brown powder. 1H-NMR (CDCl3) delta: 1.39 (3H, t, J= 7.2 Hz), 4.37 (2H, q, J= 7.2 Hz), 6.51 (1H, d, J= 3.3 Hz), 7.28-7.32 (1H, m), 7.42 (1H, t, J= 8.0 Hz), 7.70 (1H, d, J= 7.8 Hz), 8.09 (1H, s), 8.29 (1H, d, J= 8.1 Hz), 8.49 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h; | Example 171 Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(2-methoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride <strong>[84905-80-6]4-Chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (500 mg) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (830 mg) and 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (920 mg) were added and the mixture was stirred at room temperature for 12 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=50:50 ? 0:100). The obtained oil was dissolved in isopropyl alcohol (10 mL), and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline was added. The mixture was stirred at 90C for 4 hrs, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 ? ethyl acetate:methanol=90:10), and crystallized from 4N hydrochloric acid-ethyl acetate solution/hexane to give the title compound (277 mg). 1H-NMR(DMSO-d6) delta: 3.06 (3H, s), 3.33 - 3.35 (2H, m), 3.55 - 3.61 (2H, m), 3.83 - 3.86 (2H, m), 4.83 - 4.86 (2H, m), 6.71 (1H, d, J= 3 Hz), 7.24 - 7.72 (7H, m), 7.99 - 8.04 (2H, m), 8.77 (1H, s), 9.92 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4.5h; | (i) Production of 4-chloro-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine <strong>[84905-80-6]4-Chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (1 g) was dissolved in N,N-dimethylformamide (13 mL), cesium carbonate (6.37 g) and 2-bromo-1,1-diethoxyethane (2.94 mL) were sequentially added and the mixture was stirred at 80C for 4.5 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50 ? 0/100) to give the title compound (1.26 g) as a yellow oil. 1H-NMR (CDCl3) delta 1.14 (6H, t, J= 6 Hz), 3.40 (2H, m), 3.72 (2H, m), 4.08 (1H, m), 4.56 (2H, d, J= 5 Hz), 6.71 (1H, d, J= 3 Hz), 7.55 (1H, d, J= 3 Hz), 8.69 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 140℃; for 2h; | To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (63 mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (149 mg), and the mixture was heated to 140C and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with a mixed solvent (25 mLx3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0 ? 8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (112 mg) as pale-yellow powder crystals. 1H-NMR (DMSO-d6) delta 5.27 (2H, s), 6.48 (1H, d, J= 2.4 Hz), 7.25 (1H, d, J= 8.7 Hz), 7.37 (1H, dd, J= 5.1, 7.5 Hz), 7.55-7.60 (2H, m), 7.66 (1H, s), 7.89 (1H, t, J= 7.5 Hz), 8.20 (1H, dd, J= 1.5, 2.4 Hz), 8.35 (1H, d, J= 1.5 Hz), 8.60 (1H, dd, J= 0.6, 4.8 Hz), 9.25 (1H, s), 12.78 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | (i) Production of {4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol <strong>[84905-80-6]4-Chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (307 mg) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (304 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture was stirred at room temperature for 16 hrs. After diluting with water (30 mL), the mixture was extracted with ethyl acetate/tetrahydrofuran (3:1, 80 mL*2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 ? 0:100) to give the title compound (383 mg) as a powder. 1H-NMR(CDCl3) delta: 2.15 (1H, br s), 4.69 (2H, d, J= 4 Hz), 5.71 (2H, s), 6.76 (1H, m), 7.06 (2H, d, J= 8 Hz), 7.34 (2H, d, J= 8 Hz), 7.50 (1H, d, J= 3 Hz), 8.69 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 96h; | (i) Production of 5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g), 5-<strong>[15848-22-3]bromopentyl acetate</strong> (0.71 mL), cesium carbonate (1.59 g) and N,N-dimethylformamide (5.0 mL) was stirred at 40C for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:3 ? 6:4) to give the title compound (637 mg) as a white solid. 1H-NMR (CDCl3) delta: 1.33-1.46 (2H, m), 1. 61-1. 72 (2H, m), 1.84-1.97 (2H, m), 2.04 (3H, s), 4.05 (2H, t, J= 6.6 Hz), 4.48 (2H, t, J= 7.5 Hz), 6.71 (1H, d, J= 3.3 Hz), 7.46 (1H, d, J= 3.3 Hz), 8.69 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 80℃; for 4h; | Example 66 Production of [2-(benzyloxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)phenyl]methanol A mixture of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (307 mg), [5-amino-2-(benzyloxy)phenyl]methanol (459 mg) and N,N-dimethylformamide (10 mL) was stirred at 80C for 4 hrs. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 ? 30:70). Ethanol and ethyl acetate were added and the precipitate was collected by filtration to give the title compound (279 mg) as a brown powder. 1H-NMR (DMSO-d6) delta: 4.60 (2H, d, J= 5.5 Hz), 5.12 (2H, s), 5.17 (1H, t, J= 5.5 Hz), 6.45 (1H, m), 7.03 (1H, d, J= 8.8 Hz), 7.29-7.51 (5H, m), 7.62 (1H, t, J= 2.9 Hz), 7.65 (1H, d, J= 2.7 Hz), 7.93 (1H, dd, J= 8.8, 2.7 Hz), 8.29 (1H, s), 9.08 (1H, s), 11.05 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 80℃; for 4h; | Example 67 Production of N-[4-(benzyloxy)-3-methoxyphenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine A mixture of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (200 mg), 4-(benzyloxy)-3-methoxyaniline (298 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 80C for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=10:80 ? 20:80) and recrystallized from methanol-ethyl acetate to give the title compound (269 mg) as a pale-gray powder. 