5-Amino-2-fluoropyridine → HCID 86723663, compound

HRID 1485321Notes

Reaction equation

HRID 1485321 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.[OH:14][C@H:15]1[CH2:19][N:18]([C:20]2[N:21]=[C:22]([NH:29][C:30]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[NH:32][N:31]=3)[C:23]3[CH2:28][CH2:27][CH2:26][C:24]=3[N:25]=2)[C@H:17]([C:38](OC)=[O:39])[CH2:16]1>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:38]([C@@H:17]2[CH2:16][C@@H:15]([OH:14])[CH2:19][N:18]2[C:20]2[N:21]=[C:22]([NH:29][C:30]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[NH:32][N:31]=3)[C:23]3[CH2:28][CH2:27][CH2:26][C:24]=3[N:25]=2)=[O:39])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 86723664HCID 86723664, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 86723663HCID 86723663, compoundYield 13.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
25 °C

Procedure

To a solution of 6-fluoropyridin-3-amine (4.64 mg, 4.14 mmol) in dry THF (5 mL) was added 2 M solution of isopropylmagnesium chloride (1.98 mL, 3.96 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 (2S,4R)-methyl 4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (400 mg, 1.04 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at 25° C. for 4 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with water (25 mL). The product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (2×100 mL) followed by brine (100 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue which was purified by reverse phase HPLC to afford 66 mg of (2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 0.99-1.30 (m, 6H), 2.10-2.30 (m, 4H), 2.65-2.74 (m, 2H), 2.78-2.98 (m, 4H), 3.78-3.05 (m, 1H), 3.91-3.99 (m, 1H), 4.70-4.78 (m, 1H), 4.92-4.98 (m, 1H), 6.34 (s, 1H), 6.77 (s, 1H), 6.82 (dd, 1H), 7.93 (s, 1H), 8.08-8.18 (m, 1H). The other diasteromers are prepared using appropriate chiral starting materials.

Workup

  1. customThe reaction was quenched with saturated ammonium chloride solution (10 mL)
  2. additiondiluted with water (25 mL)
  3. extractionThe product was extracted with EtOAc (2×50 mL)
  4. washThe combined organic layer was washed with water (2×100 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. customRemoval of EtOAc under reduced pressure
  7. customgave an oily residue which
  8. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-b17d24de078d4e1db8eaa7a801c923d3
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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