Aminopyrazine → HCID 178522391, compound

HRID 1485300Notes

Reaction equation

HRID 1485300 reaction equation
[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[CH:13]1([C:16]2[CH:20]=[C:19]([NH:21][C:22]3[C:23]4[CH2:39][CH2:38][CH2:37][C:24]=4[N:25]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33](OC)=[O:34])[N:27]=3)[NH:18][N:17]=2)[CH2:15][CH2:14]1>C1COCC1>[CH:13]1([C:16]2[CH:20]=[C:19]([NH:21][C:22]3[C:23]4[CH2:39][CH2:38][CH2:37][C:24]=4[N:25]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:34])[N:27]=3)[NH:18][N:17]=2)[CH2:15][CH2:14]1

Participants

5

Reactant 3

HCID 78747AminopyrazineHCID 178418918HCID 178418918, compoundHCID 178498053HCID 178498053, compound

Product 1

HCID 178522391HCID 178522391, compoundYield 37.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of pyrazin-2-amine (284 mg, 2.99 mmol) in dry THF (12 mL) was added 2M solution of isopropylmagnesium chloride (1.5 mL, 2.99 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-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (200 mg, 0.746 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 1.5 h. The reaction was quenched with saturated ammonium chloride solution (20 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 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide (120 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.57-0.67 (m, 2H), 0.78-0.95 (m, 2H), 1.70-1.81 (m, 1H), 2.02-2.18 (m, 4H), 2.25-2.39 (m, 2H), 2.63-2.78 (m, 2H), 2.79-2.85 (m, 2H), 3.60-3.77 (m, 1H), 3.78-3.94 (m, 1H), 4.73-4.81 (m, 1H), 6.25 (s, 1H), 8.26 (d, 1H), 8.30 (s, 1H), 9.31 (s, 1H). Separation by chiral HPLC provided enantiomers 6a and 6b.

Workup

  1. customThe reaction was quenched with saturated ammonium chloride solution (20 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-c8a595ee4fe9401bb5ed609307b5da18
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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