5-Amino-2-fluoropyridine → HCID 76283470, compound

HRID 1485297Notes

Reaction equation

HRID 1485297 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:40][CH2:39][CH2:38][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH:30]4[C:34](OC)=[O:35])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:40][CH2:39][CH2:38][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH:30]4[C:34]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:35])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 86723633HCID 86723633, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 76283470HCID 76283470, compoundYield 47.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 6-fluoropyridin-3-amine (6.09 g, 54.4 mmol) in dry THF (100 mL) was added a 2M solution of isopropylmagnesium chloride (27.2 mL, 54.4 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (5 g, 13.5 mmol) in THF (20 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (200 mL). The product was extracted with EtOAc (2×80 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a solid residue which was purified by column chromatography on silica gel using 2-2.5% MeOH-DCM system as eluent to afford 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide (2.85 g, 47% yield) as the racemate. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.56-0.72 (m, 2H), 0.82-0.94 (m, 2H), 1.70-1.82 (m, 1H), 2.00-2.20 (m, 4H), 2.21-2.38 (m, 2H), 2.70-2.77 (m, 2H), 2.78-2.82 (m, 2H), 3.58-3.78 (m, 1H), 3.79-3.81 (m, 1H), 4.70 (dd, 1H), 6.25 (s, 1H), 6.98 (dd, 1H), 7.95 (s, 1H), 8.18 (s, 1H). Separation by chiral HPLC provided enantiomers 2a and 2b.

Workup

  1. customThe reaction was quenched with saturated ammonium chloride solution (200 mL)
  2. extractionThe product was extracted with EtOAc (2×80 mL)
  3. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  4. customRemoval of EtOAc under reduced pressure
  5. customgave a solid residue which
  6. customwas purified by column chromatography on silica gel using 2-2.5% MeOH-DCM system as eluent

Sources & evidence

ORD record
ord-8c5a31e73c18498a9da6d86c2cc117b9
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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