Trifluoroacetic acid → alpha-(R)-(3-(S)-((4-(6-ethoxy-benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid

HRID 1068148Notes

Reaction equation

HRID 1068148 reaction equation
F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9](=[N:19][OH:20])[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=O)[CH3:17])[CH2:12][CH2:11]1.[OH-].[K+].C([C@@H]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][N:27]([C@H:36]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[C:37]([O:39]CC2C=CC(OC)=CC=2)=[O:38])[CH2:26]1)=O.[C:55](O)([C:57](F)(F)F)=[O:56].C1(OC)C=CC=CC=1>CCO>[CH2:55]([O:56][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]4[C@@H:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:28][N:27]([C@H:36]([CH:49]5[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]5)[C:37]([OH:39])=[O:38])[CH2:26]4)[CH2:12][CH2:11]3)=[N:19][O:20][C:2]=2[CH:7]=1)[CH3:57]

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 14797Potassium HydroxideHCID 53654320alpha-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl esterHCID 867570241-(4-((2,4-Difluorophenyl)-hydroxyimino-methyl)piperidin-1-yl)ethanone

Product 1

HCID 20664145alpha-(R)-(3-(S)-((4-(6-ethoxy-benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of 1-(4-((2,4-difluorophenyl)-hydroxyimino-methyl)piperidin-1-yl)ethanone (from Step A) and KOH (45 wt. % solution) in EtOH was refluxed for 24 hours. The products were coupled with of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) using a procedure analogous to that described in Example 89, Step C. The products were treated with TFA and anisole for 18 hours and concentrated under reduced pressure. The residue was purified by prep HPLC (Zorbax-RX C8 column, 30% CH3CN 15 min. and 100% CH3CN, 20 mL/min., 254 nm) to provide α-(R)-(3-(S)-((4-(6-ethoxy-benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid: ESI-MS 546 (M+1); HPLC A: 3.01 min.; and α-(R)-(3-(S)-((4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid: ESI-MS 520 (M+1); HPLC A: 2.88 min.

Workup

  1. concentrationconcentrated under reduced pressure
  2. customThe residue was purified by prep HPLC (Zorbax-RX C8 column, 30% CH3CN 15 min. and 100% CH3CN, 20 mL/min., 254 nm)

Sources & evidence

ORD record
ord-b97bae13a51246a8b96f41e872f9bf65
Source dataset
uspto-grants-2001_06
Patent number
US06248755B1

Reaction notes

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