Tetrahydrofuran → (4S)-5-(4-fluorophenyl)-6-{(R)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-3,4-dihydro-spiro[chromen-2,1'-cyclobutan]-4-ol

Under argon, 3.1 mg (0.02 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 3 ml of abs. tetrahydrofuran, 0.15 ml (0.84 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 105 mg (0.21 mmol) of 5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 53A), dissolved in 4 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 6 h. 3 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 10:1). This gives 110 mg of a mixture of the two target compounds. Subsequent chromatographic separation on a chiral phase [column: chiral silica gel selector based on poly(N-methacryloyl-L-leucine-tert-butylamide), 670 mm×40 mm; mobile phase: MTBE/isohexane 15:85; flow rate: 80 ml/min; 24° C.; detection: 280 nm] gives 36 mg (36% of theory, 98% ee) of Example 30 and 45 mg (43% of theory, >99% ee) of Example 31.

1. stirringthe mixture is then stirred at room temperature for 6 h
2. stirringthe mixture is stirred for 15 min
3. concentrationconcentrated to dryness
4. washwashed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution
5. dry with materialThe organic phase is dried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customThe crude product is purified on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 10:1)
9. customSubsequent chromatographic separation on a chiral phase [column: chiral silica gel selector based on poly(N-methacryloyl-L-leucine-tert-butylamide), 670 mm×40 mm; mobile phase: MTBE/isohexane 15:85; flow rate: 80 ml/min; 24° C.; detection: 280 nm]
10. customgives 36 mg (36% of theory, 98% ee) of Example 30 and 45 mg (43% of theory, >99% ee) of Example 31

ORDレコード

ord-72e44c10c7294645b69a4dc78a93da6a

出典データセット

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08227511B2