Acetic Acid → (R)-N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)acetamide

HRID 526719Notes

Reaction equation

HRID 526719 reaction equation
O[C@H]([C@@H](O)C(O)=O)C(O)=O.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([F:22])[CH:21]=1)[O:18][CH2:17][C@H:16]([NH2:23])[CH2:15]2.[S-:24][C:25]#[N:26].[K+].C(O)(=O)C.[CH2:32]([NH:39][C:40](=[O:46])[CH2:41][C:42](=O)[CH2:43]O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>CC(O)C.O>[CH2:32]([NH:39][C:40](=[O:46])[CH2:41][C:42]1[N:23]([C@@H:16]2[CH2:15][C:14]3[C:19](=[C:20]([F:22])[CH:21]=[C:12]([F:11])[CH:13]=3)[O:18][CH2:17]2)[C:25](=[S:24])[NH:26][CH:43]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 516872Potassium thiocyanate4×HCID 516892Sodium BicarbonateHCID 25118723(R)-6,8-difluorochroman-3-amine (2R,3R)-2,3-dihydroxysuccinateHCID 71502813N-benzyl-4-hydroxy-3-oxobutanamide5×

Product 1

HCID 71153280(R)-N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)acetamideYield 65.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of (R)-6,8-difluorochroman-3-amine(2R,3R)-2,3-dihydroxysuccinate (compound JT′, 15 g, 44.7 mmol) and potassium thiocyanate (5.22 g, 53.7 mmol) in 2-propanol (150 ml) was added acetic acid (38.4 ml, 671 mmol) followed by N-benzyl-4-hydroxy-3-oxobutanamide (compound C, 11.13 g, 53.7 mmol) in 5 portions during 1 hours. The mixture was heated with stirring at 80° C. for 2 hours. More N-benzyl-4-hydroxy-3-oxobutanamide (1.854 g, 8.95 mmol) and potassium thiocyanate (0.870 g, 8.95 mmol) added, stirred for 1 hour. More N-benzyl-4-hydroxy-3-oxobutanamide (1.854 g, 8.95 mmol) and potassium thiocyanate (0.870 g, 8.95 mmol) added, stirred for 1 hour (in total N-benzyl-4-hydroxy-3-oxobutanamide (14.83 g, 71.6 mmol) and potassium thiocyanate (6.96 g, 71.6 mmol)), purified by HPLC at 210 nm (Kromasil 100 5C4 250×4.6 column, 0.1% TFA-ACN 50:50, 1 ml/min) with less than 1.5% compound JT′. Diluted with water (110 ml) at approx 50° C., cooled to 5° C. and aged for 1 hour. Precipitate was collected, washed with water. Wet filter cake was re-slurried in water (300 ml), solution of sodium bicarbonate (4.13 g, 49.2 mmol) in water (100 ml) was added in portions, the mixture was stirred for 15 min, filtered, washed with water (wet weight 21 g), dried on air to give (R)—N-benzyl-2-(3-(6,8-difluorochroman-3-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)acetamide (12.2 g, 29.4 mmol, 65.6% yield).

Workup

  1. temperatureThe mixture was heated
  2. stirringstirred for 1 hour
  3. custompurified by HPLC at 210 nm (Kromasil 100 5C4 250×4.6 column, 0.1% TFA-ACN 50:50, 1 ml/min) with less than 1.5% compound JT′
  4. additionDiluted with water (110 ml) at approx 50° C.
  5. temperaturecooled to 5° C. and aged for 1 hour
  6. customPrecipitate was collected
  7. washwashed with water
  8. stirringthe mixture was stirred for 15 min
  9. filtrationfiltered
  10. washwashed with water (wet weight 21 g)
  11. customdried on air

Sources & evidence

ORD record
ord-3ba4ac0dcc1c41c7bccab2d35256a320
Source dataset
uspto-grants-2016_05
Patent number
US09346751B2

Reaction notes

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