* 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.
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 24 h;
2,4-Dichloro-5H-pyrrolo [3,2-d] pyrimidine(600 mg, 3.19 mmol) was placed in a round bottom flask,N, N-dimethylformamide DMF (5 mL) was added to dissolve it,Methyl iodide (544 mg, 3.83 mmol) and cesium carbonate (520 mg, 1.60 mmol) were added successively and the reaction was stirred at room temperature for 24 h.Treatment: The reaction solution was added to water and extracted with ethyl acetate,The organic phase was collected, dried over anhydrous sodium sulphate, filtered off with suction and concentrated. A yellow solid. Yield: 91percent.
88%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6 h;
General procedure: Compound 20a (30 mg, 0.058 mmol) and K2CO3 (16 mg, 0.12 mmol) were added to a 2 mL solution of CH3I (21 mg, 0.15 mmol) in DMF. The mixture was stirred at room temperature for 6 h. The reaction mixture was quenched by adding water, followed by extracting with EtOAc. Then the organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified via silica gel column chromatography using CH2Cl2/MeOH(100/1) to give 21a (31 mg, 100 percent) as a yellow solid.
86%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
Dissolve 5H-pyrrolo[3,2-d]pyrimidine (510 mg, 1 eq) in N,N-dimethylformamide (10 ml).Add iodomethane (1.93g, 5eq) and potassium carbonate (1.13g, 3eq) for 2h at room temperature, add water,Dichloromethane extraction, concentration,Dry to give a solid (497 mg, 86percent).
81%
With caesium carbonate In water; N,N-dimethyl-formamide for 1.5 h;
INTERMEDIATE 32 2,4-Dichloro-5 -methylpyrrolo [3 ,2-d]pyrimidine lodomethane (0.98 mL, 16 mmol) was added to a suspension of 2,4-dichloro-5H- pyrrolo[3,2-d]pyrimidine (3 g, 15.8 mmol) and cesium carbonate (5.14 g, 15.8 mmol) in DMF (50 mL). The reaction mixture was stirred for 1.5 h, then water was added. The resulting thick white precipitate was filtered off, then washed with water and isohexane. The residue was concentrated by evaporation to provide the title compound (2.58 g, 81percent)as a white solid. LCMS (ES+) [M+H] 202, 204, RT 1.13 minutes (method 1).
51%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Stage #2: at 20℃;
[00348] To a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 2.66 mmol) in DMF (8 mL) was added NaH (127 mg, 3.19 mmol, 60percent) at 0 °C. The reaction mixture was stirred for 30 mm at 0 °C, then iodomethane (3.78 g, 26.60 mmol) was added. The reaction mixture was stirred at rt overnight. Water (50 mL) was added to quench the reaction, and the mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatograph (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (275 mg, 51 percent).MS (ESI, pos. ion) m/z: 202.00 [M+H]+1H NMR (400 MHz, CDC13) (ppm): 7.47 (d, J = 3.1 Hz, 1H), 6.64 (d, J = 3.0 Hz, 1H), 4.16 (s, 3H).
Reference：
[1] Patent: CN107312006, 2017, A, . Location in patent: Paragraph 0037-0039
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3486 - 3492
[3] Patent: CN104177363, 2018, B, . Location in patent: Paragraph 0247; 0250-0251
[4] Patent: WO2015/193168, , A1, . Location in patent: Page/Page column 59[4] Patent: , 2015, , . Location in patent: Page/Page column 59
[6] Patent: WO2017/97234, 2017, A1, . Location in patent: Paragraph 00348
[7] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2750 - 2755
[8] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 39
[9] Patent: EP1970373, 2008, A1, . Location in patent: Page/Page column 95
2
[ 77-78-1 ]
[ 63200-54-4 ]
[ 129872-81-7 ]
Yield
Reaction Conditions
Operation in experiment
70%
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5 h; Inert atmosphere
Compound 1 (100 mg, 0.53 mmol), cesium carbonate (350 mg, 1.06 mmol) were dissolved in 1 ml DMF. To the solution was added dimethyl sulfate (1 mL) in nitrogen atmosphere. The resulting reaction liquid was stirred at room temperature for 5 hours. The reaction was stopped. To the reaction liquid was added slowly 50 mL of water. After the system was cooled, added ethyl acetate, and the liquid was separated. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydride sodium sulfate, concentrated and purified by silica-gel column chromatography (petroleum ether/ethyl acetate=2/1) to yield compound 10 (white solid, 76.3 mg, yield 70percent), which was used directly for the reaction in next step. MS (ESI) m/z: 203 [M+H]+.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;
2,4-Dichloro-5H-pyrrolo [3,2-d] pyrimidine(600 mg, 3.19 mmol) was placed in a round bottom flask,N, N-dimethylformamide DMF (5 mL) was added to dissolve it,Methyl iodide (544 mg, 3.83 mmol) and cesium carbonate (520 mg, 1.60 mmol) were added successively and the reaction was stirred at room temperature for 24 h.Treatment: The reaction solution was added to water and extracted with ethyl acetate,The organic phase was collected, dried over anhydrous sodium sulphate, filtered off with suction and concentrated. A yellow solid. Yield: 91%.