1H-NMR (DMSO-d6) delta: 3.82 (3H, s), 5.06 (2H, s), 6.45 (1H, m), 7.03 (1H, d, J= 8.9 Hz), 7.30-7.49 (6H, m), 7.51 (1H, d, J= 2.5 Hz), 7.63 (1H, t, J= 2.9 Hz), 8.30 (1H, s), 9.07 (1H, s), 11.06 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 140℃; for 2.5h; | Example 1 Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride <strong>[84905-80-6]4-Chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (770 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.52 g) were dissolved in 1-methyl-2-pyrrolidone (10 mL), and the mixture was stirred with heating at 140C for 2.5 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL), and stirred at room temperature for 1 hr. The precipitated powder was collected by filtration, washed with ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (1.62 g). 1H-NMR(DMSO-d6) delta: 5.27 (2H, s), 6.63 (1H, d, J= 3 Hz), 7.0-7.5 (5H, m), 7.78 (1H, dd, J= 3 Hz,9 Hz), 8.00 (1H, m), 8.15 (1H, d, J= 3 Hz), 8.79 (1H, s), 11.79 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 80℃; for 4h; | Example 68 Production of N-[4-(benzyloxy)-3-chlorophenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine A mixture of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (200 mg), 4-(benzyloxy)-3-chloroaniline (365 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 80C for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 ? 15:75) and recrystallized from ethanol-ethyl acetate to give the title compound (226 mg) as a pale-brown powder. 1H-NMR (CDCl3) delta: 5.15 (2H, s), 6.56 (1H, s), 6.98 (1H, d, J= 8.9 Hz), 7.28-7.43 (4H, m), 7.48 (2H, d, J= 7.5 Hz), 7.69 (1H, d, J= 8.9 Hz), 7.80 (1H, d, J= 2.6 Hz), 8.50 (1H, s), 8.63 (1H, s), 10.56 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h; | A mixture of 4-chloro-5H-pyrrolo [3,2-d]pyrimidine (923 mg, 6.00 mmol), 2-bromoethylmethylether (877 mg, 6.31 mmol), cesium carbonate (3.91 g, 12.0 mmol) and N,N-dimethylformamide (50 mli) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chi3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane=l/l solution to give the title compound (1.21 g, 96%) as a yellow solid.1H-NMR (DMSO-d6, 300 MHz) delta 3.19 (3H, s) , 3.68 (2H, t, J = 5.4 Hz), 4.65 (2H, t, J = 5.4 Hz), 6.71 - 6.72 (IH, m) , 7.97 (IH, d, J = 3.3 Hz), 8.60 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With caesium carbonate; In N,N-dimethyl-formamide; | Intermediate 2 4-Chloro-5-ethyl-pyrrolo[3,2-d]pyrimidine To a soiution of 4-chloro-5H-pyrroio[3,2-d]pyrimidine (150mg, 0.98mmol) and caesium carbonate (637mg, 1.96mmol) in DMF (5ml) was added bromoethane (128mg, 1. 8mmo) and stirred overnight. The mixture was diluted with EtOAc and washed with water (x3). The organic phase was separated, dried and concentrated to give a brown solid <156mg, 88%); 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 146 (t, J=7.3 Hz, 3 H), 4.50 (q, J=6.9 Hz, 2 H), 6.66 (d, J=3.2 Hz, 1 H), 7.47 (d, J=3.2 Hz, 1 H), 8.63 (s, 1 H); LC-MS (ESI): (MH+) 182 / 184 |
63% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | A mixture of 4-chloro-5H-pyrrolo [3, 2-d]pyrimidine (1075 mg, 7.0 mmol) , bromoethane (915 mg, 8.4 mmol), cesium carbonate (3421 mg, 10.5 mmol) and N,N-dimethylformamide (10 ITiL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate (chi3) . The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50_>0/100) to give the title compound (806 mg, 63%) as a yellow solid.1H-NMR (DMSOd6, 300 MHz) delta 1.41 (3H, t, J = 7.1 Hz), 4.53 (2H, q, J = 7.1 Hz), 6.74 (IH, d, J = 3.2.Hz), 8.08 (IH, d, J = 3.2 Hz) , 8.62 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 93h; | A mixture of 4-chloro-5H-pyrrolo [3, 2-d]pyrimidine (1.54 g, 10.0 iranol) , <strong>[683-57-8]2-bromoacetamide</strong> (1.51 g, 10.9 mmol) , cesium carbonate (3.58 g, 11.0 mmol) and N,N-dimethylformamide (13 mL) was stirred at room temperature for 69 hr. Cesium carbonate (1.30 g, 3.99 mmol) was added, and the reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chi7) . The organic layers were combined, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure to give the title compound (1.81 g, 86%) as a yellow solid.1H-NMR (DMSOd6, 300 MHz) delta 5.14 (2H, s) , 6.73 (IH, d, J = 3.3 Hz), 7.30 (IH, br s) 7.68 (IH, br s) , 7.95 (IH, d, J = 3.3 Hz) , 8.61 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | A mixture of 4-chloro-5H-pyrrolo [3, 2-d] pyrimidine (768 EPO <DP n="116"/>nag, 5.0 mmol) , l-bromo-2- (2-methoxyethoxy) ethane (90%, 1000 mg, 4.9 mmol), cesium carbonate (2118 mg, 6.5 mmol) and N, N- dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water and 5 extracted with ethyl acetate (chi3) . The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=90/10_>0/100) to give the title compound (1173 mg, 93%) as a pale-yellow oil.10 1H-NMR (CDCl3, 300 MHz) delta 3.31 (3H, s), 3.40 - 3.50 (2H, m) , 3.50 - 3.60 (2H, m) , 3.88 (2H, t, J = 5.1 Hz), 4.74 (2H, t, J = 5.1 Hz), 6.86 (IH, d, J = 3.3 Hz), .7.74 (IH, d, J = 3.3 Hz), 8.76 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h; | A mixture of 4-chloro-5H-pyrrolo [3, 2-d] pyrimidine (2.30 g, 15 mmol), 2-iodopropane (2.81 g, 16.5 mmol), cesium carbonate (9.77 g, 30 mmol) and N, N-dimethylformamide (15 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10->0/100) to give the title compound (2.20 g, 75%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz) delta 1-53 (6H, d, J = 6.7 Hz), 5.41 (IH, EPO <DP n="123"/>sept, J = 6. 7 Hz ) , 6. 80 ( IH, d, J = 3 .2 Hz) , 8 .24 ( IH, d, J = 3 .2 Hz ) , 8 . 62 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 18h; | A mixture of 4-chloro-5H-pyrrolo [3, 2-d]pyrimidine (3,07 g, 20 mmol), <strong>[17609-80-2]4-amino-3-chlorophenol</strong> (3.44 g, 24 mmol), EPO <DP n="122"/>potassium carbonate (8.29 g, 60 mmol) and N-methylpyrrolidone (20 mL) was stirred at 1200C for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=70/30-»0/100) and recrystallized from ethyl acetate to give the title compound (2.31 g, 44%) . 