Methanol → Methyl cis(+/-)1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate

HRID 255384Notes

Reaction equation

HRID 255384 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]3[C:22]([O:24][CH3:25])=[O:23])[C:7]=2[CH:26]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:34]/[CH:35]=[CH:36]/[C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[F:44].CO>C(O)C.ClCCl>[F:44][C:38]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=1/[CH:36]=[CH:35]/[CH2:34][N:19]1[CH2:20][CH2:21][C@H:16]([CH2:15][CH2:14][CH2:13][N:8]2[C:7]3[CH:26]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18]1

Participants

7

Reactant 4

HCID 887MethanolHCID 11430Potassium CarbonateHCID 11608064(E)-2-(3-Chloroprop-1-en-1-yl)-1,4-difluorobenzene2×HCID 66775079methyl 4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate2×

Product 1

HCID 86642666Methyl cis(+/-)1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylateYield 56.3%

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

A solution of methyl 4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Intermediate 220) (150 mg, 0.414 mmol) in ethanol (2 mL) was treated with K2CO3 (63 mg, 0.455 mmol) followed by a solution of 2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124) (86 mg, 0.455 mmol) in ethanol (1 mL). The reaction was warmed to 40° C. for 18 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with dichloromethane (2×20 mL). The organic extracts were combined, dried over MgSO4 and concentrated at reduced pressure to obtain a yellow oil. Chromatography on silica gel eluting with (0-2.5%) methanol in dichloromethane gave the title compound as a yellow oil (120 mg, 56%).

Workup

  1. customThe reaction was partitioned between ethyl acetate and water
  2. extractionThe aqueous layer was extracted with dichloromethane (2×20 mL)
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated at reduced pressure
  5. customto obtain a yellow oil

Sources & evidence

ORD record
ord-5b2f476166484b7a9b24026ec9e0c885
Source dataset
uspto-grants-2011_01
Patent number
US07875715B2

Reaction notes

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