5-Amino-2-fluoropyridine → HCID 86723644, compound

HRID 1485306Notes

Reaction equation

HRID 1485306 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]([C:17]1[NH:21][CH:20]=[C:19]([NH:22][C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[N:26]=[C:25]([N:33]3[CH2:37][CH2:36][CH2:35][CH:34]3[C:38](OC)=[O:39])[N:24]=2)[CH:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:38]([CH:34]2[CH2:35][CH2:36][CH2:37][N:33]2[C:25]2[N:24]=[C:23]([NH:22][C:19]3[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[NH:21][CH:20]=3)[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[N:26]=2)=[O:39])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 86723645HCID 86723645, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 86723644HCID 86723644, compoundYield 51.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 6-fluoropyridin-3-amine (1.41 g, 12.5 mmol) in THF (30 mL) was added 2M solution of isopropylmagnesium chloride in THF (6.2 mL, 12.4 mmol) dropwise at 0° C. The resultant mixture was stirred at the same temperature for 20 min followed by the dropwise addition of a solution of methyl 1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate (1.2 g, 3.12 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with saturated aqueous NH4Cl (40 mL) and was extracted with EtOAc (3×50 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product which was purified by column chromatography on silica (100-200 mesh using 1% MeOH-DCM system as eluent to afford N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide (750 mg) as racemate. The enantiomers were separated by chiral HPLC to afford (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8 tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide (200 mg), and its (S) enantiomer. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 1.10-1.30 (m, 6H), 1.80-2.20 (m, 7H), 2.35-2.46 (m, 2H), 2.58-2.80 (m, 3H), 2.81-2.99 (m, 1H), 3.58-3.77 (m, 2H), 4.75 (brs, 1H), 6.20 (s, 1H), 6.83 (dd, 1H), 6.95 (s, 1H), 7.91 (s, 1H), 8.18 (s, 1H), 10.80 (brs, 1H).

Workup

  1. customThe progress of reaction
  2. customThe reaction mixture was quenched with saturated aqueous NH4Cl (40 mL)
  3. extractionwas extracted with EtOAc (3×50 mL)
  4. washThe organic layer was washed with water (50 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated under vacuum
  7. customto obtain a crude product which
  8. customwas purified by column chromatography on silica (100-200 mesh

Sources & evidence

ORD record
ord-34e8661ac6d649fb9595a358d4d9c731
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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