1H-NMR (DMSO-de, 300 MHz) delta 5.33 (2H, s) , 6.61 (IH, d, J = 3.0 Hz), 6.85 (IH, d, J = 8.7 Hz), 6.99 (IH, dd, J = 8.7, 2.7 Hz), 7.21 (IH, d, J = 2.7 Hz), 7.77 (IH, d, J = 3.0 Hz), 8.30 (IH, s) , 12.26 (IH, br s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h; | A mixture of 4-chloro-5H-pyrrolo [3, 2-d]pyrimidine (5.01 g, 32.5 mmol) , <strong>[66-27-3]methyl methanesulfonate</strong> (3.07 g, 34.2 mmol) , cesium carbonate (21.2 g, 65.2 mmol) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chi3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The' filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane=l/l solution to give the title compound (4.36 g, 80%) as a yellow solid. 1H-NMR (DMSOd6, 300 MHz) delta 4.09 (3H, s) , 6.67 - 6.68 (IH, m) , EPO <DP n="113"/>7 . 95 ( IH, d, J = 3 . 0 Hz ) , 8 . 57 ( IH, s ) . |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | 4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (4.00 g) was dissolved in N,N-dimethylformamide (100 mL), <strong>[66-27-3]methyl methanesulfonate</strong> (2.5 mL) and potassium carbonate (6.03 g) were added, and the mixture was stirred at room temperature for 18 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (hexane:ethyl acetate=95:5?50:50) to give the title compound (3.00 g) as white crystals. 1H-NMR (CDCl3) delta: 4.16 (3H, s), 6.70 (1H, d, J = 3.0 Hz), 7.42 (1H, d, J = 3.0 Hz), 8.69 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 1h; | To a solution of 3-methoxy-4-nitrophenol (250 mg, 1.48 mmol) in methanol (10 mL) was added palladium carbon (50% water-containing product, 25 mg) , and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and dried, ands the residue was dissolved in N-methylpyrrolidone (3 mL) . Potassium carbonate (613 mg, 4.44 mmol) and 4-chloro-5H-pyrrolo [3, 2- d] pyrimidine (216 mg, 1.40 mmol) were added, and the mixture was stirred at 1100C for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chi3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate/hexane=l0/90->100/0) . The residue was dissolved in tetrahydrofuran (7 mL) , and triethylamine (77.0 muL, 0.555 mmol) and 3- (trifluoromethyl) phenylisocyanate (31.0 muL, 0.222 mmol) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chi3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate/hexane=10/90_>100/0) and recrystallized from ethyl acetate-hexane to give the title compound (11.0 mg, 2%) as a EPO <DP n="218"/>white solid.1H-NMR (DMSCHd6, 300 MHz) delta 3.88 (3H, s) , 6.63 (IH, d, J = 3.2 Hz), 6.84 (IH, dd, J = 8.9, 2.2 Hz), 7.05 (IH, d, J = 2.2 Hz), 7.28 - 7.37 (IH, m) , 7.50 - 7.58 (2H, m) , 7.79 (IH, d, J = 3.2 Hz), 8.05 (IH, s), 8.14 (IH, d, J = 8.9 Hz), 8.30 - 8.34 (2H, m) , 9.67 (IH, s), 12.29 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrogenchloride; In diphenylether; diethyl ether; at 120 - 200℃; for 4h; | To a suspension of 27 (0,400g, 2,60mmol) FG.B. Evans. R.H. Furneaux, et.al J.Ore. Chem.. 2001, 66. 17. 5723-5730] in diphenylether (25ml) was added 2-fluoro-4-nitrophenol (614 mg, 3.90mmol) and HC1 (2N in Et2O) (0.19 ml, 3.90mmol). The reactionmixture was heated at 120C for 4 hours, cooled to room temperature and concentratedunder reduced pressure, to afford title compound 243 (610 mg, 86% yield) as a black solid.MS(m/z):274.1(M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 15h; | A mixture' of 4-chloro-5H-pyrrolo [3, 2-d]pyrimidine (2.13 g, 13.9 mmol), 2-(2-[(4- methylphenyl) sulfonyl] oxy} ethoxy) ethyl benzoate (4.19 g, 14.6 mmol), cesium carbonate (9.02 g, 27.7 mmol) and N, N- EPO <DP n="115"/>dimethylformaralphaide (25 mL) was stirred at 600C for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chi3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80-»100/0) to give the title compound (3.73 g, 78%) . 1H-NMR (DMSO-d6, 300 MHz) delta 3.66 - 3.69 (2H, m) , 3.82 - 3.86 (2H, m) , 4.27 - 4.30 (2H, m) , 4.65 - 4.68 (2H, m) , 6.60 (IH, d, J = 3.0 Hz), 7.46 - 7.51 (2H, m) , 7.61 - 7.66 (IH, m) , 7.80 - 7.84 (2H, m) , 7.95 (IH, d, J = 3.0.Hz) , 8.56 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | Production of 5-(2-[tert- butyl (dimethyl) silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2- d] pyrimidine4-Chloro-5H-pyrrolo [3, 2-d] pyrimidine (2.00 g) , (2- bromoethoxy) ( tert-butyl ) dimethylsilane (4.00 g) and cesium carbonate (6.40 g) were dissolved in N,N- dimethylformamide (10 mL) and the mixture was stirred at room temperature for 4 hr. Under ice-cooling, brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20: 80?40: 60) to give the title compound (3.02 g) as a brown solid.1H-NMR (DMSO-d6) delta: -0.24 (6H, s), 0.69 (9H, s), 3.90- 3.93 (2H, m) , 4.61-4.64 (2H, m) , 6.76 (IH, s), 8.00 (IH, s) , 8.61 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.333333h; | To a room temperature solution of 4-chloro-5H-pyrrolo[3,2-</]pyrimidine (1.2 g, 7.8 mmol, ) and allyl bromide in 40 mL of DMF was added 60% sodium hydride (625 mg, 15.6 mmol, 2 equiv.) in several portions. After 20 minutes, the reaction was quenched with water and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide 1.3 g (88%) of 5-allyl-4-chloro-5H-pyrrolo[3,2-T|pyrimidine as a yellow oil which was used without further purification. |
86% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.333333h;Inert atmosphere; | <strong>[84905-80-6]4-Chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (1.20 g, 7.81 mmol), 3-bromoprop-1-ene (1.86 g, 15.4 mmol), and DMF (40 mL) were added to a 100-mL round-bottom flask fitted with a nitrogen inlet and magnetic stir bar. Sodium hydride (625 mg, 26.0 mmol) was added in portions and the resulting solution was stirred for 20 min at room temperature. The reaction was then quenched by the addition of water (40 mL) and extracted with ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography eluting with ethyl acetate/petroleum ether (3:10, v/v) to afford 5-allyl-<strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (1.30 g, 86%). LCMS: (ESI) m/z 194 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium acetate;bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; In