Cyanomethylenetributylphosphorane → tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate

HRID 1502084Notes

Reaction equation

HRID 1502084 reaction equation
[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([CH:10]([OH:28])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][CH2:26]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([CH:10]2[CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]3[CH2:25][CH2:26][O:28]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]

Participants

4

Reactant 2

HCID 4622928CyanomethylenetributylphosphoraneHCID 89619232Tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

Product 1

HCID 89618843tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Conditions

Temperature
100 °C

Procedure

tert-Butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (2.61 g, 6.41 mmol) and dissolved in benzene (60 mL) and added cyanomethylene tributyl phosphorane (2.78 g, 11.5 mmol). The mixture was placed into four separate 20 mL microwave tubes then heated at 100° C. overnight. The reaction mixtures were combined, concentrated then purified by MPLC chromatography using a 330 g ISCO Redi-Sep column and 5% acetone-95% DCM solvent system. Under these purification conditions was separated tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate cis diastereomers from the trans diastereomers LC-MS (IE, m/z): 334 [(M-56)+1]+; The cis-diastereomers were further separated to S,R and R,S diastereomers using the following conditions: Chiral IC column: 30×250 mm, 20% MeOH:/CO2, 70 mL/min, 100 bar, 50 mg/ml in MeOH, 35° C., 330 nm: cis-diastereomer A: 1H-NMR (600 MHz, CDCl3) δ ppm 7.88 (dd, J=8.7, 6.2 Hz, 1H), 7.04 (t, J=8.6 Hz, 1H), 4.83 (s, 1H), 4.03 (d, J=12.9 Hz, 1H), 3.86 (t, J=11.3 Hz, 1H), 3.79-3.96 (b, 2H), 2.93 (q, 2H), 2.83 (b, 1H), 2.56-2.63 (m, 4H), 2.53 (s, 3H), 1.78-1.87 (m, 2H), 1.49 (s, 9H).

Workup

  1. customseparate 20 mL microwave tubes
  2. customThe reaction mixtures
  3. concentrationconcentrated
  4. customthen purified by MPLC chromatography
  5. customUnder these purification conditions
  6. customwas separated tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate
  7. customThe cis-diastereomers were further separated to S,R and R,S diastereomers
  8. custom35° C., 330 nm

Sources & evidence

ORD record
ord-b1526c19b06c4313bb339892a8781a10
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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