Hydrochloric Acid → (2R,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one

Temperature

-78 °C

A solution of (5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 12) (5.77 g, 14.82 mmol) in DCM (75 mL) was cooled to −78° C. under nitrogen and a solution of borane tert-butylamine complex (1.43 g, 16.44 mmol) in DCM (15 ml) was added dropwise maintaining the internal temperature below −70° C. over 10 mins. The mixture was stirred at −78° C. for 90 mins and then the cooling bath was removed and 5M hydrochloric acid (30 mL, 150 mmol) was added via the dropping funnel over 1-2 mins. The mixture was brought to 25-30° C. with a water bath and the mixture stirred vigourously for 30 mins. More DCM (200 ml) was added and the mixture was then slowly poured into a beaker containing sodium carbonate (17.28 g, 163.01 mmol) in water (150 ml) and the mixture was stirred for 10 mins. The layers were separated and the aqueous layer (pH 9) was re-extracted with DCM (2×150 ml). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a yellow gum, a 15:1 mixture of (2R,5S) and (2S,5S) isomers. This mixture was separated by chromatography using a Biotage SNAP 340 g cartridge eluting with 5% of 0.5M methanolic ammonia in ethyl acetate (isocratic) to obtain the major isomer (2R,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (5.76 g), increasing to 10% of 0.5M methanolic ammonia to elute the minor (2S,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one isomer (111 mg) which was contaminated by traces of the (2R,5S) isomer. The (2R,5S) isomer was identical spectroscopically to that prepared in Example 1. This was then converted to the salt form: Sulphuric acid (0.75 mL, 13.48 mmol) was added to a solution of (2R,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (5.27 g, 13.48 mmol) in DCM (70 mL) at 20° C. and the reaction stirred for 5 mins. The solvent was evaporated and the residue was triturated with diethyl ether and dried. This solid (approx. 6 g) was dissolved in acetone (30 ml) and then added dropwise to diethyl ether (600 ml) with rapid stirring.

1. temperaturemaintaining the internal temperature below −70° C. over 10 mins
2. customthe cooling bath was removed
3. customThe mixture was brought to 25-30° C. with a water bath
4. stirringthe mixture stirred vigourously for 30 mins
5. additionthe mixture was then slowly poured into a beaker
6. stirringthe mixture was stirred for 10 mins
7. customThe layers were separated
8. extractionthe aqueous layer (pH 9) was re-extracted with DCM (2×150 ml)
9. washThe combined organic layers were washed with brine
10. dry with materialdried (Na2SO4)
11. concentrationconcentrated
12. customto give a yellow gum
13. additiona 15:1 mixture of (2R,5S) and (2S,5S) isomers
14. customThis mixture was separated by chromatography
15. washeluting with 5% of 0.5M methanolic ammonia in ethyl acetate (isocratic)

ORD record

ord-461902da91f94c24a26b27c63295bbf0

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09303032B2