water; butan-1-ol; at 100℃; for 1h; | A mixture of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (0.500 g, 3.26 mmol), 2- fluoropyridin-3-ylboronic acid (0.688 g, 4.88 mmol) and potassium acetate (0.959 g, 9.77 mmol) in 1-butanol (25 mL) and water (5 mL) was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2(P1Bu2Ph)2 (0.0243 g, 0.0391 mmol) was added.The reaction mixture was stirred in a 100 0C oil bath for 60 min. The brown solution was concentrated in vacuo to a solid residue. The residue was treated with 3:1 CHC^rlPA (100 mL) and water (7O mL). The mixture was sonicated and the layers separated. The aqueous phase was extracted with 3:1 CHC^IPA (50 mL). The combined organic extracts were washed with water (3 x 70 mL), brine (50 mL), dried over Na2Stheta4, filtered and concentrated in vacuo to give 0.74 g crude product as a yellow solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 80% to 100% EtOAc in CH2Cl2, to provide 4-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (0.51 g, 73% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 215 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of <strong>[84905-80-6]4-chloropyrrolo[3,2-d]pyrimidine</strong> (2.0 g) in tetrahydrofuran (25 ML) was treated with sodium hydride and benzyl chloromethyl ether as described in Example 3.1.. benzyl alcohol (4 ML) was added followed by more sodium hydride (0.8 g, 60% dispersion) and the resulting mixture was stirred at room temperature for 3 h, then partitioned between chloroform and water.. The organic phase was processed normally and the benzyl alcohol was distilled off under high vacuum (bath temperature 150 C.).. The crude residue was treated with N-bromosuccinimide and isolated as described in Example 3.1 to give 4-benzyloxy-5-N-benzyloxymethyl-7-bromopyrrolo[3,2-d]pyrimidine (2.27 g) as a solid. 13C NMR (CDCl3) delta 156.3, 151.3, 149.1, 137.0, 136.3, 132.1, 129.1, 128.8, 128.7, 128.4, 127.9, 115.9, 92.7, 78.0, 71.0, 68.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Scheme 31Sodium hydride (60% dispersion in mineral oil, 2.38 g, 59.4 mmol) is added to a suspension of 4-chloro-5 - -pyrrolo[3,2-d]pyrimidine (152) (4.56 g, 29.7 mmol) in THF (70.0 mL, 854 mmol) at 0 C and the mixture is stirred at 0 C for 20 min. Benzyl chloromethyl ether (8.95 mL, 38.6 mmol) is added dropwise and the mixture is warmed to ambient temperature and stirred for 1 h.t-Butanol (20.0 mL) and DMF (20.0 mL) are added followed by NaH (60% dispersion in mineral oil, 2.38 g, 59.4 mmol) and the reaction mixture is stirred at ambient temperature for 18 h. The reaction mixture is quenched with water (50.0 mL) and the THF is removed under reduced pressure. Water (150 mL) and EtOAc (100 mL) are added and the biphasic mixture is filtered through Celite, separated and the organic phase is dried, and concentrated under reduced pressure. The crude product is purified by flash chromatography (8:2 to 1 :1 v/v petroleum ether-EtOAc) to give the 5-[(benzyloxy)methyl]- 4-(terf-butoxy)-5H-pyrrolo[3,2-c/]pyrimidine (153) as a pale yellow solid (4.00 g, 43%). | |
5-N-Benzyloxymethyl-7-bromo-4-tert-butoxypyrrolo[3,2-d]pyrimidine A suspension of <strong>[84905-80-6]4-chloropyrrolo[3,2-d]pyrimidine</strong> (5.0 g) in tetrahydrofuran (100 ML) was treated with sodium hydride and benzyl chloromethyl ether as described in Example 3.1.. Dry N,N-dimethylformamide (20 ML) and tert-butanol (20 ML) were added followed by more sodium hydride (2.0 g, 60% dispersion) and the resulting mixture was stirred at room temperature for 16 h, then partitioned between chloroform and water.. The organic phase was processed normally and the crude product was treated with N-bromosuccinimide and isolated as described for the equivalent product in Example 3.1 to give 5-N-benzyloxymethyl-7-bromo-4-tert-butoxypyrrolo[3,2-d]pyrimidine (5.8 g) as a solid. 13C NMR (CDCl3) delta 156.3, 151.1, 148.7, 137.1, 131.4, 128.9, 128.4, 127.8, 117.0, 92.6, 84.0, 77.6, 70.5, 29.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (11.5 g), prepared according to Example 2, was converted into <strong>[84905-80-6]4-chloropyrrolo[3,2-d]pyrimidine</strong> as described in Imai, K., Chem. Pharm. Bull . , 1964, 12, 1030-1042.. A suspension of 4-chloropyrrolo[3,2-d]-pyrimidine (6.94 g) in dry tetrahydrofuran (100 ml) was stirred with cooling in an ice bath while sodium hydride (60%, 2.17 g, 1.2 eq) was added slowly.. Then benzyl chloromethyl ether (7.1 ml) was added slowly with cooling and the resulting mixture was stirred at room temperature for 0.5 h.. methanol (25 ml) was added carefully and the resulting solution was cooled in an ice bath while sodium hydride (60%, 1.81 g) was added slowly and then allowed to warm to room temperature.. The solvents were removed, the residue was dissolved in chloroform and washed with water, then processed normally.. The crude product in methylene chloride (50 ml) was treated with N-bromosuccinimide (8.0 g) and the solution stirred at room temperature for 0.5 h.. The solution was evaporated and chromatography of the residue afforded 5-N-benzyloxymethyl-7-bromo-4-methoxypyrrolo[3,2-d]pyrimidine (7.0 g).. 13C NMR (CDCl3) delta 156.8, 151.4, 148.8, 136.9, 131.9, 128.9, 128.5, 128.1, 116.0, 92.8, 77.6, 70.8, 54.2. | ||
2.36 g | Step 1: (0692) To a suspension of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (1.53 g, 10.0 mmol) in 30 mL of THF was added NaH (560 mg, 14.0 mmol, 60% in mineral oil) by portion under N2. After the mixture was cooled to 0 C., benzyl chloromethyl ether (1.71 mL, 13.0 mmol) was added. Then the mixture was stirred at RT for 1 h (monitored by TLC 40% EtOAc/Hex). 8 mL of anhydrous MeOH was added into the reaction mixture followed by NaH (400 mg, 10.0 mmol, 60% mineral oil) by portion. The resulting mixture was stirred at RT overnight. After being quenched with sat. NH4Cl, the mixture was extracted with EtOAc (3×). The organic layer was washed with sat.NaHCO3 (aq), brine, then dried (MgSO4) and concentrated. Silica gel chromatography (elution with 0-30% EtOAc/Hex) afforded product 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (2.36 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In ethanol; at 60℃; for 16h; | N-(4-Methoxybenzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (15); 4-Chloro-5H-pyrrolo[3,2-cdpyrinnidine (4.68 g, 30.5 mmol) and 4-methoxybenzylamine (11.94 mL, 91 mmol) were heated at 60 0C in EtOH (50 mL) for 16 h. The solvent was evaporated and the residue chromatographed on silica gel (CH2CI2-MeOH, 97:3 ? 95:5) to give the crude product as an oily solid which was triturated with Et2O and the resulting solid filtered off and dried (~5 g). Recrystallization from MeOH-water gave N- (4-methoxybenzyl)-5/-/-pyrrolo[3,2-cdpyrimidin-4-amine as a tan coloured solid (3.37 g, 44%). An analytical sample was obtained by recrystallization once more from MeOH. 1H NMR (300 MHz, (I6-DMSO, TMS) delta 10.90 (br.s, 1H), 8.20 (s, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.36-7.29 (m, 3H), 6.92 (d, J = 8.6 Hz, 2H), 6.37 (d, J = 2.8 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 3.73 (s, 3H). 13C NMR (75.5 MHz, Qf6-DMSO, solvent delta 39.7) delta 158.6 (C), 150.4 (CH), 149.4 (C), 146.8 (C), 131.7 (C), 129.2 (CH), 127.6 (CH), 114.0 (CH), 113.9 (C), 101.6 (CH), 55.3 (CH3), 43.0 (CH2). +ESI-MS CaIc. for C14H15N4O [M+H]+ 255.1246 found 255.1240. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In ethanol; for 6h;Heating / reflux; | lambdaM3enzyl-5tf-pyrrolo[3,2-d]pyrimidin-4-amine (18); A solution of chloride 1 (4.6 g, 30.0 mmole) and benzylamine (12.84 g, 120 mmol, 4 eq) in ethanol (50 ml_) was heated at reflux for 6 h. The ethanol was removed under reduced pressure and the residue taken up in acetonitrile and filtered. The filtrate was concentrated under reduced pressure and then most of the benzylamine removed by heating at 150 0C under vacuum (15 mm Hg). The residue was further purified by elution through a column of silica gel with dichloromethane-methanolic ammonia (3.5 M), 19:1 and 9:1 and then crystallised from acetonitrile to give benzyideazaadenine 18(P. Capek, M. Otmar, M. Masojidkova, I. Votruba and A. Holy, Collect. Czech. Chem.Commun., 2003, 68, 779-791) (4.2 g, 18.7 mmol, 63%) as an off-lambda/vhite solid. 1H NMR(300 MHz, DMSO-Cf6, TMS) delta 10.93 (s, 1H), 8.16 (s, 1H), 7.6-7.2 (m, 7H), 6.37 (s, 1H),4.72 (m, 2H). 13C NMR (75.5 MHz, DMSO-Cf6, solvent delta 39.8 ppm) delta 150.5, 149.6, 146.9, 140.0, 128.8, 127.9, 127.9, 127.3, 114.0, 101.8, 43.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | 4-(Benzyloxy)-5H-pyrrolo[3,2-d]pyrimidine (2). To benzyl alcohol (5 ml_) stirred under Ar and cooled with a water bath was added sodium hydride (250 mg, 60% in mineral oil, 6.25 mmol). After all sodium hydride had reacted, <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (1) (720 mg, 4.68 mmol) was added and the mixture heated to 90 0C overnight then the majority of the benzyl alcohol removed by distillation (bath temp 90 C, 0.1 mmHg). The brown residue was diluted with water and then extracted with ethyl acetate (2x). The ethyl acetate extracts were washed with brine, dried and then concentrated under reduced pressure. Purification of the residue by flash chromatography, eluting with ethyl acetate/petroleum ether 1 :1 , afforded title compound 2 as a colourless crystalline solid (744 mg, 71%). mp 159-160 0C. 1H NMR (300 MHz, CDCI3, TMS) delta 9.41 (br s, 1H), 8.57 (s, 1 H)1 7.48-7.28 (m, 6H), 6.67 (dd, J = 3.1, 2.2 Hz, 1 H)1 5.58 (s, 2H). 13C NMR (75 <n="34"/>MHz, CDCI3, solvent centre line delta 77.0) delta 155.4, 150.5, 150.0, 136.2, 128.6, 128.5, 128.4, 128.3, 115.1 , 103.2, 67.8. +ESI-MS calcd for [M+Hf C13H12N3O1: 226.0980; Found: 226.0975. Anal, calcd. for C13H11N3O1: C, 69.32; H, 4.92; N, 18.66; Found: C, - 69.05; H, 5.01 ; N, 18.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | (i) Production of 4-chloro-5-[2-(methylsulfonyl)ethyl]-5H-pyrrolo[3,2-d]pyrimidine A mixture of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (497 mg), methylvinylsulfone (0.43 mL), cesium carbonate (1.63 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1?1:4) to give the title compound (185 mg) as a pale-yellow powder. 1H-NMR (CDCl3) delta: 2.79 (3H, s), 3.60 (2H, t, J=6.5 Hz), 5.02 (2H, t, J=6.5 Hz), 6.79 (1H, d, J=3.2 Hz), 7.64 (1H, d, J=3.2 Hz), 8.75 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a solution of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (1.0 g), 1-bromo-2-chloroethane (930 mg) in N,N-dimethylformamide (25 mL) was added potassium carbonate (1.5 g), and the mixture was stirred at room temperature for 2 hr. Saturated brine was added to the reaction system under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:0?1:1) to give the title compound (806 mg) as yellow crystals. 1H-NMR (DMSO-d6) delta: 3.97-4.06 (2H, m), 4.65-4.76 (2H, m), 6.51 (1H, d, J = 3.0 Hz), 7.72 (1H, d, J = 3.0 Hz), 8.74 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a solution of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (1.0 g), 1-bromoacetone (890 mg) in N,N-dimethylformamide (25 mL) was added potassium carbonate (1.5 g), and the mixture was stirred at room temperature for 2 hr. Saturated brine was added to the reaction system under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:0?1:1) to give the title compound (406 mg) as yellow crystals. 1H-NMR (DMSO-d6) delta: 2.15 (3H, s), 5.30 (2H, br s), 6.51-6.68 (1H, m), 7.78 (1H, d, J = 3.0 Hz), 8.72 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (100 mg) and 3-chloro-4-(1H-indol-4-yloxy)aniline (277 mg) was dissolved in isopropyl alcohol (5 mL), pyridine hydrochloride (5 mg) was added, and the mixture was stirred at 80C for 8 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=10:90?0:100?ethyl acetate:methanol=90:10), and crystallized from diisopropyl ether/ethyl acetate to give the title compound (125 mg) as colorless crystals. 