88%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
General procedure: Compound 20a (30 mg, 0.058 mmol) and K2CO3 (16 mg, 0.12 mmol) were added to a 2 mL solution of CH3I (21 mg, 0.15 mmol) in DMF. The mixture was stirred at room temperature for 6 h. The reaction mixture was quenched by adding water, followed by extracting with EtOAc. Then the organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified via silica gel column chromatography using CH2Cl2/MeOH(100/1) to give 21a (31 mg, 100 %) as a yellow solid.
86%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
Dissolve 5H-pyrrolo[3,2-d]pyrimidine (510 mg, 1 eq) in N,N-dimethylformamide (10 ml).Add iodomethane (1.93g, 5eq) and potassium carbonate (1.13g, 3eq) for 2h at room temperature, add water,Dichloromethane extraction, concentration,Dry to give a solid (497 mg, 86%).
81%
With caesium carbonate; In water; N,N-dimethyl-formamide; for 1.5h;
INTERMEDIATE 32 2,4-Dichloro-5 -methylpyrrolo [3 ,2-d]pyrimidine lodomethane (0.98 mL, 16 mmol) was added to a suspension of 2,4-dichloro-5H- pyrrolo[3,2-d]pyrimidine (3 g, 15.8 mmol) and cesium carbonate (5.14 g, 15.8 mmol) in DMF (50 mL). The reaction mixture was stirred for 1.5 h, then water was added. The resulting thick white precipitate was filtered off, then washed with water and isohexane. The residue was concentrated by evaporation to provide the title compound (2.58 g, 81%)as a white solid. LCMS (ES+) [M+H] 202, 204, RT 1.13 minutes (method 1).
51%
[00348] To a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 2.66 mmol) in DMF (8 mL) was added NaH (127 mg, 3.19 mmol, 60%) at 0 C. The reaction mixture was stirred for 30 mm at 0 C, then iodomethane (3.78 g, 26.60 mmol) was added. The reaction mixture was stirred at rt overnight. Water (50 mL) was added to quench the reaction, and the mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatograph (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (275 mg, 51 %).MS (ESI, pos. ion) m/z: 202.00 [M+H]+1H NMR (400 MHz, CDC13) (ppm): 7.47 (d, J = 3.1 Hz, 1H), 6.64 (d, J = 3.0 Hz, 1H), 4.16 (s, 3H).
(5) To 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (19.9g) in acetonitrile (530ml) was gradually added 60% sodium hydride (5.08g) under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was dropped methyl iodide (18.03g) at 8C and the mixture was stirred at room temperature for overnight. After filtering insoluble materials over Celite, the filtrate was concentrated in vacuo. The residue was washed with diisopropyl ether to give 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (11.0g). APCI-MS (m/e): 202/204 (M+H)+
(5) 60% Sodium hydride(5.08 g) was added to a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine(19.9 g) in acetonitrile(530 mL) under ice-cooling and the mixture was stirred at room temperature for 30 minutes. Methyl iodide(18.03 g) was added dropwise to the reaction solution at 8C, and the mixture was stirred at room temperature overnight. The insoluble material was filtered through Celite and the filtrate was concentrated. The residue was washed with diisopropyl ether to give 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine(11.0 g). APCI-MS(m/e):202/204[M+H]+.
Example 122-Chloro-4-(mesityloxy)-5-methyl-5H-pyrrolo [3,2-d pyrimidineTo a stirred suspension of NaH (8.9 mg, 0.22 mmol) in dry NMP (1.0 mL) was added 2,4,6-trimethyl phenol (30.2 mg, 0.22 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-methyl-5H- pyrrolo[3,2-d]pyrmiidme (44.6 mg, 0.22 mmol) in dry NMP (1.0 mL) and heated at 90 0C for 16 h. After completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1-2:1), to give the product as a light yellow solid (52.7 mg, 80%).
