Cyanomethylenetributylphosphorane → (9aR)-tert-butyl 3-(2-chloro-3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

HRID 1502052Notes

Reaction equation

HRID 1502052 reaction equation
[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11](O)[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@@H:14]1[CH2:26][OH:27].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]1[O:27][CH2:26][C@H:14]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[CH2:12]1

Participants

4

Reactant 2

HCID 4622928CyanomethylenetributylphosphoraneHCID 86727083HCID 86727083, compound

Product 1

HCID 71273621(9aR)-tert-butyl 3-(2-chloro-3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Conditions

Temperature
100 °C

Procedure

(3R)-tert-butyl 4-(2-(2-chloro-3-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (15.6 g, 37.3 mmol) and cyanomethylene tri-n-butyl phosphorane (16.4 g, 67.8 mmol) were dissolved in benzene (90 mL), degassed and heated at 100° C. for 16 h. The reaction mixture was concentrated and chromatographed through a 330 g ISCO Redi-sep column and eluted with 35% EtOAc/hexane to yield the title compound (cis-trans diastereomers mixture). LC-MS (IE, m/z): 396 [M+1]+; The cis-trans diastereomers were separated by SFC-HPLC using the following condition: Chiralpak AD 21×250 mm, 20% IPA, 50 ml/min, ˜85 mg/mL in 1:1 MeOH/MeCN, 100 bar, 220 nm, 35° C. 31A: 1H-NMR (600 MHz, CDCl3) δ ppm 7.826 (dd, J=8.7, 6.5 Hz, 1H), 7.184 (t, J=8.4 Hz, 1H), 4.975 (dd, J=9.6, 1.9 Hz, 1H), 3.989 (b, 2H), 3.953 (dd, J=5.7, 3.2 Hz, 1H) 3.484 (t, J=10.85 Hz, 1H), 3.015 (dd, J=11.4, 2.2 Hz, 2H), 2.733 (d, J=10.3 Hz, 1H), 2.52 (b, 1H), 2.18-2.26 (m, 2H), 1.981 (t, J=10.85 Hz, 1H), 1.474 (s, 9H). 31B: 1H-NMR (600 MHz, CDCl3) δ ppm 8.331 (s, 1H), 7.163 (t, J=8.35 Hz, 1H), 5.038 (t, J=3.7 Hz, 1H), 3.738-3.947 (b, 2H), 3.649 (d, J=10.9 Hz, 1H) 3.371 (s, 1H), 3.02 (dd, J=12, 4.1 Hz, 2H), 2.843 (dd, J=12, 3.8 Hz, 1H), 2.784 (d, J=9.4 Hz, 2H), 2.556 (b, 2H), 1.471 (s, 9H).

Workup

  1. customdegassed
  2. concentrationThe reaction mixture was concentrated
  3. customchromatographed through a 330 g ISCO Redi-sep column
  4. washeluted with 35% EtOAc/hexane

Sources & evidence

ORD record
ord-480070ff41ff4db2b26d0fef73bfd889
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

Loading…