Hydrochloric Acid → (1S,4R)-4-Fluoro-2-(2,2,7-trifluoro-3-oxo-4-prop-2-ynyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylcarbamoyl)-cyclopentanecarboxylic acid

HRID 1184340Notes

Reaction equation

HRID 1184340 reaction equation
[C:1](C1NC=CN=1)([C:3]1NC=CN=1)=[O:2].[NH2:13][C:14]1[C:29]([F:30])=[CH:28][C:17]2[O:18][C:19]([F:27])([F:26])[C:20](=[O:25])[N:21]([CH2:22][C:23]#[CH:24])[C:16]=2[CH:15]=1.C(N(CC)CC)C.[F:38][C@@H:39]1[CH2:43]N[C@@H:41]([C:44]([OH:46])=[O:45])[CH2:40]1.Cl>C(#N)C>[F:38][C@H:39]1[CH2:40][C@H:41]([C:44]([OH:46])=[O:45])[CH:3]([C:1](=[O:2])[NH:13][C:14]2[C:29]([F:30])=[CH:28][C:17]3[O:18][C:19]([F:26])([F:27])[C:20](=[O:25])[N:21]([CH2:22][C:23]#[CH:24])[C:16]=3[CH:15]=2)[CH2:43]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 5250894Bis-(1H-imidazol-2-YL)-methanoneHCID 7023050(2R,4S)-4-fluoropyrrolidine-2-carboxylic acidHCID 866695376-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

Product 1

HCID 86690133(1S,4R)-4-Fluoro-2-(2,2,7-trifluoro-3-oxo-4-prop-2-ynyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylcarbamoyl)-cyclopentanecarboxylic acidYield 90%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

Carbonyl diimidazole (1519 mg, 9.37 mmol) was added to a stirred solution of 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (the product of Step 1.6 above, 800 mg, 3.12 mmol) and triethylamine (0.457 ml, 3.28 mmol) in anhydrous acetonitrile (15 ml) at room temperature under nitrogen. The resulting mixture was heated to 80° C. Then (2R,4S)-4-fluoropyrrolidine-2-carboxylic acid (416 mg, 3.12 mmol) was added. The resulting suspension was stirred at reflux. After 2 hours a red/brown clear solution was obtained. LCMS analysis indicated that full conversion had occurred. The reaction mixture was gradually cooled to room temperature, poured into 1 N hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to yield the desired compound (1.34 g, ca. 90% purity), which was used without further purification in the following step.

Workup

  1. temperatureat reflux
  2. customAfter 2 hours a red/brown clear solution was obtained
  3. temperatureThe reaction mixture was gradually cooled to room temperature
  4. extractionextracted three times with ethyl acetate
  5. washThe combined organic extracts were washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. customevaporated in vacuo

Sources & evidence

ORD record
ord-980cdb457c994a04bf942fd99864d455
Source dataset
uspto-grants-2014_03
Patent number
US08669208B2

Reaction notes

Loading…