Sodium Hydroxide → N-[(4-chlorophenyl)-methyl]-2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamide

HRID 515190Notes

Reaction equation

HRID 515190 reaction equation
[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[C:12]([CH3:22])[C:8]=2[C:9]([NH2:11])=[O:10])[CH2:3]1.[OH-].[Na+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>O1CCCC1.C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:11][C:9](=[O:10])[C:8]2[C:12]([CH3:22])=[CH:13][C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:15][C:7]=2[N:4]2[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]2)=[CH:28][CH:27]=1

Participants

7

Reactant 3

HCID 14798Sodium HydroxideHCID 693291-(Bromomethyl)-4-chlorobenzeneHCID 86699757HCID 86699757, compound

Product 1

HCID 72188141N-[(4-chlorophenyl)-methyl]-2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamideYield 22%

Reagents, catalysts & solvents 3

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 8028TetrahydrofuranSolventHCID 22633675Benzene tetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamide (0.13 g, 0.42 mmol) in tetrahydrofuran/benzene (1:1) (6 ml) is added tetrabutylammonium hydrogen sulfate (15.0 mg, 0.04 mmol) followed by the addition of 15% aqueous sodium hydroxide (3.7 ml) at room temperature. A solution of 4-chloro-benzyl bromide (0.087 g, 0.42 mmol) in tetrahydrofuran (1 ml) is slowly added to the solution and the resulting mixture is heated to 80° C. for 45 min. The mixture is cooled to room temperature and extracted with ethyl acetate (3×10 ml). The combined organic layers are washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to get crude product, which is purified by flash column chromatography (silica gel, 10% acetone/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamide (example 38) (0.04 g, 0.09 mmol, 22%). [M+H]+ 432.2.

Workup

  1. temperatureThe mixture is cooled to room temperature
  2. extractionextracted with ethyl acetate (3×10 ml)
  3. washThe combined organic layers are washed with water (10 ml), brine (10 ml)
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customto get crude product, which
  7. customis purified by flash column chromatography (silica gel, 10% acetone/hexane)

Sources & evidence

ORD record
ord-688dfca2752544d7a09df13384ac6e1f
Source dataset
uspto-grants-2015_08
Patent number
US09108936B2

Reaction notes

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