5-Amino-2-fluoropyridine → HCID 86723642, compound

HRID 1485305Notes

Reaction equation

HRID 1485305 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[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH:30]4[C:35](OC)=[O:36])[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[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][C@H:31]([OH:34])[C@@H:30]4[C:35]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:36])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 86723643HCID 86723643, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 86723642HCID 86723642, compoundYield 3.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 6-fluoropyridin-3-amine (292 mg, 2.61 mmol) in dry THF (12 mL) was added 2M solution of isopropylmagnesium chloride in THF (1.3 mL, 2.60 mmol) 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 (3S)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (250 mg, 0.65 mmol) in THF (2 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 (50 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded an oily residue that was purified by reverse phase HPLC to afford (2R,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide (10 mg). Compound No. 11a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H), 2.19-2.30 (m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m, 2H), 6.28 (brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H). Compound No. 11b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H), 2.19-2.30 (m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m, 2H), 6.28 (brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H). Separation by chiral HPLC provided additional diastereomers 11c and 11d.

Workup

  1. customThe reaction was quenched with saturated ammonium chloride solution (50 mL)
  2. extractionThe product was extracted with EtOAc (2×40 mL)
  3. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  4. customRemoval of EtOAc under reduced pressure
  5. customafforded an oily residue that
  6. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-b172cf251e4e48deadc694e6e4adb6ff
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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