Methanone, (6-?bromoimidazo[1,?2-?a]?pyridin-?3-?yl)?-?4-?morpholinyl- synthesis

Yield:1434089-03-8 84%

Reaction Conditions:

Stage #1: 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid in 1,4-dioxane at 20; for 0.25 h;Inert atmosphere;
Stage #2: with thionyl chloride in 1,4-dioxane;N,N-dimethyl-formamide at 0 - 102;Reflux;Inert atmosphere;
Stage #3: morpholine in 1,4-dioxane;N,N-dimethyl-formamide at 20;Inert atmosphere;

Steps:

5 Synthesis of compound 9

[003211 Example 5[00322] Synthesis of compound 9:[00323] 1. An appropriately sized round bottom flask (5 L) was equipped with a mechanical stirrer,[00324] thermocouple, addition funnel, nitrogen inlet and a cooling bath.[00325] 2. The flask was charged with dioxane (2.73 L) and compound 8 (273 g) at room temperature under a[00326] nitrogen atmosphere.[00327] 3. The resulting slurry was stirred for 15 minuntes at room temperature.[00328] 4. DMF (8.3 g) was added at room temperature.[00329] 5. The reaction mixture was cooled to 0°C to 5°C.[00330] 6. Thionyl Chloride (269 g) was slowly added via the addition funnel to the reaction mixture, maintaining an internal temperature between 0°C to 5°C. The addition funnel was rinsed with a minimum amount of 1,4-Dioxane (135 mL; 0.5 vol).[00331] 7. The reaction mixture was heated to reflux (98°C to 102°C) and stirred for 12 to 20 hours.[00332] 8. The reaction progress was monitored by HPLC.[00333] 9. Upon completion, the reaction mixture was cooled to 0°C to 10°C.[00334] 10. Morpholine (492 g) was added slowly via the addition funnel to the reaction mixture, maintainingan internal temperature between 0°C to 10°C under a nitrogen atmosphere.[00335] 11. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 to 18 hours.[00336] 12. Progress of the reaction was monitored by HPLC.[00337] 13. Upon completion, the solvent was removed under vacuum at [00338] 14. The slurry was transferred into a round bottom flask and cooled to room temperature.[00339] 15. Water (5.46 L) was added at room temperature.[00340] 16. The resulting mixture was stirred for 3 hours at room temperature.[00341] 17. The solid was collected by filtration and washed with water (2 x 1.4 L) and heptane (2 x 1.4L).18. The solid was dried under vacuum at 50°C to constant weight to givecompound 9 as a beige solid (296 g, 84 % yield; HPLC purity 99.5 %; 'HNMR (DMSO-d6, 300 MHz) ? 9.2 (s, 1H), 7.8 (s, 1H), 7.58- 7.5 (d, 1H), 7.45-7.38 (d, 1H), 3.9-3.7 (m, 8H)).

References:

WO2013/71272,2013,A1 Location in patent:Paragraph 00321-00341