1H-NMR (DMSO-d6) delta: 6.30 (1H, t, J = 2.1 Hz), 6.41 (1H, d, J = 7.5 Hz), 6.50 (1H, dd, J = 1.7 Hz, 2.7 Hz), 6.93-7.10 (2H, m), 7.19 (1H, d, J = 8.1 Hz), 7.31 (1H, t, J = 2.7 Hz), 7.57 (1H, dd, J = 2.7 Hz, 8.9 Hz), 7.69 (1H, t, J = 2.7 Hz), 8.32-8.44 (2H, m), 9.41 (1H, s), 11.12 (1H, br s), 11.28 (1H, br s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | To a stirred solution of 4-chloro-5No.-pyrrolo[3,2-d]pyrimidine (27) (J. Org.Chem., 2001, 66, 17, 5723-5730) (643 mg, 4.15 mmol) inDMF (41 mL) was added NaH(60% in mineral oil, 330 mg, 8.3 mmol) in one portion at 0C and the mixture was stirredfor 1 h followed by addition of methyl iodide (0.28 mL, 4.5 mmol). The reaction mixturewas allowed to warm up to the room temperature, stirred for an additional hour andquenched with AcOH (1 mL) to form a suspension which was stirred for 10 min andconcentrated under reduced pressure to give a solid. This material was dissolved in AcOEt,the solution was washed with cold saturated NaHCO3 solution and water, dried overNaaSO^ and concentrated to produce the title compound 28 as a pale yellow solid (640 mg,93%yield). .HNMR (400 MHx, CD3OD) 8(ppm): 8.51 (s, 1H), 7.75 (d, J = 3.3 Hz, 1H),6.62 (d, J = 3.3 Hz, 2H), 4.15 (s, 1H). LRMS (M+l) 168.1 (100%), 170.1 (34%). | |
85% | Intermediate 1 4-Chloro-5-methyl-pyrrolo[3,2-d]pyrimidine To a solution of sodium hydride (60% dispersion in mineral oil) (1.625g, 42mmol) in THF (75ml), at 0C, was added 4-chloro-5H-pyrrolo [3,2-d]pyrimidine (5g, 32mmol) and stirred for 1 hour, iodomethane (3.046mi, 49mmol) was added and the mixture stirred overnight. The mixture was concentrated, taken up in EtOAc and washed with water. The organic layer was separated, dried and concentrated to an orange solid (4.63g, 85%); 1H NMR (400 MHz, DMSO-c/6) delta ppm 4.07 (s, 3 H), 6.66 (d, J=3.20 Hz, 1 H), 7.94 (d, J=3.21 Hz, 1 H), 8.56 (s, 1 H); LC-MS (ESI): (MH+) 168 / 170. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In tetrahydrofuran; for 1h; | Step 4-3) 7-bromo-4-chloro-5H-pyrrolo["3,2-dlpyrimidine To 4-chloro-5H-pyrrolo[3,2-i/]pyrimidine (100 mg), tetrahydrofuran (5 mL) was added, and N-bromosuccinimide (116 mg) was further added thereto, followed by stirring for 1 hour. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound. 'H NMR (300 MHz, DMSO-i¼): delta 12.95 (s, 1 H), 8.71 (s, 1 H), 8.24 (d, 1 H). | |
With N-Bromosuccinimide; In tetrahydrofuran; for 1h; | To 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg), tetrahydrofuran (5 mL) was added, and N-bromosuccinimide (116 mg) was further added thereto, followed by stirring for 1 hour. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound. [0211] 1H NMR (300 MHz, DMSO-d6): delta 12.95 (s, 1H), 8.71 (s, 1H), 8.24 (d, 1H) | |
With N-Bromosuccinimide; In tetrahydrofuran; for 1h; | Step 3: Preparation of 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine Tetrahydrofuran (5 mL) and N-bromosuccinimide (116 mg) were added to 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg). The mixture was stirred for 1 hr and, upon completion of the reaction, ethyl acetate was added thereto, and washed with water. The mixture was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): delta 12.95 (s, 1 H), 8.71 (s, 1 H), 8.24 (d, 1 H) |
With N-Bromosuccinimide; In tetrahydrofuran; for 1h; | Step 3: Preparation of 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine Tetrahydrofuran (5 mL) and N-bromosuccinimide (116 mg) were added to 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg). The mixture was stirred for 1 hr and, upon completion of the reaction, ethyl acetate was added thereto, and washed with water. The mixture was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): delta 12.95 (s, 1H), 8.71 (s, 1H), 8.24 (d, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Example 169 2-(1-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one To a solution of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (0.100 g, 0.653 mmoles) in DMF (4 ml), cesium carbonate (0.425 g, 1.30 mmoles) was added and stirred at RT for 10 min. To this mixture intermediate 36 (0.455 g, 1.30 mmoles) was added and stirred for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid (0.080 g, 29% yield). MP: 166-168 C. 1H-NMR (delta ppm, CDCl3, 400 MHz): delta 8.66 (s, 1H), 8.24 (dd, J=7.9, 1.4 Hz, 1H), 7.86 (d, J=3.4 Hz, 1H), 7.78 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.30 (m, 2H), 7.09 (dt, J=8.5, 2.0 Hz, 1H), 6.80 (d, J=3.4 Hz, 1H), 6.74 (m, 1H), 6.50 (q, J=7.1 Hz, 1H), 1.99 (d, J=7.1 Hz, 3H). Mass: 419.89 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | In 1-methyl-pyrrolidin-2-one at 100℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / N,N-dimethyl-formamide / 96 h / 40 °C 2: isopropyl alcohol / 12 h / 80 °C 3: hydrogenchloride / tetrahydrofuran; water / 20 h / 60 °C 4: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide / 72 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In 1-methyl-pyrrolidin-2-one at 100℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium diacetate; potassium carbonate; triphenylphosphine; In ethanol; at 80℃; for 3h;Inert atmosphere; | A mixture of Pd(OAc)2 (20 mg, 0.10 mmol), PPh3 (100 mg, 0.250 mmol), potassium 2-furyltrifluoroborate (390 mg, 2.13 mmol), K2CO3 (450 mg, 3.20 mmol), and <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (280 mg, 1.83 mmol) (15b) in EtOH (50 mL, 96%) was stirred at 80 C for 3 h under Ar, and evaporated in vacuo. The product was purified by flash chromatography on silica gel eluting with acetone/hexane (2:3); yield 260 mg (78%), mp 160-162 C, colorless solid. 