Dichloromethane → (S)-1-cyclopropyl-3-(3-fluoro-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea

HRID 1626676Notes

Reaction equation

HRID 1626676 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[C:28]([F:41])[CH:27]=2)=[O:24])[CH2:21][CH2:20]1.ClCCl.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:19]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]4[CH3:18])[C:5]4[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=4[N:7]=3)=[C:28]([F:41])[CH:27]=2)=[O:24])[CH2:21][CH2:20]1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 666792291-Cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea2×HCID 86663154(S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine2×

Product 1

HCID 66679048(S)-1-cyclopropyl-3-(3-fluoro-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)ureaYield 11%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 86587095Dimethoxyethane ethanol waterSolvent

Conditions

Temperature
115 °C

Procedure

To a solution of (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) (150 mg, 0.55 mmol) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (212 mg, 0.69 mmol) in DME/EtOH/H2O (7/3/2) (2 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (22 mg, 0.027 mmol) and Cs2CO3 (538 mg, 1.65 mmol). The reaction mixture was then heated by microwave at 115° C. for 45 min. The crude reaction mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by preparative HPLC at low pH to afford a yellow solid (25 mg, 0.06 mmol, 11%).

Workup

  1. customThe crude reaction mixture
  2. customwas partitioned between EtOAc (25 ml) and water (25 ml)
  3. customThe organic layer was recovered
  4. customthe solvent removed in vacuo
  5. customResidue was then purified by preparative HPLC at low pH

Sources & evidence

ORD record
ord-c036a9900a7d4a54a46543dd7f8ae3aa
Source dataset
uspto-grants-2014_07
Patent number
US08785457B2

Reaction notes

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