5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

General procedure: To a solution of readily available 3a (20mmol) in N, N-dimethylformamide (DMF) (15mL) was added NCS/NBS (21mmol) and the reaction mixture was stirred at room temperature for 72h. Then ice water (150mL) was poured into the mixture, the precipitate was filtered, washed with water (3×100mL), and dried to give 3b and 3c.Dissolve 4-chloro-pyrrolo[2, 3-d]pyrimidine (20 mmol) in DMF (6 mL), add NBS or NCS (21 mmol) in portions on ice bath, react at room temperature for 12 h, and pour the reaction mixture into 80 mL of ice. In the water, a large number of off-white solids precipitated and were filtered. The filter cake was washed with 15 mL of water and dried to give Intermediate 2. 4-Chloro-5-bromo-pyrrolo[2, 3-d]pyrimidine (2b) Off-white solid, yield 95percentA solution of 4-chloro-71-I-pyrroio[2, 3-dipyrimidine (56a) (50 g, 0.32 mol) in DMF (300 mL) was charged with N-bromosuccininiide (64.0 g, 0.35 mol) and stirred at RT for 15 h. The reaction mixture was quenched with ice-cold water (1 IL), filtered, rinsed with ice-cold water (200 mL), and dried on high vacuum, The crude compound was redissoived in 20percent MeOH in DCM (2 IL), dried over anhvdrous sodium sulfate and concentrated under reduced pressure to obtain 56b as light brown solid (73 g, 0.31 mol, 95percent yield), ‘H NMR (400 MHz, DMSO-d6): ö 1297 (s, IFI). 862 (s, IH), 7.95 (s, 11:1). LCMS Purity: 98.7percent: ERMS (ESI) m/z calcd for [M±FIj: 231.93/233.93. Found: 23 1.92/233.92.4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (20mmol) was dissolved in 20ml DMF, was added NBS (21mmol), stirred at room temperature 12h, After the reaction was completed, the reaction solution was poured into 200 ml of ice water. Filtration, the filter cake was washed with water and dried to give Intermediate 2. Off-white solid with a yield of 94.6percent.Scheme 4 Synthesis of 5-Pyrrolidine-pyrrolor2, 3-d1pyrimidine compoundsmιn 1 INTERMEDIATE; 5-Bromo-4-chloro-7H-pyrrolor2.3-dlpyrimidine.Chemical Formula: C4-Chloro-7H-pyrrolo[2, 3-d]pyrimidine (2 g, 13.02 mmol) was dissolved in 20 mL dimethylformamide. N-Bromosuccinimide (2.55 g, 14.33 mmol) was added under argon atmosphere. The reaction was stirred at room temperature overnight. The crude was poured into water and the precipitate formed was filtered and washed with water. The yellow solid obtained was dried in the vacuum oven to give 2.77 g (91 .5percent yield) of the title compound. Purity 99percent.LRMS (m/z): 232 (M+1 )METHOD K To a solution of 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (3.00 g) in chloroform (85 mL)) was added N-bromosuccinimide (3.55 g), and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, and the precipitates were collected by filtration and purified by column chromatography on silica gel (solvent; hexane/ethyl acetate = 70/30 to 20/80) to give 5-bromo-4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (3.83 g) as a colorless powder (yield: 84percent). MS(APCI)m/z; 232/234[M+H]Synthesis 2-1 -A; 5-Bromo-4-chloro-7H-pyrrolo[2, 3-d]pyrimidine; A suspension of 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (0.49 g, 3.2 mmol) and N-bromosuccinimide (0.68 g, 3.8 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 2.5 hours. The suspension was diluted with methanol and evaporated onto silica. The crude product was purified using flash column chromatography, eluting with 2:1 hexanes-ethyl acetate, to yield the title compound as an off-white solid (0.613 g, 2.64 mmol, 83percent).A. 6.18. Example 18(S)-4-(5-cyano-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-N-(3-(isopropylcarbamoyl)phenyl)-2-methylpiperazine-1-carboxamide A. Preparation of 5-bromo-4-chloro-7H-pyrrolo[2, 3-d]pyrimidine. To a solution of 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (1.2 g, 7.8 mmol) in CHTo a suspension of 4-Chloro-7H-pyrrolo [2, 3-d] pyrimidine (2.5g, 16 mmol) in CDC13 (65 mL) was added NBS (2.9g, 16 mmol) and the reaction mixture stirred and heated at reflux for 2.5 hours. The mixture was cooled to room temperature, the solids isolated by vacuum filtration, rinsed with cold CHC13 and air dried to give 5-Bromo-4-chloro-7H- pyrrolo [2, 3-d] pyrimidine (3. 0g, 79percent. ) LCMS (APCI+) m/z 232 and 234 [M+H] + ; Rt: 2.32 min. 1H NMR (DMSO-d6, 400 MHz) 6 12. 98 (1H, br. s), 8.63 (1H, s), 7.96 (1H, s. )To a solution of 4-chloro-7H-pyrrolo[2, 3-d] pyrimidine Q-1 (870 mg, 5.67 mmol) in DMF (14.2 mE, 0.4M) was added N135 (1.1 g, 6.23 mmol) at room temperature. The reaction was stirred overnight for 16 h. ECMS showed the starting material was consumed and product formed. The reaction mixture was quenched with sat. aq. NaHCO3, then extracted with EtOAc. The EtOAc was washed with brine, dried with Na2504, filtered and concentrated to give a dark brown solid. The solid was suspended in CH2C12, then loaded onto a 12 g ISCO solid load cartridge and purified 0-50percent EtOAc/Heptane to give 204mg as a light tan solid. The insoluble light brown solid was also the product and dried to give 839mg as a light brown solid. The combined material gave 5-bromo-4-chloro-7H-pyrrolo[2, 3-d]pyrimi- dine (Q-3)(1.043 g, 79percent). ECMS [M+1] 232/234; ‘H NMR (400 MHz, DMSO-d5) ö ppm 12.96 (bt s., 1H), 8.62 (s, 1H), 7.94 (s, 1H)4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (2-E, 20.0 g, 130.7 mmol) dissolved in DCM (800 mL) was treated portion-wise with N-bromosuccinimide (26.7 g, 149.8 mmol), while maintaining the temperature around 25-30° C. Step 1 : 5-bromo-4-chloro-7H-pyrrolo[2, 3-i ]pyrimidine (Intermediate 2-F) [00140] 4-chloro-7H-pyrrolo[2, 3-fiT]pyrimidine (2-E, 20.0 g, 130.7 mmol) dissolved in DCM (800 mL) was treated portion-wise with N-bromosuccinimide (26.7 g, 149.8 mmol), while maintaining the temperature around 25-30 °C. The reaction mixture was stirred at room temperature overnight. Water was added (500 mL) and the phases were separated. The organic phase was dried over Na4-chloro-7H-pyrrolo2, 3-dipyrimidine (2-E, 20.0g, 130.7mmol) dissolved in DCM (800 mL) was treated portion-wise with N-bromosuccinimide (26.7 g. 149.8 mmol), while maintaining the temperature around 25-30°C. The reaction mixture was stirred at room temperature overnight. Water was added (500 mL) and the phases were separated. The organic phase was dried over NaSO4, filtered and concentrated in vacuo. The crude product was triturated in Et2O affording after filtration 5-bromo-4-chloro-7H-pyrrolo[2, 3-d]pyrimidine as a white solid (2-F, 22.43 g, 74percent).PREPARATION 155-bromo-4-chloro-1 /-/-pyrrolo[2, 3-c/]pyriA mixture of 4-chloro-1 H-pyrrolo[2, 3-c ]pyrimidine (10 g, 65.1 mmol) in CHPREPARATION 6; PREPARATION H5-bromo-4-chloro-7H-pyrrolor2, 3-dlpyrimidine; Intermediate 50: 5-bromo-4-chloro-7H-pyrrolo[2., 3-dlpyrimidineN-Bromosuccinimide (6.84 g, 38.42 mmol) was added portionwise to 4-chloro-7H- pyrrolo[2, 3-d]pyrimidine (5 g, 32.56 mmol) in DCM, dry (125 mL) at 2OSynthesis of Compound 16.1 To a stirred solution of 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (2 g, 13 mmol) in DCM (80 ml) was added N-Bromosuccinamide (3.2 g, 18 mmol) at RT. After 1 hour, the solvent was removed in vacuo, and then the solid was washed (water) and recrystalized (MeOH) to afford compound 16.1 (2 g, 66percent) as an off-white solid. To a suspension of 4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (3.99 g, 26.0 mmol, 1.0 eq) in dry DCM(150 mL) under argon, N-bromosuccinimide (6.02 g, 33.8 mmol, 1.3 eq) was added and the resulting mixture was stirred at RT for 3 h. The reaction mixture was diluted with MeOH (30 mL) and then concentrated in vacuo to yield a slight brown solid. The residue was triturated with H

Molecular Weight:232.46
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:230.91989
Monoisotopic Mass:230.91989
Topological Polar Surface Area:41.6
Heavy Atom Count:11
Complexity:157
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes