2-AMINO-5-BROMO-3-IODOPYRIDINE

Brown powder

Preparation 9-Benzenesulfonyl-3-bromo-5-hvdroxy-9H-dipyridor2, 3-b;4\3Example 62-amino-5-bromo-3-iodopyridine (11 )2 CHgCN (75percent) 11 a) NIS procedure:To a solution of 2-amino-5-bromopyridine (2) in DMF was added tnfluoroacetic acid (1 .2 equiv). At room temperature, N-iodosuccinimide (1 .1 equiv) was added and the reaction mixture was heated at 50°C for 3 h. HPLC indicated complete conversion. After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1 N NaOH the title compound (11 ) was collected by filtration as a brown solid in 90percent yield.a) NIS Procedure:To a solution of 2-amino-5-bromopyridine (2) in DMF was added trifluoroacetic acid (1.2 equiv). At room temperature, N-iodosuccinimide (1.1 equiv) was added and the reaction mixture was heated at 50° C. for 3 h. HPLC indicated complete conversion. After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1N NaOH the title compound (11) was collected by filtration as a brown solid in 90percent yield.4.5.5 To a solution of 2-amino-5-bromo pyridine in DMF, trifluoro acetic acid (1.1 equiv) wasadded at room temperature, followed by addition of N-Iodo succinimide (1 .1 equiv) and the reaction mixture was heated at 50°C for 180min. After completion of the reaction, reaction mass was cooled to room temperature and the product was precipitated by adding the reaction mixture to water. After neutralization with sodium thiosulfate and iN NaOH the title compound was collected by filtration as a brown solid with 90percent yield.Preparation of 2-amino-5-bromo-3-iodopyridine (IIa); In a 1000 mL double-jacket reactor (under a nitrogen atmosphere) 38.28 g iodine is suspended in 21 g acetic acid and 62 g acetonitrile. To the brown mixture is added at 20 to 40° C. 14.6 g sulfuric acid 96percent. The addition is strongly exothermic. The dropping funnel is rinsed with 20 g water. The resulting mixture is heated with a jacket temperature of 90° C. When the temperature of the mixture is 70° C., the mixture is treated within 3 to 6 minutes with 45.20 g periodic acid (50percent in water). The addition is endothermic. The funnel is rinsed with 10 g water. The solution is then treated at 65 to 75° C. within 5 to 10 minutes with a previously prepared solution of 58.00 g 2-amino-5-bromopyridine in 67 g acetonitrile and 31.5 g acetic acid. The dropping funnel is rinsed with 15 g acetonitrile. The resulting solution is heated to 77 to 82° C. and stirred under slightly reflux conditions for 3 to 4 hours (approx. 90° C. jacket temperature). In-process control (proposed target value: <2.0percent starting material). Upon complete conversion the mixture is immediately cooled down and treated at 60 to 70° C. drop wise with 66 g sodium hydrogen sulfite (38-40percent in water). Immediately after the addition, the mixture is diluted at 60 to 70° C. within 30 to 60 minutes with 360 g water. The mixture is then treated at 60 to 70° C. within 50 to 90 minutes with approximately 202 g sodium hydroxide 28percent to adjust the pH to 7.3 to 7.6. When the desired pH is reached the suspension is stirred at 60 to 70° C. for 30 to 60 minutes. The suspension is cooled to 20 to 25° C. within 2 to 5 hours and then stirred at this temperature for 2 to 5 hours. The crystals are filtered off and washed in two portions with a mixture of 270 g water and 23 g acetonitrile. The wet crystals (approx. 120 g) are dried at 40 to 50° C./<30 mbar until constant weight. Yield: 90.5 g of slightly brownish crystals with an assay of 95.0percent (m/m). This corresponds to a corrected yield of 86percent.Example 62-amino-5-bromo-3-iodopyridine (11 ) b) l2/NalOTo a stirred solution of 5-bromopyridin-2-amine (4.0 g, 23.12 mmol), TFA (2.316 mL, 30.1 mmol) in DMF (100 mL) at 0 °C were added portion wise NIS (6.76 g, 30.1 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with ice cold water and sodium thiosulphate solution (3 : 1), the product was precipitated by adding the saturated NaHCCb solution (adjust pH-8), stirred for 10 min at 0 °C. The resulting solid compound was collected by filtration to afford 5-bromo-3-iodopyridin-2 -amine (5.1 g, 17.06 mmol, 73.8 percent yield) as a brown solid. MS (EIA solution of iodine (2.6 g, 10.8 mmol) in glacial acetic acid (25 mL) wasprepared and was added dropwise to a solution of 2a(3 g, 17.3 mmol) and periodic acid (0.7 g, 5.2 mmol) inglacial acetic acid (10 mL). After addition of concentrated sulfuric acid (0.4mL) and water (2 mL), the reaction mixture was refluxed for 24h. The mixturewas quenched with a saturated solution of NaThe corresponding starting material was prepared as follows:IExample B-5: Preparation of (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2, 3-b]pyridin-5-yl)-1H- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-5) A flask fitted with a mechanical stirrer, a nitrogen inlet and a thermocouple was placed into a water bath and charged with 8a (520 g, 2.37 mol) and dichloromethane (10 L). To the solution was added solid N-bromosuccinimide (373 g, 2.133 mol) in portions over a 30 minute period. The reaction was stirred for 2 hours and the progress was checked by HPLC. More N-bromosuccinimide was added in small portions until complete consumption of starting material as determined by HPLC (40 g). The solution was poured into warm water (6 L), layers separated and the organics washed with warm water (2.x.6 L), an aqueous solution of sodium thiosulfate (200 g per liter, 2.x.4 L), followed by washing with saturated sodium chloride solution (6 L). The organics were dried over sodium sulfate and solvent removed under reduced pressure. The residue was purified by passing through a short bed of silica to yield 9a as a tan solid. Yield: 620 g, 88percent.Referential

Molecular Weight:298.91
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:297.86026
Monoisotopic Mass:297.86026
Topological Polar Surface Area:38.9
Heavy Atom Count:9
Complexity:101
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes