5-Amino-2-fluoropyridine → HCID 86723653, compound

HRID 1485314Notes

Reaction equation

HRID 1485314 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[CH2:42][CH2:41][CH2:40][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][C@H:32]([O:34][CH3:35])[CH2:31][CH:30]4[C:36](OC)=[O:37])[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[CH2:42][CH2:41][CH2:40][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][C@H:32]([O:34][CH3:35])[CH2:31][C@@H:30]4[C:36]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:37])[N:28]=3)[CH:18]=2)[CH2:15][CH2:16]1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 86723651HCID 86723651, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 86723653HCID 86723653, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 6-fluoropyridin-3-amine (1.2 g, 11.30 mmol) in dry THF (20 mL) was added 2M solution of isopropylmagnesium chloride in THF (9.4 mL, 18.8 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 (4R)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate (3 g, 7.53 mmol) in THF (10 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT overnight. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×100 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded a diastereomeric mixture of Compound 21. The diastereomers were separated by reverse phase followed by chiral HPLC to afford (2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide (Compound No. 21a, 208 mg) and (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide (Compound No. 21b, 193 mg). Compound No. 21a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.78 (m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m, 1H), 2.08-2.20 (m, 2H), 2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s, 3H), 2.70-2.81 (m, 1H), 3.90-4.02 (m, 1H), 4.15-4.21 (m, 1H), 4.72-4.78 (m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H), 8.00 (brs, 1H), 8.28 (brs, 1H). Compound No. 21b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.78 (m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m, 1H), 2.08-2.20 (m, 2H), 2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s, 3H), 3.80-4.01 (m, 2H), 4.15-4.21 (m, 1H), 4.72-4.78 (m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H), 8.00 (brs, 1H), 8.28 (brs, 1H).

Workup

  1. customThe reaction was quenched with saturated ammonium chloride solution (50 mL)
  2. extractionThe product was extracted with EtOAc (2×100 mL)
  3. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  4. customRemoval of EtOAc under reduced pressure
  5. customafforded
  6. customThe diastereomers were separated by reverse phase

Sources & evidence

ORD record
ord-b949e4928d474d8091f7ebafdfec4cbb
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

Loading…