2,4-Dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine

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.General procedure: Compound 20a (30 mg, 0.058 mmol) and KDissolve 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).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).[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).Compound 1 (100 mg, 0.53 mmol), cesium carbonate (350 mg, 1.06 mmol) were dissolved in 1 ml DMF. 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.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]+.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]+.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]+.

Molecular Weight:202.04
XLogP3:2.3
Hydrogen Bond Acceptor Count:2
Exact Mass:200.9860526
Monoisotopic Mass:200.9860526
Topological Polar Surface Area:30.7
Heavy Atom Count:12
Complexity:178
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes