2-Amino-2-methyl-1-propanol → (2S,3S)-2-(3-fluorophenyl)-3,5,5-trimethylmorpholin-2-ol

HRID 1399525Notes

Reaction equation

HRID 1399525 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@H:9]2[CH3:10])[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 118072-Amino-2-methyl-1-propanolHCID 67749Trifluoromethanesulfonic anhydrideHCID 88675Proton spongeHCID 46838072(R)-1-(3-fluorophenyl)-2-hydroxypropan-1-one

Product 1

HCID 46837648(2S,3S)-2-(3-fluorophenyl)-3,5,5-trimethylmorpholin-2-olYield 39%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Compound 4c was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-fluorophenyl)-2-hydroxypropan-1-one (10c, 3.94 g, 0.024 mol), Proton sponge (6.0 g), triflic anhydride (4.6 mL, 25.8 mmol), and 2-amino-2-methyl-1-propanol (4.6 g, 0.052 mol) in acetonitrile (50 mL). After purification, 2.2 g (39%) of the free base 4c was isolated and converted to the hemi-D-tartrate salt, which had >99% ee: mp 131-132° C.; [α]20D +20.4° (c 1.0, CH3OH); 1H NMR (methanol-d4) δ 7.45-7.41 (m, 2H), 7.35-7.31 (m, 1H), 7.11-7.09 (m, 1H), 4.33 (s, 1H), 4.26 (d, 1H, J=12.0 Hz), 3.56-3.45 (m, 2H), 1.59 (s, 3H), 1.34 (s, 3H), 1.06 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 178.1, 165.4, 162.1, 144.8, 130.8, 123.2, 116.3 (d), 114.3 (d), 96.2, 74.5, 67.0, 54.3, 23.6, 20.8, 13.7; LCMS (ESI) m/z 240.0 [(M-tartrate)+, M=C15H21FNO5]; Anal. (C15H21FNO5.0.5H2O) calcd: C, 55.72; H, 6.86; N, 4.33. found: C, 55.61; H, 6.89; N, 4.33.

Workup

  1. customCompound 4c was synthesized by a procedure similar to
  2. customAfter purification

Sources & evidence

ORD record
ord-7f136fcd4ebd49b98049b26a044371f0
Source dataset
uspto-grants-2014_12
Patent number
US08906908B2

Reaction notes

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