6-Fluoro-N-methyl-3-pyridinamine → HCID 86723673, compound

HRID 1485328Notes

Reaction equation

HRID 1485328 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:15]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[C:25]3[CH2:41][CH2:40][CH2:39][C:26]=3[N:27]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[C:35](OC)=[O:36])[N:29]=2)[CH:19]=1)([CH3:17])[CH3:16]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:35]([C@H:31]2[CH2:32][CH2:33][CH2:34][N:30]2[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[C:18]([CH:15]([CH3:17])[CH3:16])[NH:22][N:21]=3)[C:25]3[CH2:41][CH2:40][CH2:39][C:26]=3[N:27]=2)=[O:36])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 591907156-Fluoro-N-methyl-3-pyridinamineHCID 86723649HCID 86723649, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 86723673HCID 86723673, compoundYield 6.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

To a solution of 6-fluoro-N-methylpyridin-3-amine (272 mg, 2.16 mmol) in THF (70 mL) was added isopropyl magnesium chloride solution 2M in THF (1.08 mL, 2.16 mmol) dropwise at 0° C. The mixture was allowed to stir at 0° C. for 20 min. Then, a solution of (R)-methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (200 mg, 0.54 mmol) in THF (3 mL) was added and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC to afford 17 mg of (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide. 1HNMR (400 MHz, CDCl3) δ (ppm): 1.20-1.35 (m, 6H), 1.79-2.25 (m, 6H), 2.57-2.68 (m, 2H), 2.79-2.82 (m, 2H), 2.91-3.01 (m, 1H), 3.30 (s, 3H), 3.59-3.80 (m, 2H), 4.35-4.45 (m, 1H), 6.16 (s, 1H), 6.90-7.05 (m, 2H), 8.01 (brs, 1H), 8.40 (brs, 1H). The other enantiomer is prepared using the (S) chiral starting material.

Workup

  1. stirringto stir at RT for 2 h
  2. customThe reaction was quenched with saturated ammonium chloride solution (50 mL)
  3. extractionthe mixture was extracted with EtOAc (3×50 mL)
  4. washThe combined organic layer was washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. customRemoval of EtOAc under reduced pressure
  7. customgave an oily residue that
  8. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-64ed0781c1704f40af842b015fd9c7dc
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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