5-Amino-2-fluoropyridine → HCID 86723646, compound

HRID 1485307Notes

Reaction equation

HRID 1485307 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[CH:21]=[C:20]([NH:22][C:23]3[C:32]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=4[N:26]=[C:25]([N:33]4[CH2:37][CH2:36][CH2:35][CH:34]4[C:38](OC)=[O:39])[N:24]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:18][N:19]=[C:20]([NH:22][C:23]3[C:32]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=4[N:26]=[C:25]([N:33]4[CH2:37][CH2:36][CH2:35][C@@H:34]4[C:38]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:39])[N:24]=3)[CH:21]=2)[CH2:16][CH2:15]1

Participants

5

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 178418918HCID 178418918, compoundHCID 178498054HCID 178498054, compound

Product 1

HCID 86723646HCID 86723646, compoundYield 23%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a stirred solution of 6-fluoropyridin-3-amine (2.58 g, 23.01 mmol) in THF (40 mL) was added a 2M solution of isopropylmagnesium chloride in THF (11.5 mL, 23 mmol) at 0° C. After 20 min of stirring, to this was added a solution of methyl 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate (2.2 g, 5.75 mmol) in THF (10 mL) at 0° C. The reaction mixture was further stirred at RT for 2 h. After completion of reaction it was quenched with saturated ammonium chloride and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layer was treated with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography on 100-200 mesh silica gel using MeOH-DCM (1:10) as eluent to obtain as racemate (0.6 g, 23% yield). The enantiomers were separated by chiral HPLC to afford (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide (130 mg), and its (S) enantiomer. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 0.60-0.77 (m, 2H), 0.85-0.98 (m, 2H), 1.77-1.90 (m, 6H), 1.91-2.20 (m, 3H), 2.38-2.43 (m, 2H), 2.60-2.80 (m, 3H), 3.59-3.78 (m, 2H), 4.71 (d, 1H), 6.17 (s, 1H), 6.80-6.83 (m, 1H), 6.91 (s, 1H), 7.95 (s, 1H), 8.20 (brs, 1H), 10.90 (brs, 1H).

Workup

  1. stirringThe reaction mixture was further stirred at RT for 2 h
  2. customAfter completion of reaction it
  3. customwas quenched with saturated ammonium chloride
  4. extractionthe aqueous layer was extracted with EtOAc (3×50 mL)
  5. additionThe combined organic layer was treated with brine
  6. dry with materialdried over Na2SO4
  7. customevaporated under reduced pressure
  8. customto obtain a crude product, which
  9. customwas purified by column chromatography on 100-200 mesh silica gel
  10. customto obtain as racemate (0.6 g, 23% yield)
  11. customThe enantiomers were separated by chiral HPLC

Sources & evidence

ORD record
ord-71282595b2e74330b4a39ba99fa0d5e7
Source dataset
uspto-grants-2016_08
Patent number
US09422267B2

Reaction notes

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