Isopropanol → HCID 178503490, compound

HRID 474020

Reaction equation

HRID 474020 reaction equation
Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=2)[CH:3]=1.Cl.[CH:18]1([C:21]2([F:25])[CH2:24][NH:23][CH2:22]2)[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.C(O)(C)C>CCCCCC>[CH:18]1([C:21]2([F:25])[CH2:24][N:23]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]4[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=4)[CH:3]=3)[CH2:22]2)[CH2:20][CH2:19]1

Participants

6

Reactant 4

HCID 3776IsopropanolHCID 81531DiisopropylethylamineHCID 665896423-Cyclopropyl-3-fluoroazetidine hydrochlorideHCID 178418729HCID 178418729, compound

Product 1

HCID 178503490HCID 178503490, compoundYield 80%

Reagents, catalysts & solvents 1

HCID 8058HexaneSolvent

Conditions

Temperature
85 °C

Procedure

To a mixture of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine (150 g, 0.58 mol) and 3-cyclopropyl-3-fluoroazetidine hydrochloride (132.2 g, 0.87 mol) was added diisopropylethylamine (208 g, 1.61 mol) and isopropanol (1.125 L). The mixture was heated to reflux for 23 hours. The reaction was then cooled to 85° C. (a slightly hazy solution) and filtered. The homogeneous solution was concentrated to a minimal volume. EtOAc was then added (1 L) and the solution was concentrated to a minimal volume. EtOAc (1 L) and H2O (1 L) were then added and the layers were separated. Crystallized product began to crystallize out of the organic layer during the extraction. The aqueous layer was further extracted with EtOAc (500 ml). The 1st organic layer was concentrated to dryness to give a white solid. Hexane (750 ml) was added to the second organic extract and the slurry was stirred at ambient temperature, and then cooled to 0° C. for 30 min. The slurry was filtered and washed with copious Heptane. The filter cake was dried under vacuum. The filter cake and the white solid from the 1st extraction were combined to afford 155.1 g of the desired product. (155.1 g, 77%). 1H NMR (DMSO, 400 MHz) 0.44 (2H; m), 0.60 (2H, m), 1.38-1.43 (1H, m), 2.18 (3H, s), 2.42 (3H, s), 3.89-3.97 (4H, m), 5.92 (1H, br s), 6.04 (1H, br s), 9.23 (1H, s), 11.86 (1H, s). ES+335

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 23 hours
  3. filtrationfiltered
  4. concentrationThe homogeneous solution was concentrated to a minimal volume
  5. additionEtOAc was then added (1 L)
  6. concentrationthe solution was concentrated to a minimal volume
  7. additionEtOAc (1 L) and H2O (1 L) were then added
  8. customthe layers were separated
  9. customto crystallize out of the organic layer during the extraction
  10. extractionThe aqueous layer was further extracted with EtOAc (500 ml)
  11. concentrationThe 1st organic layer was concentrated to dryness
  12. customto give a white solid
  13. extractionorganic extract
  14. temperaturecooled to 0° C. for 30 min
  15. filtrationThe slurry was filtered
  16. washwashed with copious Heptane
  17. customThe filter cake was dried under vacuum
  18. extractionThe filter cake and the white solid from the 1st extraction

Sources & evidence

ORD record
ord-f3de0036ed194f67bb2ee5f1088d20ac
Source dataset
uspto-grants-2014_01
Patent number
US08637511B2

Linked notes

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