Trifluoroacetic acid → (R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochloride

HRID 331155Notes

Reaction equation

HRID 331155 reaction equation
COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:55])([CH3:54])[C:29]([F:53])([F:52])[C@:30]([C:33]3[CH:38]=[C:37]([C:39]4[CH:40]=[N:41][N:42]([C:44]5[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=5)[CH:43]=4)[CH:36]=[CH:35][C:34]=3[F:51])([CH3:32])[N:31]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[ClH:50].[Cl:50][C:46]1[CH:45]=[C:44]([N:42]2[CH:43]=[C:39]([C:37]3[CH:36]=[CH:35][C:34]([F:51])=[C:33]([C@:30]4([CH3:32])[C:29]([F:52])([F:53])[C:28]([CH3:54])([CH3:55])[O:27][CH2:26][C:25]([NH2:24])=[N:31]4)[CH:38]=3)[CH:40]=[N:41]2)[CH:49]=[CH:48][CH:47]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 68380365[bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine

Product 1

HCID 68380068(R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochlorideYield 133.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine (174 mg, 228 μmol) in dichloromethane (4 ml) was treated at room temperature with trifluoro acetic acid (178·1, 2.28 mmol). The reaction mixture was stirred at room temperature for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the dark red residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 30:60 as the eluent. For further purification, the product (146 mg) was treated with a solution of hydrochloric acid in dioxane (4M, 1 ml). After evaporation at reduced pressure, the residue was triturated with diethyl ether (2 ml). The solid residue was dried at high vacuum an yielded the (R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochloride (76 mg, 67% yield) as a white solid. MS (ISP): m/z=463.2 [M+H]+ and 465.2 [M+2+H]+.

Workup

  1. customFor the workup, the reaction mixture was evaporated at reduced pressure
  2. customthe dark red residue was directly purified by chromatography on an amine-silica phase
  3. customFor further purification
  4. additionthe product (146 mg) was treated with a solution of hydrochloric acid in dioxane (4M, 1 ml)
  5. customAfter evaporation at reduced pressure
  6. customthe residue was triturated with diethyl ether (2 ml)
  7. customThe solid residue was dried at high vacuum

Sources & evidence

ORD record
ord-70bbea4ee8d747c9868545b8fc43a43e
Source dataset
uspto-grants-2014_11
Patent number
US08877744B2

Reaction notes

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