4-(2-Chloro-5-methyl-5H-pyrrolo[3,2-</]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrileTo a stirred solution of NaH (42.1 mg, 1.05 mmol) in dry NMP (2.5 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (154.7 mg, 1.05 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5- methyl-5H-pyrrolo[3,2-<phiyrimidine (211.3 mg, 1.05 mmol) in dry NMP (2.7 mL) and heated at 160 0C for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (3 : 1 - 1 : 1 ), to give the product as a light yellow solid (294 mg, 85%).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;Inert atmosphere;
Step 2: A mixture of <strong>[129872-81-7]2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine</strong> (1.25 g,6.19 mmol), morpholine (1.08 mL, 12.37 mmol), and N,N-diisopropylethylamine (2.37 mL, 13.61 mmol) in N,N-dimethylformamide (36 mL) was stirred at RT under N2 for 15h. The reaction mixture was diluted with 1 : 1 diethyl ether / ethyl acetate, and the organic layer was washed with 1 : 1 water / brine (3X) and brine (IX), dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1.47g (94.0%) of 4-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)morpholine as a white solid. MS(ESI) m/z: 253.1/255.1 [M+l] +.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h;Inert atmosphere;
Step 1 : A mixture of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (2.67 g, 14.2 mmol), methanesulfonic acid methyl ester (1.26 mL, 14.9 mmol) and cesium carbonate (9.25 g, 28.4 mmol) in anhydrous N,N-dimethylformamide (21 mL) was stirred at RT (room temperature) under N2 for 15h. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 1 : 1 water / brine (3X) and brine (IX), dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 2.50 g (87.1%) of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine as a white solid. MS(ESI) m/r.[M+1] +.
With N-ethyl-N,N-diisopropylamine; In ethanol; N,N-dimethyl-formamide; at 20℃;Sealed tube; Inert atmosphere;
General procedure: An oven-dried 15 mL pressure tube cooled under nitrogen, charged with 123 mg (0.61 mmol) of 2,6 dichloro-7-methyl-7H-purine (See US 20110086840 A1 for synthesis) and anhydrous ethanol/ DMF (0.5 mL/0.3 mL, 0.76M). N,N-diisopropylethylamine (0.130 mL,0.73mmol) was added via syringe followed by morpholine (0.064 mL, 0.73 mmol). The pressure tube was flushed with nitrogen and the septa replaced by a Teflon screw cap. The reaction mixture stirred overnight at room temperature. The reaction mixture was poured into 50 % ether/ethyl acetate and washed 1x with 50% brine and 1x with brine.The organic layer was dried (MgSO4), filtered , concentrated to yield 119 mg of crude product (77.6%) which was taken directly into the next step. 1H NMR (400MHz, DMSO d6) d 8.44 (s, 1H), 3.96 (s, 3H), 3.80 - 3.71(m, 4H), 3.53 - 3.44 (m, 4H). LC/MS-m/z FontWeight="Bold" FontSize="10" 254.5 (M+H)+.
With N-ethyl-N,N-diisopropylamine; In ethanol; N,N-dimethyl-formamide; at 20℃;Sealed tube; Inert atmosphere;
General procedure: An oven-dried 15 mL pressure tube cooled under nitrogen, charged with 123 mg (0.61 mmol) of 2,6 dichloro-7-methyl-7H-purine (See US 20110086840 A1 for synthesis) and anhydrous ethanol/ DMF (0.5 mL/0.3 mL, 0.76M). N,N-diisopropylethylamine (0.130 mL,0.73mmol) was added via syringe followed by morpholine (0.064 mL, 0.73 mmol). The pressure tube was flushed with nitrogen and the septa replaced by a Teflon screw cap. The reaction mixture stirred overnight at room temperature. The reaction mixture was poured into 50 % ether/ethyl acetate and washed 1x with 50% brine and 1x with brine.The organic layer was dried (MgSO4), filtered , concentrated to yield 119 mg of crude product (77.6%) which was taken directly into the next step. 1H NMR (400MHz, DMSO d6) d 8.44 (s, 1H), 3.96 (s, 3H), 3.80 - 3.71(m, 4H), 3.53 - 3.44 (m, 4H). LC/MS-m/z FontWeight="Bold" FontSize="10" 254.5 (M+H)+.
