4-Methylmorpholine → 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-2-methyl-thiazole-5-carboxylic acid amide

HRID 925279Notes

Reaction equation

HRID 925279 reaction equation
[F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57][NH2:58])=[CH:55][CH:54]=1>CN(C=O)C>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([NH:58][CH2:57][C:56]1[CH:59]=[CH:60][C:53]([F:52])=[CH:54][CH:55]=1)=[O:13]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 673264-FluorobenzylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 867201724-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid

Product 1

HCID 762877054-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-2-methyl-thiazole-5-carboxylic acid amideYield 58.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid (0.25 g, 0.72 mmol) in DMF (4 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (347 mg, 1.08 mmol) and N-methylmorpholine (0.16 ml, 1.44 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (0.01 ml, 0.86 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×15 ml). The combined organic layers are washed with brine (20 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 5% acetone/hexane) followed by preparative HPLC affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-2-methyl-thiazole-5-carboxylic acid amide (example 15) (0.2 g, 0.42 mmol, 36%). [M+H]+ 455.1.

Workup

  1. customAfter completion of the reaction
  2. additionthe mixture is poured onto ice-water
  3. extractionextracted with EtOAc (3×15 ml)
  4. washThe combined organic layers are washed with brine (20 ml)
  5. dry with materialdried over sodium sulfate
  6. customevaporated to dryness
  7. customto yield the crude product, which
  8. customis purified by column chromatography (silica gel, 5% acetone/hexane)

Sources & evidence

ORD record
ord-99118658be3f4d9e85c4f5a373a7b1e1
Source dataset
uspto-grants-2016_03
Patent number
US09284286B2

Reaction notes

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