1H NMR (DMSO-d6, 300 MHz) delta 11.86 (s, 1H, NH), 8.80 (s, 1H, H-2), 8.04 (dd, J=1.8, 0.8 Hz, 1H, H-5 in furyl), 7.90 (d, J=3.1 Hz, 1H, H-6), 7.47 (dd, J=3.5, 0.8 Hz, 1H, H-3 in furyl), 6.82 (dd, J=3.5, 1.8 Hz, 1H, H-4 in furyl), 6.67 (dd, J=3.1, 1.7 Hz, 1H, H-7); 13C NMR (DMSO-d6, 75 MHz) delta 152.2 (C-2 in furyl or C-3a), 152.0 (C-2 in furyl or C-3a), 150.8 (C-2), 146.7 (C-5 in furyl), 138.9 (C-4), 135.0 (C-6), 121.4 (C-3b), 113.5 (C-4 in furyl), 113.2 (C-3 in furyl), 102.3 (C-7); MS EI m/z (rel %) 185 (100, M+), 157 (27), 129 (9), 118 (7), 103 (6); HRMS (EI) calcd for C10H7N3O: 185.0589. Found 185.0589. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 130℃; | Example 147(S)-N-(1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine 147Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (8 mL), <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> from Example 20 (155 mg, 0.99 mmol, 0.99 equiv, 98%) and N-ethyl-N-isopropylpropan-2-amine (400 mg, 3.03 mmol, 3.02 equiv, 98%). The resulting solution was stirred overnight at 130 C. and concentrated under vacuum. The residue was purified by applying onto a C18 column eluted with water/acetonitrile (95:5-20:80) to afford 150 mg (41%) of 147 as a light-yellow solid. LC-MS (ES, m/z): 355 [M+H]+. 1H-NMR (300 MHz, CD3OD, ppm): delta 8.49 (s, 1H), 7.85-7.48 (m, 9H), 7.32-7.30 (m, 1H), 6.63 (d, 1H), 5.81-5.74 (m, 1H), 1.89 (d, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-iodo-succinimide; In tetrahydrofuran; at 20℃; for 4h; | To a solution of <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (25.0 g, 162.8 mmol) in THF (700 ml_) was added N-iodosuccinamide (40.1 g, 179 mmol) at the resulting mixture was stirred for 4 h at RT and then was concentrated in vacuo. The residue triturated in Et20, the resulting solid was collected by filtration and washed with Et20. The crude compound was purified by_silica gel column chromatography eluting with 20-30% EtOAc/petroleum ether to afford 4-chloro-7-iodo-5H- pyrrolo[3,2-d]pyrimidine (CH6) as a yellow solid (32.0 g, 70%); LC-MS. Rt 2.29 min, (0854) AnalpH2_MeOH_4min(1 ); (ESI+) m/z 280.0, 282.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 3h; | Into a 20-mL vial was placed <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (250.00 mg; 1.63 mmol), (4-phenoxyphenyl)boronic acid (522.64 mg: 2.44 mmol), palladium acetate (18.27 mg; 0.08 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (66.83 mg; 0.16 mmol), potassium carbonate (674.97 mg; 0.16 mmol) suspended in dioxane (3.00 ml) and water (0.30 ml). The reaction mixture was heated at 150 C for 3 hours. The reaction mixture was allowed to cool to rt. The crude mixture was purified using flash column chromatography. Fractions containing the desired product were combined and concentrated under reduced pressure. The product was then lyophilized overnight to afford 4-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine (422.40 mg, 90% yield) as a yellow solid. MS: m/z = 288 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 3h; | Into a 20-mL vial was placed <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (500.00 mg; 3.26 mmol), cesium carbonate (3.18 g: 9.77 mmol), and 4-phenoxyphenol (909.40 mg; 4.88 mmol) suspended in DMF (6.00 ml). The reaction mixture was heated at 160 C for 3 hours. The reaction mixture was allowed to cool to rt. The mixture was purified using flash column chromatography. Fractions containing the desired product were combined and concentrated under reduced pressure. The product was then lyophilized overnight to afford 4-(4-phenoxyphenoxy)-5H- pyrrolo[3,2-d]pyrimidine (611.4 mg, 62% yield) as a yellow solid. MS: m/z = 288 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetonitrile; at 100℃; | Into a 20-mL vial was placed <strong>[84905-80-6]4-chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (250.00 mg; 1.63 mmol), and 4-phenoxyaniline (452.29 mg: 2.44 mmol) suspended in acetonitrile (3.00 ml). The reaction mixture was heated at 100 C overnight. The murky reaction mixture was allowed to cool to rt. The solid was filtered and washed with acetonitrile. The solid was dried under vacuum to afford N-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (580.00 mg, 100% yield) as a yellow solid. MS: m/z = 303 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Step 1 (4-chloro-5-(p-tolylsulfonyl)pyrrolo[3, 2-d]pyrimidine) NaH (60% in mineral oil, 0.17 g, 4.23 mmol) was added portion wise to a stirred solution of 4-chioro-5H-pyrrolopyrimidine (0.5 g, 3.26 mmol) in DMF (20 mL) at 0C under N2. The solution was stirred at 0 C for 10 minutes, then p-toluenesulfonyl chloride (683 mg, 0.04 mmol) was added and the reaction stirred at rt for 4h. The reaction mixture was quenched at 0 C with water (30 mL) and extracted with DCM (x 3). The combined organics were washed with water (3 x 30 mL), brine, dried (MgS04) and then solvent was removed in vacuo to give the desired product as a white solid (0.63 g, 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In N,N-dimethyl-formamide; at 20℃; for 3h; | Intermediate 23 4-( Methylsulfanyl)-5 -pyrrolo{3, 2 d]pyrimidine A mixture of 4-chioro-5H-pyrrolo[3,2-d]pyrimidine (5.0 g, 32.5 mmol) and sodium thiomethoxide (6.8 g, 97.4 mmol) in DMF (75 ml) was stirred at rt for 3 hours. The mixture-was diluted with EtOAc and water and the organic phase was washed with water (x3) and brine (x1). The original aqueous phase was re-extracted with DCM. The DCM iayer was washed with water (x2). The EtOAc and DCM extracts were combined, dried and concentrated. The crude product was pre-absorbed onto silica gei and purified by flash chromatography on silica gel eluting with 3:1 EtOAc: petroieum ether then EtOAc and finaiiy with 5% MeOH in EtOAc to give a pale yellow solid 2.97 g (55%). 