6-Fluoro-N-methyl-3-pyridinamine → HCID 86723658, compound

HRID 1485317Notes

Reaction equation

HRID 1485317 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[CH2:42][CH2:41][CH2:40][C:26]=3[N:27]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[C:35](OCC)=[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]([CH3:16])[CH3:17])[NH:22][N:21]=3)[C:25]3[CH2:42][CH2:41][CH2:40][C:26]=3[N:27]=2)=[O:36])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 591907156-Fluoro-N-methyl-3-pyridinamineHCID 86723659HCID 86723659, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 86723658HCID 86723658, compoundYield 19.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 6-fluoro-N-methyl-pyridin-3-amine (1.05 g, 8.34 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2M in THF) (4.15 mL, 8.34 mmol) dropwise at 0° C. The reaction mixture was stirred at the same temperature for 30 min. followed by the dropwise addition of solution of ethyl (2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate (0.8 g, 2.083 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was quenched with saturated solution of ammonium chloride (30 mL) and extracted with EtOAc (2×30 mL). The organic layer was washed with water (40 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude which was purified by reverse phase HPLC to afford (2S)—N-(6-fluoro-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-N-methylpyrrolidine-2-carboxamide (190 mg) as solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 1.19-1.30 (m, 6H), 1.80-2.30 (m, 6H), 2.58-2.68 (m, 2H), 2.70-2.88 (m, 2H), 2.91-3.00 (m, 1H), 3.28 (s, 3H), 3.61-3.78 (m, 1H), 3.79-3.90 (m, 1H), 4.40 (brs, 1H), 6.18 (s, 1H), 6.66 (s, 1H), 7.00 (brs, 1H), 8.01 (brs, 1H), 8.20 (s, 1H). The other enantiomer was obtained by using the chiral (R) starting material.

Workup

  1. stirringThe reaction mixture was stirred at RT for 2 h
  2. customThe progress of reaction
  3. customThe reaction mixture was quenched with saturated solution of ammonium chloride (30 mL)
  4. extractionextracted with EtOAc (2×30 mL)
  5. washThe organic layer was washed with water (40 mL)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated under vacuum
  8. customto obtain crude which
  9. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-1d4f10ae35a649e3ab2278d8582ec2d0
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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