反应详情

温度

7.5 °C

Isopropyl acetate (570 mL, 488 g) was charged to a (3-L) four-necked reactor (reactor A) equipped with mechanical stirrer, condenser with nitrogen inlet, powder addition funnel, and a thermocouple. 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (Example 90) was charged to the reactor with stirring. The reaction mixture was cooled to 5-10° C. with an ice-bath and DMF (13.8 g) was added. Ammonium hydroxide (28% aqueous, 607 g) and water (144 g) were added to another (5-L), 4-neck reactor (reactor B) equipped with an overhead stirrer, thermocouple, and condenser under nitrogen. The contents of reactor B were cooled 5-10° C. Reactor B was connected to a caustic scrubber. Oxalyl chloride (94.3 g, 0.74 mol) was added through an addition funnel to the stirring slurry in reactor A maintaining temperature between 5 and 15° C. The funnel was rinsed with 50 mL of isopropyl acetate and the reaction mixture was allowed to warm to 10-15° C. The reaction mixture was stirred for an additional 30 min after addition of oxalyl chloride and an aliquot (3 drops) of the reaction mixture was quenched with 0.11 mL of 28% aq. ammonium hydroxide then diluted with CH3CN to 2 mL, and monitored for disappearance of the acid by HPLC (<10-11 area % of the acid). When the reaction was complete, the contents of reactor A were cooled to 5-10° C. The acid chloride from reactor A was transferred to the cooled ammonium hydroxide solution in reactor B over 30 min to 45 min maintaining temperature between 5-15° C. followed by a 50 mL isopropyl acetate rinse. The reaction mixture was stirred at 5-10° C. for 30 min when solids separated out. Heptane (540 mL) was charged at 10-15° C. and stirring continued for 30 min. The slurry was filtered through a funnel lined with polypropylene and the collected solid washed with 800 mL of cold water followed by 800 mL of n-heptane. The solid was dried under vacuum (<20 mm Hg) at 40° C. to give 140.4 g of 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide (94% yield). Chiral purity is 99.4% by HPLC and MW 232(LC/MS).

1. customequipped with mechanical stirrer, condenser with nitrogen inlet, powder addition funnel
2. customequipped with an overhead stirrer
3. temperatureThe contents of reactor B were cooled 5-10° C
4. customReactor B was connected to a caustic scrubber
5. washThe funnel was rinsed with 50 mL of isopropyl acetate
6. temperatureto warm to 10-15° C
7. stirringThe reaction mixture was stirred for an additional 30 min
8. additionafter addition of oxalyl chloride
9. customan aliquot (3 drops) of the reaction mixture was quenched with 0.11 mL of 28% aq. ammonium hydroxide
10. additionthen diluted with CH3CN to 2 mL
11. temperaturethe contents of reactor A were cooled to 5-10° C
12. customThe acid chloride from reactor A was transferred to the cooled ammonium hydroxide solution in reactor
13. temperatureB over 30 min to 45 min maintaining temperature between 5-15° C.
14. washrinse
15. stirringThe reaction mixture was stirred at 5-10° C. for 30 min when solids
16. customseparated out
17. additionHeptane (540 mL) was charged at 10-15° C.
18. stirringstirring
19. filtrationThe slurry was filtered through a funnel
20. washthe collected solid washed with 800 mL of cold water
21. customThe solid was dried under vacuum (<20 mm Hg) at 40° C.