Acetic Acid → HCID 59458670, compound

HRID 238844Notes

Reaction equation

HRID 238844 reaction equation
[F:1][C:2]1([F:41])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH:39]=O)[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1.[NH:42]([CH3:44])[CH3:43].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:1][C:2]1([F:41])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH2:39][N:42]([CH3:44])[CH3:43])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:27])[F:28])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 674DimethylamineHCID 5003444Sodium cyanoborohydrideHCID 59458908HCID 59458908, compound

Product 1

HCID 59458670HCID 59458670, compoundYield 44%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of (R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-formylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (20 mg, 0.03 mmol) in MeOH (2 mL) was added NHMe2 (0.009 mL) and a drop of acetic acid. The reaction mixture was stirred at rt for 30 min, followed by addition of NaCNBH3 (2 mg, 0.03 mmol). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between sat. NaHCO3 and EtOAc. The organic phase was concentrated and purified by prep HPLC (Phemomenex Luna 5u C18 Axia column, 21×100 mm, 10%-90% H2O/ACN with 0.1% TFA/, monitoring at 220 nm) to yield (R)-1-(3,3-difluorocyclobutyl)-3-(1-(3-((dimethylamino)methyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (Example 328, 8 mg, 44% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (d, J=2.27 Hz, 1H), 7.09 (m, 7H), 6.88 (d, J=8.84 Hz, 1H), 6.63 (d, J=7.07 Hz, 2H), 6.51 (br. s., 1H), 5.88 (m, 1H), 4.34 (d, J=12.63 Hz, 1H), 4.10 (m, 2H), 3.87 (m, 1H), 3.31 (d, J=12.63 Hz, 2H), 2.92 (m, 3H), 2.74 (d, J=2.78 Hz, 3H), 2.70 (d, J=3.28 Hz, 3H), 2.46 (m, 2H).

Workup

  1. stirringThe reaction mixture was stirred at rt for 1 h
  2. customThe solvent was removed under reduced pressure
  3. customthe residue was partitioned between sat. NaHCO3 and EtOAc
  4. concentrationThe organic phase was concentrated
  5. custompurified by prep HPLC (Phemomenex Luna 5u C18 Axia column, 21×100 mm, 10%-90% H2O/ACN with 0.1% TFA/, monitoring at 220 nm)

Sources & evidence

ORD record
ord-3aec4c3f7b474d41bb0db716c9aef1dc
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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