Sodium Bicarbonate → 4-Fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide

HRID 1516331Notes

Reaction equation

HRID 1516331 reaction equation
C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[F:16][C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:32]=3)[O:27][CH2:26][C@@H:25]2[OH:40])=[O:22])=[CH:19][CH:18]=1.[O:43]1[CH2:46][C:45](=O)[CH2:44]1.C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[F:16][C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([N:34]4[CH2:39][CH2:38][N:37]([CH:45]5[CH2:46][O:43][CH2:44]5)[CH2:36][CH2:35]4)[CH:32]=3)[O:27][CH2:26][C@@H:25]2[OH:40])=[O:22])=[CH:19][CH:18]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride3×HCID 150242543-Oxetanone3×HCID 672807314-Fluoro-N-[(3R,4S)-3-hydroxy-6-piperazin-1-yl-chroman-4-yl]benzamide hydrochloride

Product 1

HCID 672813934-Fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamideYield 73%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

Add sodium triacetoxyborohydride (20 g, 94.4 mmol) to a slurry of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-piperazin-1-yl-chroman-4-yl]benzamide hydrochloride (32.0 g, 78.5 mmol) and 3-oxetanone (6.87 g, 98.1 mmol) in acetonitrile (300 mL). Stir the slurry for 20 min. and add more sodium triacetoxyborohydride (20 g, 94.4 mmol) in one portion. Stir the brown mixture at 28° C. for approximately 2 hr. Add additional sodium triacetoxyborohydride (10 g, 47.2 mmol) and stir the mixture for 30 min. Add 3-oxetanone (2 g, 28.6 mmol) and after 20 min add additional 3-oxetanone (1 g, 14.3 mmol). Stir for 30 min., pour the mixture into a saturated aqueous sodium bicarbonate solution (1 L) and add dichloromethane (1 L). Separate the organic layer and concentrate in vacuo to obtain a pale grey solid. Purify the solid by silica gel column chromatography eluting with 3 to 6% isopropanol/dichloromethane to obtain the title compound as a white solid (19.2 g, 73%). LC-ES/MS m/z 428 [M+H]+.

Workup

  1. stirringStir the brown mixture at 28° C. for approximately 2 hr
  2. stirringstir the mixture for 30 min
  3. stirringStir for 30 min.
  4. customSeparate the organic layer
  5. concentrationconcentrate in vacuo
  6. customto obtain a pale grey solid
  7. customPurify the solid by silica gel column chromatography
  8. washeluting with 3 to 6% isopropanol/dichloromethane

Sources & evidence

ORD record
ord-d64a0cba9e394e3985162187c5a0d06c
Source dataset
uspto-grants-2012_07
Patent number
US08227468B2

Reaction notes

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