tert-Butyl methyl ether → N-[(3R,4S)-6-Bromo-3-hydroxy-chroman-4-yl]-4-fluoro-benzamide

HRID 1516325Notes

Reaction equation

HRID 1516325 reaction equation
[NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[O:5][CH2:4][C@@H:3]1[OH:13].C(=O)(O)[O-].[Na+].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(OC)(C)(C)C>O1CCCC1.O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][C@H:3]([OH:13])[C@H:2]2[NH:1][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1

Participants

7

Reactant 4

HCID 15413tert-Butyl methyl etherHCID 678794-Fluorobenzoyl chlorideHCID 516892Sodium BicarbonateHCID 67280416(3R,4S)-4-Amino-6-bromochroman-3-ol

Product 1

HCID 67281102N-[(3R,4S)-6-Bromo-3-hydroxy-chroman-4-yl]-4-fluoro-benzamideYield 221.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of (3R,4S)-4-amino-6-bromo-chroman-3-ol (692 g, 2.84) and sodium bicarbonate (476 g, 5.67 mol) in tetrahydrofuran (3.0 L) and water (3.0 L) at 17° C. add 4-fluorobenzoyl chloride (369 mL, 3.12 mol) dropwise via addition funnel over 15 min. and stir for 2 hr. Add water (2 L) and methyl tert-butyl ether (3.5 L) and stir for 5 min. Separate the organic phase and wash it with water (2 L) and brine (2 L). Dry the organic portion over anhydrous magnesium sulfate and concentrate in vacuo to obtain a pale yellow solid (2.3 kg). Triturate the solid in heptane (5 L) at 25° C. for 3 h. Collect by filtration and dry in an oven at 50° C. for 12 hr. to obtain the title compound (975 g, 94%) as a white solid. LC-ES/MS m/z (79Br/81Br) 366/368 [M+H]+.

Workup

  1. additiondropwise via addition funnel over 15 min.
  2. customSeparate the organic phase
  3. washwash it with water (2 L) and brine (2 L)
  4. dry with materialDry the organic portion over anhydrous magnesium sulfate
  5. concentrationconcentrate in vacuo

Sources & evidence

ORD record
ord-3809c7f988284d59bd6339e466ef7ebe
Source dataset
uspto-grants-2012_07
Patent number
US08227468B2

Reaction notes

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