Methanol → t-butyl 4-[2-(4-cyano-2-fluoro-5-methoxyphenoxy)ethyl]-5-cyclopropyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate

HRID 516262Notes

Reaction equation

HRID 516262 reaction equation
F[C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1([C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20][C:19]=3[CH:18]=[C:17]3[O:33][CH2:34][CH2:35][N:36]([CH2:37][CH2:38][OH:39])[C:16]=23)[CH2:14][CH2:13]1.C[C:41](C)([O-:43])C.[K+].CO>C1COCC1.C(OCC)(=O)C>[C:4]([C:3]1[C:2]([O:43][CH3:41])=[CH:9][C:8]([O:39][CH2:38][CH2:37][N:36]2[C:16]3=[C:15]([CH:12]4[CH2:13][CH2:14]4)[C:25]4[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20][C:19]=4[CH:18]=[C:17]3[O:33][CH2:34][CH2:35]2)=[C:7]([F:11])[CH:6]=1)#[N:5]

Participants

7

Reactant 4

HCID 887Methanol2×HCID 5938132,4,5-TrifluorobenzonitrileHCID 23665647Potassium tert-butoxide3×HCID 66982760t-butyl 5-cyclopropyl-4-(2-hydroxyethyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate

Product 1

HCID 71280857t-butyl 4-[2-(4-cyano-2-fluoro-5-methoxyphenoxy)ethyl]-5-cyclopropyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylateYield 104.9%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-30 °C

Procedure

To a solution of 210 mg of 2,4,5-trifluorobenzonitrile and 500 mg of t-butyl 5-cyclopropyl-4-(2-hydroxyethyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 15 ml of THF was added portionwise 150 mg of potassium t-butoxide, followed by stirring at −30° C. for 2 hours. Further, to the reaction mixture was added 0.15 ml of MeOH and then 150 mg of potassium t-butoxide was added portionwise thereto, followed by elevating the temperature to −10° C. and stirring for 15 hours. Further, to the reaction mixture were added 0.15 ml of MeOH, and then 150 mg of potassium t-butoxide was added portionwise thereto, followed by elevating the temperature to 0° C. and stirring for additional 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc)) to obtain 726 mg of t-butyl 4-[2-(4-cyano-2-fluoro-5-methoxyphenoxy)ethyl]-5-cyclopropyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a colorless viscous substance.

Workup

  1. customto −10° C.
  2. stirringstirring for 15 hours
  3. customto 0° C.
  4. stirringstirring for additional 14 hours
  5. washwashed with water and saturated brine
  6. dry with materialdried over anhydrous magnesium sulfate
  7. filtrationfiltered
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customThe residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc))

Sources & evidence

ORD record
ord-f0e7665ac94f410da92775eeb880a1b3
Source dataset
uspto-grants-2015_08
Patent number
US09108977B2

Reaction notes

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