2-Amino-4,6-dichloropyrimidine → 2,6-Difluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile

HRID 2367574Notes

Reaction equation

HRID 2367574 reaction equation
Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C([O-])(O)=O.[Na+].ClC1C=C(Cl)N=C(N)N=1.[C:31]([C:33]1[C:38]([F:39])=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[F:43])#[N:32]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[F:39][C:38]1[CH:37]=[C:36]([C:2]2[CH:7]=[C:6]([N:13]3[CH2:14][CH2:15][CH2:16][C@H:12]3[CH3:11])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=2)[CH:35]=[C:34]([F:43])[C:33]=1[C:31]#[N:32]

Participants

10

Reactant 5

HCID 655222-Amino-4,6-dichloropyrimidineHCID 2598804,6-Dichloro-n-methylpyrimidin-2-amineHCID 516892Sodium BicarbonateHCID 641544(R)-2-MethylpyrrolidineHCID 55252910(4-Cyano-3,5-difluorophenyl)boronic acid

Product 1

HCID 585045032,6-Difluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrileYield 36%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
117 °C

Procedure

A mixture of 4,6-dichloro-N-methyl-2-pyrimidinamine (1.2 g, 6.74 mmol), (2R)-2-methylpyrrolidine (0.631 g, 7.41 mmol), and NaHCO3 (2.83 g, 33.7 mmol) in dioxane (40 mL) and water (20 mL) was stirred overnight at 117° C. in a sealed tube. The reaction was allowed to cool to room temperature. LCMS showed most of the starting material 4,6-dichloro-2-pyrimidinamine had been consumed. Then (4-cyano-3,5-difluorophenyl)boronic acid (1.233 g, 6.74 mmol) and Pd(Ph3P)4 (0.156 g, 0.135 mmol) were added, and the reaction mixture was stirred for 24 hours at 117° C. The mixture was poured into water (30 mL) and EtOAc (100 mL). The compound stayed in the EtOAc layer. The organic layer was separated from the aqueous layer. There was some black colored suspension in the organic layer, which was filtered out. (they were not product). The organic layer was rotavaped to dryness to afford the title compound (0.8 g) as a light yellow solid. LC-MS (ES) m/z=330 [M+H]+.

Workup

  1. temperatureto cool to room temperature
  2. customhad been consumed
  3. stirringthe reaction mixture was stirred for 24 hours at 117° C
  4. customThe organic layer was separated from the aqueous layer
  5. filtrationwas filtered out

Sources & evidence

ORD record
ord-809c51157a0c4b6bba63739ddd7fa204
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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