1H NMR (400 MHz, DMSO-d6) delta ppm 2.67 (s, 3 H), 6.53 - 6.62 (m, 1 H), 7.67 - 7.79 (m, 1 H), 8.64 (s, 1 H), 12.03 (br.s., 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; at 140℃; for 0.5h;Microwave irradiation; | Example 45 N-(4-fluoro-2-isopropoxy^henyl)~5H^yrroIo[3,2-d]pyrimidin~4-amine 4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-4-amine (75 mg, 0.49 mmol), 4-fluoro-2- isopropoxyaniline (99 mg, 0.59 mmol), isopropanol (2ml) and 4M HCI in dioxane (0.1 ml) were combined in a vial and irradiated in a Biotage Initiator 60 microwave reactor at 140 C for 30 min. The mixture was concentrated and purified by preparative HPLC to give an off white solid (25 mg, 18%). H N (400 MHz, DMSO-cfe) 6 ppm 0.46 (d, J=6.41 Hz, 6 H), 3.78-3.88 (m, 1 H), 5.63 (dd, J=2.75, 1.83 Hz, 1 H), 5.92-5.98 (m, 1 H), 6.20 (dd, J=10.99, 2.75 Hz, 1 H), 6.80-6.82 (m, 1 H), 7.21 (dd, J=8.93, 6.64 Hz, 1 H), 7.37 (s, 1 H), 7.38 - 7.40 (m, 1 H), 10.78 (br. s., 1 H); m/z (ES+APCI)+ : 287 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg | With potassium phosphate; palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere; | Procedure: Amine 4 (0.143 g, 0.93 mmoles), Chloride 18 (0.143 g), BINAP (0.115 g, 0.186 mmoles), and K3PO4 (0.395 g, 1.86 mmoles) were suspended in dry dioxane (15 ml). The mixture was purged with N2 for 25 minutes and then kept under N2. Pd(OAc)2 (0.021 g, 0.093 mmoles) was added and the reaction heated for 18 hours at 90 C. The reaction was cooled, and filtered with the aid of dichloromethane (50 ml). The filtrate was concentrated and the crude purified by tlc chromatography using dichloromethane/methanol (9:1) and gave 40 mgs of red foam 19. 1H NMR (400 MHz, CDCl3): delta 8.46 (1H, d), 8.42 (1H, s), 7.60 (2H, m), 7.44 (1H, m), 7.26 (1H, d), 6.64 (1H, m), 6.54 (1H, d) 6.40 (2H, br s), 3.79 (2H, q), 3.36 (2H, q), 2.80 (4H, m), 2.37 (3H, s), 2.29 (3H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With potassium carbonate; In acetonitrile; at 150℃;Inert atmosphere; | <strong>[84905-80-6]4-Chloro-5H-pyrrolo[3,2-d]pyrimidine</strong> (200mg, 1.3 mmol), potassium carbonate (900 mg, 6.5 mmol) and trans-N,N-dimethylcyclohexane-1,4-diamine (556 mg, 3.9 mmol) were suspended in MeCN (10 mL) under nitrogen. The reaction was heated to 150 C for 20 h in an oil bath, then and cooled to RT, filtered through Celite and evaporated. The residue was purified by preparative HPLC (XBridge Prep C18 OBD column, 5mu silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing NH4HCO3) and MeCN as eluents to afford the title compound (50 mg, 15%) as a colourless solid. 1H NMR (300 MHz, DMSO-d6, 303 K) 1.16 - 1.43 (4H, m), 1.85 (2H, br d,J 10.5), 2.10 (2H, br d, J 10.5), 2.13 - 2.25 (7H, m), 3.95 (1H, br s), 6.32 (1H, dd,J 2.85, 1.95), 6.83 (1H, d,J 7.5), 7.46 (1H, t, J 2.85), 8.13 (1H, s), 10.88 (1H, s). HRMS (ESI+): Anal cald for C14H21N5 (M+H)+: 260.1875; Found: 260.1884. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.2% | With 1,4-diaza-bicyclo[2.2.2]octane; triethylamine; trichlorophosphate; In toluene; at 50℃; for 15h; | Adding 4-hydroxypyrrolopyrimidine to 1000 ml of toluene to form an organic mixed solution of 4-hydroxypyrrolopyrimidine;After adding a chlorinating reagent-triethylenediamine to the organic mixed solution of 4-hydroxypyrrolopyrimidine, the temperature is raised to 50 C.Adding organic lye triethylamine,After the completion of the dropwise addition, the temperature was raised to 50 C, and the reaction was further concentrated for 15 hours. The concentrate was poured into ice water, the pH was adjusted to 7-8 with sodium carbonate, and the solid was collected by filtration. The solid was dissolved in acetone, decolorized, and recrystallized. White solid 4-chloropyrrolopyrimidine in a yield of 93.2%. The total yield was 77.3% and the purity was greater than 99.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 20℃; for 16h; | General procedure: To a solution of 1-chloroisoquinoline 1a (2g, 12.225 mmol) in ethanol was added 4-fluorobenzenethiol 2a (1.436 mL, 13.447 mmol). The reaction was stirred at roomtemperature for 16h. The mixture was concentrated in vacuo. The crude waspurified by silica gel column chromatography using ethyl acetate/hexane to yieldpure compound (686 mg, 22%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 160℃; for 1h; | 91 N-tetralin-1-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (137) In a sealed tube, 4-chloro-7H-pyrrolo[3,2-d]pyrimidine (200 mg, 1.31 mmol, 1.0 eq.) was dissolved in 6 mL of isopropanol and the addition was made of 1,2,3,4-tetrahydro-1-naphthylamine (0.22 mL, 1.5 mmol, 1.2 eq.) and diisopropylethylamine (0.68 mL; 3.93 mmol, 3.0 eq.). The reaction was initiated in a microwave reactor for 1 h at 160° C. disappearance of the starting reagent was monitored by TLC, and on completion of the reaction the solution was diluted with 50 mL of acOEt. The solution was washed with 50 mL of water then 50 mL of saturated aqueous NaCl solution and dried over MgSO4. after filtering, the solvent was evaporated and the residue purified on silica gel (eluting gradient: 0 to 80% acOEt/100 to 20% PE). The product was obtained in the form of a white solid (148 mg, 43%). Rf (PE/acOEt 20:80): 0.20. 1H NMR (400 MHz, Cd3Od) 8.16 (s, 1H), 7.28 (m, 1H), 7.14 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 5.57 (m, 1H), 2.88 (m, 2H), 2.16 (m, 1H), 1.97 (m, 3H). 13C NMR (101 MHz, Cd3Od) 157.6, 152.2, 150.5, 138.8, 130.0, 129.5, 128.0, 127.0, 122.2, 104.3, 100.2, 31.5, 30.4, 21.6. IR (diamond aTR, cm-1) n 3189, 3095, 2931, 2852, 1584, 1473, 1354, 1321, 1160, 1138, 897, 819, 656. HRMS (EI-MS): m/z calculated for Cl6H17N4[M+H]+: 265.1447, found: 265.1445. Tm: 226-228° C. |
Tags: 84905-80-6 synthesis path| 84905-80-6 SDS| 84905-80-6 COA| 84905-80-6 purity| 84905-80-6 application| 84905-80-6 NMR| 84905-80-6 COA| 84905-80-6 structure
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