Diisopropylethylamine → 1-[(4R)-7,8-difluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)urea

HRID 868889Notes

Reaction equation

HRID 868889 reaction equation
Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]2)=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C.[Cl-].[F:35][C:36]1[C:45]([F:46])=[C:44]2[C:39]([C@H:40]([NH3+:49])[CH2:41][C:42]([CH3:48])([CH3:47])[O:43]2)=[CH:38][CH:37]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:35][C:36]1[C:45]([F:46])=[C:44]2[C:39]([C@H:40]([NH:49][C:2]([NH:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][C:20](=[O:24])[NH:21]4)=[CH:16][CH:15]=3)=[O:4])[CH2:41][C:42]([CH3:47])([CH3:48])[O:43]2)=[CH:38][CH:37]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 52002427-amino-3,4-dihydro-1H-quinolin-2-oneHCID 86689139(R)-7,8-difluoro-2,2-dimethylchroman-4-aminium chloride

Product 1

HCID 716119071-[(4R)-7,8-difluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ureaYield 255.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 516892Sodium BicarbonateSolvent

Procedure

Triphosgene (0.281 g, 0.948 mmol) (Sigma-Aldrich) in THF (5 mL) was added to a to a solution of 7-amino-3,4-dihydroquinolin-2(1H)-one (0.4659 g, 2.87 mmol) (Astatech, Inc) and DIEA (2.01 mL, 11.5 mmol) (Aldrich) in THF (28 mL) at room temperature. After 10 minutes (R)-7,8-difluoro-2,2-dimethylchroman-4-aminium chloride (0.717 g, 2.87 mmol) (B-8; WO2010/04401) was added and the mixture was stirred for an additional 2 hours. The mixture was diluted with saturated aqueous NaHCO3 (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with 1 N aqueous HCl (30 mL) and concentrated. The residue was purified by silica gel chromatography (5% MeOH/CH2Cl2) to afford the title compound (0.970 g, 2.42 mmol, 84% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.50 (s, 1H), 7.14-6.84 (m, 5H), 6.44 (d, J=8.6 Hz, 1H), 4.95 (dd, J=15.7, 9.7 Hz, 1H), 2.78 (t, J=7.5 Hz, 2H), 2.41 (dd, J=8.4, 6.5 Hz, 2H), 2.16 (dd, J=13.4, 6.1 Hz, 1H), 1.80 (dd, J=13.2, 11.3 Hz, 1H), 1.45 (s, 3H), 1.32 (s, 3H); MS (ESI+) m/z 402 (M+H)+, 400 (M−H)+.

Workup

  1. extractionextracted with EtOAc (3×30 mL)
  2. washThe combined organic extracts were washed with 1 N aqueous HCl (30 mL)
  3. concentrationconcentrated
  4. customThe residue was purified by silica gel chromatography (5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-ca3cd2a80ddf4d1eb95eb4f162de6273
Source dataset
uspto-grants-2015_03
Patent number
US08969325B2

Reaction notes

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