Hydrochloric Acid → (4r,7s)-2-(2,4-Difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one

A solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; ˜15 mmol) in 1,2-dichloroethane (25 mL) was added by syringe over a period of 5 min to a cooled (0° C.) solution of N-(2,4-difluoro-phenyl)-N′-ethylidene-hydrazine (Intermediate 26; 2.32 g, 13.6 mmol) and pyridine (1.8 mL, 22.3 mmol) in 1,2-dichloroethane (15 mL). The flask containing the acid chloride was rinsed with 1,2-dichloroethane (10 mL). The reaction mixture was stirred at room temperature for 15 min and then at 50° C. for 45 min. A solution of HCl in dioxane (Aldrich; 4 M, 11 mL, 44 mmol) was added. The solution was stirred for 5 min at room temperature and then acetic acid (18 mL) was added. The reaction mixture was stirred at 100° C. under argon for 1 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (150 mL) and 1:1 water/brine (75 mL). The organic layer was washed with 1:1 water/brine (50 mL), and the combined aqueous layers were extracted with ethyl acetate (50 mL). The combined ethyl acetate extracts were washed with brine (100 mL), dried (sodium sulfate), filtered, and evaporated to give a dark brown semi-solid which was stored in the freezer overnight and then triturated with diethyl ether. The solid was filtered off, washed with ether and air-dried to give (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.93 g, 47%) as a light brown solid which was used directly in the next step without further purification.

1. washwas rinsed with 1,2-dichloroethane (10 mL)
2. waitat 50° C. for 45 min
3. stirringThe solution was stirred for 5 min at room temperature
4. stirringThe reaction mixture was stirred at 100° C. under argon for 1 h
5. customThe solvent was evaporated
6. customthe residue was partitioned between ethyl acetate (150 mL) and 1:1 water/brine (75 mL)
7. washThe organic layer was washed with 1:1 water/brine (50 mL)
8. extractionthe combined aqueous layers were extracted with ethyl acetate (50 mL)
9. washThe combined ethyl acetate extracts were washed with brine (100 mL)
10. dry with materialdried (sodium sulfate)
11. filtrationfiltered
12. customevaporated
13. customto give a dark brown semi-solid which
14. customwas stored in the freezer overnight
15. customtriturated with diethyl ether
16. filtrationThe solid was filtered off
17. washwashed with ether
18. customair-dried

ORD record

ord-c962451b8ccd4cd7879d4908009ff0a6

Source dataset

uspto-grants-2009_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07622492B2