Trifluoroacetic acid → 4-(4-((5-Cyanopyridin-2-yloxy)methyl)-3,3-dimethyl-2-oxopyrrolidin-1-yl)azepane-1-carboxamide

HRID 16205Notes

Reaction equation

HRID 16205 reaction equation
FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=3)[C:24]([CH3:38])([CH3:37])[C:23]2=[O:39])[CH2:17][CH2:16]1)=O)(C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[NH4+:52].[OH-]>ClCCl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH:25]2[CH2:26][N:22]([CH:18]3[CH2:19][CH2:20][CH2:21][N:15]([C:13]([NH2:52])=[O:12])[CH2:16][CH2:17]3)[C:23](=[O:39])[C:24]2([CH3:38])[CH3:37])=[N:30][CH:31]=1)#[N:36]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 14923Ammonium HydroxideHCID 94429TriphosgeneHCID 666569304-[4-(5-Cyano-pyridin-2-yloxymethyl)-3,3-dimethyl-2-oxo-pyrrolidin-1-yl]-azepane-1-carboxylic acid tert-butyl ester

Product 1

HCID 167527104-(4-((5-Cyanopyridin-2-yloxy)methyl)-3,3-dimethyl-2-oxopyrrolidin-1-yl)azepane-1-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

Trifluoroacetic acid (0.75 mL) was added to a solution of Example 2F (0.108 g, 0.24 mmoles) in dichloromethane (0.75 mL) and stirred for one hour. The solvent was evaporated in vacuo. The residue was taken in dichloromethane (1.5 mL) and cooled to −78° C. Triphosgene (24 mg, 0.08 mmoles) was added and stirred for one hour. To the reaction, NH4OH (1 mL) was added and stirred at room temperature for one hour. The product was extracted with dichloromethane, dried with MgSO4, filtered, and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% trifluoroacetic acid) over eighteen minutes at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.48 (dd, J=2.33, 0.64 Hz, 1H), 7.80 (dd, J=8.66, 2.33 Hz, 1H), 6.82 (dd, J=8.66, 0.78 Hz, 1H), 5.81 (b,r, 2H), 4.50 (dd, J=10.87, 6.04 Hz, 1H), 4.36 (dd, J=10.86, 8.24 Hz, 1H), 4.03-4.19 (m, 1H), 3.16 (m, 4H), 3.46 (dd, J=9.85, 7.64 Hz, 1H), 3.08 (dd, J=9.87, 7.94 Hz, 1H), 2.45 (qd, J=7.94, 6.01 Hz, 1H), 1.43-1.82 (m, 6H), 1.24 (s, 3H), 1.06 (s, 3H). MS (APCI+) m/z 386.2 (M+H)+.

Workup

  1. customThe solvent was evaporated in vacuo
  2. stirringstirred for one hour
  3. additionwas added
  4. stirringstirred at room temperature for one hour
  5. extractionThe product was extracted with dichloromethane
  6. dry with materialdried with MgSO4
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe crude reaction mixture
  10. customwas purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size)

Sources & evidence

ORD record
ord-98f233ee8b804324a16424ad2de60716
Source dataset
uspto-grants-2010_06
Patent number
US07737137B2

Reaction notes

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