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Dichloromethane → 2-Fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile

HRID 2367536
Notes
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Reaction equation

HRID 2367536 reaction equation
Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[N:5]=[C:4]([NH:15][CH3:16])[N:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28])#[N:18].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>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].O1CCOCC1>[F:28][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@H:9]3[CH3:14])[N:5]=[C:4]([NH:15][CH3:16])[N:3]=2)[CH:23]=[CH:24][C:19]=1[C:17]#[N:18]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 2783130(4-Cyano-3-fluorophenyl)boronic acidHCID 585047304-Chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine

Product 1

HCID 585048042-Fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrileYield 109%

Reagents, catalysts & solvents

2
HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

To a 5-mL microwave vial was added 4-chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (200 mg, 0.824 mmol), (4-cyano-3-fluorophenyl)boronic acid (177 mg, 1.071 mmol), PdCl2(dppf).CH2Cl2 adduct (33.6 mg, 0.041 mmol), K2CO3 (1.236 mL, 2.472 mmol), and 1,4-dioxane (3 mL). The reaction mixture was heated at 140° C. for 10 minutes in a microwave reactor. The 1,4-dioxane was removed, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried over Na2SO4 and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in hexanes, 12 g column) to afford the title compound (294 mg) as a yellow oil. LC-MS (ES) m/z=328 [M+H]+.

Workup

  1. customThe 1,4-dioxane was removed
  2. extractionthe aqueous layer was extracted with EtOAc (2×20 mL)
  3. dry with materialThe combined organics were dried over Na2SO4
  4. concentrationconcentrated
  5. customThe resulting residue was purified by flash chromatography (0-50% EtOAc in hexanes, 12 g column)

Sources & evidence

ORD record
ord-9ccdbdcc37c6473f84e6be987af40ebc
Source dataset
uspto-grants-2014_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08697685B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes