5-Amino-2-fluoropyridine → HCID 178439371, compound

HRID 1485316Notes

Reaction equation

HRID 1485316 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[CH:21]=[C:20]([NH:22][C:23]2[C:24]3[CH2:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:25]=3[N:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[C:34](OC)=[O:35])[N:28]=2)[NH:19][N:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:27]2[N:28]=[C:23]([NH:22][C:20]3[NH:19][N:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[CH:21]=3)[C:24]3[CH2:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:25]=3[N:26]=2)=[O:35])=[CH:3][CH:4]=1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 178418918HCID 178418918, compoundHCID 178501295HCID 178501295, compound

Product 1

HCID 178439371HCID 178439371, compoundYield 17.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a stirred solution of 5-amino-2-fluoropyridine (79 mg, 0.703 mmol) in dry THF (2 mL) was added isopropyl magnesium chloride 2M in THF (0.43 mL, 0.86 mmol) dropwise under nitrogen atmosphere at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To this was added a solution of (S)-methyl 1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (70 mg, 0.175 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was cooled to 0° C. and quenched by saturated ammonium chloride solution (10 mL). The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under vacuum gave a crude oil which was purified by reverse phase HPLC to afford 15 mg of (S)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.15-1.25 (m, 6H), 1.20 (s, 6H), 2.02-2.18 (m, 2H), 2.22-2.3.8 (m, 2H), 2.58 (s, 2H), 2.62 (s, 2H), 2.79-2.90 (m, 1H), 3.60-3.70 (m, 1H), 3.78-3.87 (m, 1H), 4.77 (dd, 1H), 6.25 (brs, 1H), 6.99 (dd, 1H), 7.97 (brs, 1H), 8.20 (s, 1H). The other enantiomer was obtained using the chiral (R) starting material.

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. customquenched by saturated ammonium chloride solution (10 mL)
  3. additionThe reaction mixture was diluted with water (10 mL)
  4. extractionextracted with EtOAc (2×20 mL)
  5. washThe organic layer was washed with brine (20 mL)
  6. dry with materialdried over anhydrous sodium sulfate
  7. customRemoval of EtOAc under vacuum
  8. customgave a crude oil which
  9. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-1d5f1244a7c44fa6b7491f2c5e4feb0b
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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