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In water; N,N-dimethyl-formamide; at 80℃; for 4h;
General procedure: Pd(PPh3)2Cl2 (23 mg, 0.03 mmol), 4-trifluoromethoxyphenylboronic acid (73 mg, 0.35 mmol), compound 15 (100 mg, 0.32 mmol) and TEA (91 mg, 0.90 mmol) were added to a solution of DMF (5 mL) and H2O (0.5 mL). The mixture was stirred at 80 oC for 4 h. Water (10 mL) and EtOAc (30 mL) were added to the reaction. The layers were separated. The aqueous layer was extracted using EtOAc (10 mL). The combined organic extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified via silica gel column chromatography using petroleum ether/EtOAc (5/1) to give 16 (67 mg, 48 %) as a yellow solid.
tert-butyl (3S)-4-(2-chloro-5-methylpyrrolo[3,2-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 96h;
INTERMEDIATE 33 tert-Butyl (3S)-4-(2-chloro-5-methylpyrrolo[3 ,2-d]pyrimidin-4-yl)-3-methylpiperazine- 1-carboxylate DIPEA (4.5 mL, 26 mmol) was added to a solution of Intermediate 32 (2.58 g, 12.76 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (2.67 g, 13.3 mmol) in DMF (50 mL). The reaction mixture was heated to 110C and stirred for 4 days. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residuewas dissolved in EtOAc (50 mL), washed with saturated aqueous NaHCO3 solution (50 mL) and brine (2 x 50 mL), then dried over Na2SO4 and evaporated. The crude residue was purified by silica gel chromatography (gradient of 3 0-70% EtOAc in isohexane) to provide the title compound (3.93 g, 84%) as a brown viscous foaming gum. LCMS (ES+) [M+H] 366, 368, RT 1.51 minutes (method 1).
trans-4-[6-azaspiro[2.5]octan-6-yl]cyclohexan-1-amine[ No CAS ]
[ 129872-81-7 ]
C20H28ClN5[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With sodium carbonate; In acetonitrile; at 80℃;
Into a 100-mL round-bottom flask was placed compound 14.1 (200 mg, 0.99 mmol, 1.00 eq.), compound 23.1 (227 mg, 1.09 mmol, 1.10 eq.), and sodium carbonate (210 mg, 1.98 mmol, 2.00 eq.) in ACN (10 mL). The resulting solution was stirred overnight at 80 C in an oil bath. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with water and DCM. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 250 mg (68%) of compound 23.2 as a yellow solid.
(1r,4r)-4-(morpholin-4-yl)cyclohexan-1-amine dihydrochloride[ No CAS ]
[ 129872-81-7 ]
C17H24ClN5O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With sodium carbonate; In acetonitrile; at 80℃;
Into a 100-mL round-bottom flask was placed compound 14.1 (200 mg, 0.99 mmol, 1.00 eq.), compound 1.2 (380 mg, 1.48 mmol, 1.50 eq.), Na2C03 (210 mg, 1.96 mmol, 2.00 eq. in CH3CN (20 mL). The reaction was stirred overnight at 80 C in an oil bath. The resulting mixture was concentrated in vacuo and diluted with 100 mL of H20. The resulting solution was extracted with 3x200 mL of CH2C12; organic layers were combined, dried over anhydrous Na2S04 and concentrated in vacuo to provide 238 mg (69%) of compound 14.2 as an orange solid.
tert-butyl 3-(((2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)methyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Reflux;
Step 1: preparation of tert-buty 3-(((2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)methyl)azetidine-1-carboxylate (0272) (0273) 2,4-Dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (300 mg, 1.48 mmol) and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (290 mg, 1.56 mmol) were dissolved in tetrahydrofuran (10 mL), followed by the addition of N,N-diisopropylethylamine (258 mg, 2 mmol). The reaction solution was reacted under reflux overnight, and then cooled to room temperature. The reaction solution was concentrated and the residue was added with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 6 : 1), to give a colorless liquid (300 mg). Yield: 50.7%. MS (ESI, m/z): [M+H]+: 352.2.
