Trimethylsilyl cyanide → (2R,3S)-1-cyano-2-methyl-3-tetrahydropyranyloxy-N-[(R)-1'-phenyl-2'-hydroxyethyl]butylamine

Temperature

0 °C

(R)-phenylglycinol (115 mg, 0.84 mmol) was added at room temperature to a solution of (2S,3S)-2-methyl-3-tetrahydropyranyloxybutyraldehyde (6) (130 mg, 0.7 mmol) in dichloromethane (6 ml), and the stirring was continued for 2 hours at room temperature. The reaction mixture was cooled to 0° C., and methanol (2 ml) and TMSCN (104 mg, 140 μl, 1.05 mmol) were successively introduced. After stirring at 0° C. for 2 hours and then to room temperature for 22 hours, the reaction mixture was separated in saturated NaHCO3 and in ether. The aqueous phase was extracted with ether, the ether extracts were washed with brine, they were dried and filtered on a short disk of Celite and Na2SO4 and then evaporated. Flash chromatography on a silica gel column with, as eluent, a heptane/EtOAc=3:1 then 2:1 mixture produced a mixture of (1R,2R,3S)-1-cyano-2-methyl-3-tetrahydropyranyloxy-N-[(R)-1′-phenyl-2′-hydroxyethyl]butylamine (1R)-(19) and (1S,2R,3S)-1-cyano-2-methyl-3-tetrahydropyranyloxy-N-[(R)-1′-phenyl-2′-hydroxyethyl]butylamine (1S)-(19) (225 mg in total, 97%): IR (CHCl3) 3630, 3442, 3347, 3012, 2947, 2856, 1493, 1455, 1385, 1356, 1231, 1173 cm−1; 1H NMR (250 MHz, CDCl3) δ 7.37 to 7.27 (m, 5H); 4.72 to 4.39 (m, 1H); 4.14 to 3.39 (m, 7H); 2.30 (broad s, 2H, OH+NH); 2.05 to 1.20 (m, 7H); [1.17 (d, J=6.3 Hz), 1.08 (d, J=7.7 Hz), 1.05. (d, J=7.0 Hz), 6H]; 13C NMR (62.5 MHz, CDCl3) δ 140.6; 140.0; 138.7; 138.4; 128.6; 128.0; 127.8; 127.7; 127.3; 120.4; 119.8; 119.6; 119.2; 101.0; 100.1; 97.5; 95.6; 78.9; 76.3; 71.4; 71.2; 67.1; 66.9; 66.0; 65.6; 65.5; 63.2; 63.0; 62.8; 62.7; 53.0; 50.5; 50.1; 49.9; 42.7; 42.5; 42.3; 31.0; 30.8; 30.6; 25.2; 25.0; 21.6; 20.0; 19.6; 19.4; 18.3; 17.0; 16.1; 14.0; 12.7; 12.0; 11.7. MS (CI) m/z 333 [M+H]+. HRMS: calculated for C19H29N2O3 (M+H), 333.21780; found, 333.21668.

1. waitto room temperature for 22 hours
2. customthe reaction mixture was separated in saturated NaHCO3 and in ether
3. extractionThe aqueous phase was extracted with ether
4. washthe ether extracts were washed with brine, they
5. customwere dried
6. filtrationfiltered on a short disk of Celite and Na2SO4
7. customevaporated
8. customFlash chromatography on a silica gel column with, as eluent, a heptane/EtOAc=3:1 then 2:1 mixture produced

ORD record

ord-60b078ffadf44a6e815bd266584c665c

Source dataset

uspto-grants-2008_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07432087B2