Triethylamine → 6-[(R)-1-(2,4-difluoro-phenyl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid

HRID 926357Notes

Reaction equation

HRID 926357 reaction equation
C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:20])C(Cl)(Cl)Cl)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@H:29]([NH2:32])[CH2:30][CH3:31].C(N(CC)CC)C.[OH-].[K+]>O1CCCC1.CO.O>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@H:29]([NH:32][C:15]([C:8]1[N:9]2[C:10]([CH2:11][O:12][CH2:13][CH2:14]2)=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=1)=[O:20])[CH2:30][CH3:31]

Participants

8

Reactant 4

HCID 8471Triethylamine2×HCID 14797Potassium Hydroxide2×HCID 28496164(R)-1-(2,4-Difluorophenyl)propan-1-amine2×HCID 897269186-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester

Product 1

HCID 897269156-[(R)-1-(2,4-difluoro-phenyl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acidYield 60%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 4a) (1 g, 2.94 mmol) in anhydrous tetrahydrofuran (9 ml) was added (R)-1-(2,4-difluoro-phenyl)-propylamine (0.5 g, 2.94 mmol) and triethylamine (1.22 ml, 8.8 mmol). The resulting mixture was stirred for 24 h, then another portion of (R)-1-(2,4-difluoro-phenyl)-propylamine (0.05 g) and triethylamine (0.8 ml) was added. The mixture was stirred for 2 days and then evaporated to dryness. To the residue was added 50 ml water, 50 ml methanol and potassium hydroxide (0.84 g, 15 mmol) and the mixture was heated to 80° C. for 15 h. A further portion of potassium hydroxide (0.84 g) was added and the mixture was heated to 80° C. for 17 h. After evaporation of methanol, dilution with 70 ml water and acidification with excess aqueous 2 N hydrochloric acid, the precipitate was filtrated and washed with 50 ml water to give 0.65 g (60% over 2 steps) of 6-[(R)-1-(2,4-difluoro-phenyl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as yellowish powder. LC/MS (method 4): Rt=1.19 min; m/z=365.1 (M+H+).

Workup

  1. stirringThe mixture was stirred for 2 days
  2. customevaporated to dryness
  3. temperaturethe mixture was heated to 80° C. for 17 h
  4. customAfter evaporation of methanol, dilution with 70 ml water and acidification with excess aqueous 2 N hydrochloric acid
  5. filtrationthe precipitate was filtrated
  6. washwashed with 50 ml water

Sources & evidence

ORD record
ord-e8ab34f9cd0946998c6a54a2c5209c68
Source dataset
uspto-grants-2016_03
Patent number
US09284333B2

Reaction notes

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