Acryloyl chloride → Spebrutinib

HRID 1482672Notes

Reaction equation

HRID 1482672 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30].C(Cl)(Cl)Cl.CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[F:15][C:14]1[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:28](=[O:31])[CH:29]=[CH2:30])[CH:7]=[CH:6][CH:5]=2)=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=2)=[N:12][CH:13]=1

Participants

7

Reactant 4

HCID 13140Acryloyl chlorideHCID 516892Sodium BicarbonateHCID 21584188Chloroform methanolHCID 59174534N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine

Product 1

HCID 59174488Spebrutinib

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-30 °C

Procedure

In a 50 mL 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube and thermo pocket was charged N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine (0.40 g) in dry DCM (10 mL) and was cooled to −30° C. An acryloyl chloride solution in DCM (0.107 g in 5.0 mL DCM) was added slowly and the reaction mixture was stirred at −30° C. for approx. 40 minutes. The reaction was monitored on TLC using chloroform:methanol (9.6:0.4) as mobile phase. The reaction mixture was poured into water (100 mL) and basified using sodium bicarbonate. The reaction mixture was extracted with MDC (2×25 mL) and the combined organic layer was washed with 50 mL brine solution. The organic layer was dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Obtained solid was purified by triturating with diethyl ether (2×mL) and dried under vacuum to give 0.28 g N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide.

Workup

  1. customIn a 50 mL 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube
  2. extractionThe reaction mixture was extracted with MDC (2×25 mL)
  3. washthe combined organic layer was washed with 50 mL brine solution
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. concentrationconcentrated completely
  6. customat 40° C
  7. customObtained solid
  8. customwas purified
  9. customby triturating with diethyl ether (2×mL)
  10. customdried under vacuum

Sources & evidence

ORD record
ord-fd42b5c52ab1458693f140c23a9bbfe6
Source dataset
uspto-grants-2016_08
Patent number
US09415049B2

Reaction notes

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