(+/-)-trans-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid[ No CAS ]
(+/-)-trans-methyl 3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate[ No CAS ]
(±)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate[ No CAS ]
[ 129872-81-7 ]
(+/-)-trans-methyl 3-((2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium carbonate; In tetrahydrofuran; at 20℃;
To a solution of (+/-)-trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (236 mg, 1.17 mmol) and <strong>[129872-81-7]2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine</strong> (301 mg, 2.13 mmol) in THF (5 mL) was added K2C03 (301 mg, 2.16 mmol). Then the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL x 2), and the combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na2504 and filtered. The filtrate was concentrated in vacuo. The residue obtained was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (122 mg, 33 %).MS (ESI, pos. ion) m/z: 350.15 [M+H1b0
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; at 120℃;
Compound 10 (66 mg, 0.33 mmol), 2-methylthiobenzylamine (50 mg, 0.33 mmol) were dissolved in 2 mL tertbutanol.To the solution was added N,N-diisopropylethylamine (0.74 mL, 4.47 mmol). The resulting reaction liquid washeated in 120C oil bath with stirring until compound 10 was reacted completely (LC-MS tracking). The reaction wasstopped. The reaction liquid was concentrated and purified by silica-gel column chromatography (ethyl acetate/petroleumether=1/1) to yield compound 13 (white solid, 60 mg, yield 57%), which was used directly for the reaction in next step.MS (ESI) m/z: 319 [M+H]+.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;Inert atmosphere;
Compound 1 (100 mg, 0.53 mmol), cesium carbonate (350 mg, 1.06 mmol) were dissolved in 1 ml DMF. To the solution was added dimethyl sulfate (1 mL) in nitrogen atmosphere. The resulting reaction liquid was stirred at room temperature for 5 hours. The reaction was stopped. To the reaction liquid was added slowly 50 mL of water. After the system was cooled, added ethyl acetate, and the liquid was separated. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydride sodium sulfate, concentrated and purified by silica-gel column chromatography (petroleum ether/ethyl acetate=2/1) to yield compound 10 (white solid, 76.3 mg, yield 70%), which was used directly for the reaction in next step. MS (ESI) m/z: 203 [M+H]+.
5-methyl-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-ylformyl)phenyl)-N4-(2-(methoxyformyl)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine trifluoroacetate[ No CAS ]
Compound 10 (101 mg. 0.5 mmol) was dissolved in N,N-dimethylformamide (4 mL), added NaH (60 mg, 2.5 mmol) in ice bath, stirred for 5-10 min, and then added 2-methylthioaniline (69.6 mg, 0.5 mmol), stirred at room temperature, reacted overnight until compound 10 was reacted completely (LC-MS tracking). The reaction was stopped. To the system was added ice to quench NaH, added ethyl acetate, and the liquid was separated. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydride sodium sulfate, concentrated and purified by silica-gel column chromatography (petroleum ether/ethyl acetate=2/1) to yield compound 11 (solid, 64.7 mg, yield 42.5%), which was used directly for the reaction in next step. MS (ESI) m/z: 305 [M+H]+.
With trifluoroacetic acid; In tert-butyl alcohol; at 85℃;
Compound 10 (76.3 mg, 0.38 mmol), methyl o-aminobenzoate (62.7 mg, 0.42 mmol) were dissolved in 3 ml tert-butanol. To the solution was added trifluoroacetic acid (0.085 mL, 1.14 mmol). The resulting reaction liquid was heated in 85C oil bath with stirring until compound 10 was reacted completely (LC-MS tracking). The reaction was stopped. To the reaction liquid was added 40 mL of saturated sodium bicarbonate, and the liquid was separated. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydride sodium sulfate, concentrated and purified by silica-gel column chromatography (dichloromethane/methanol=1/25) to yield compound 12 (white solid, 43.2 mg, yield 56.2%), which was used directly for the reaction in next step. MS (ESI) m/z: 317 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h;
Compound 10 (150 mg, 0.74 mmol), 2,6-dichlorobenzylamine (130 mg, 0.74 mmol) were dissolved in 5 mLDMF. To the solution was added potassium carbonate (308 mg, 2.23 mmol). The resulting reaction liquid was heatedin 60C oil bath with stirring, reacted for 16 hours. The reaction was stopped. To the reaction liquid was added saturated40 mL of sodium chloride solution, 20 mL of ethyl acetate, and the liquid was separated. The organic phase was washedtwice with saturated sodium chloride solution, dried over anhydride sodium sulfate, concentrated to yield compound 14(yellow solid, 175.3 mg, yield 74.3%), which was used directly for the reaction in next step.MS (ESI) m/z: 318 [M+H]+.
trans-4-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)cyclohexanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.5%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Reflux;
Step 1: preparation of trans-4-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-ylamino) cyclohexanol 2,4-Dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (101 mg, 0.50 mmol) and trans-4-aminocyclohexanol (151 mg, 1.00 mmol) were dissolved in tetrahydrofuran (10 mL), followed by adding N,N-diisopropylethylamine (0.5 mL). The reaction liquid was stirred under reflux overnight and then concentrated. The residue was added into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was isolated by flash column chromatography (eluent: dichloromethane: methanol = 20: 1) to give 75 mg of product. Yield: 53.5%. MS (ESI, m/z): [M+H]+: 281.3.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
