Picolyl chloride hydrochloride → 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine

HRID 1162200Notes

Reaction equation

HRID 1162200 reaction equation
[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2

Participants

5

Reactant 3

HCID 23392Picolyl chloride hydrochlorideHCID 24758Sodium hydrideHCID 686187815-fluoro-N-1H-indazol-5-ylquinazolin-4-amine

Product 1

HCID 686183205-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amineYield 41%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred partial solution of 5-fluoro-N-1H-indazol-5-ylquinazolin-4-amine (3.35 g, 12 mmol) and 2-picolyl chloride hydrochloride (2.07 g, 12.6 mmol) in DMF (60 ml) was added portion-wise, sodium hydride (60% dispersion in mineral oil, 1.01 g, 25.2 mmol). The reaction was maintained at ambient temperature by slight cooling and stirred for 18 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (5 ml) and evaporated under high vacuum. The residue was partitioned between 2.5M aqueous NaOH and DCM and the organic phase was dried over anhydrous Na2SO4 and evaporated. The product was purified by chromatography (5% methanol/ethyl acetate) and the crystallized by trituration with ether to give 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine (1.8 g, 41%); NMR spectrum (300 MHz) 5.75 (s, 2H), 6.97 (d, 1H), 7.27 (m, 1H), 7.41 (dd, 1H), 7.54-7.75 (m, 4H), 7.84 (q, 1H), 8.12 (d, 2H), 8.50 (m, 2H), 9.23 (d, 1H); Mass spectrum MH+ 371.

Workup

  1. temperatureby slight cooling
  2. customThe reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (5 ml)
  3. customevaporated under high vacuum
  4. customThe residue was partitioned between 2.5M aqueous NaOH and DCM
  5. dry with materialthe organic phase was dried over anhydrous Na2SO4
  6. customevaporated
  7. customThe product was purified by chromatography (5% methanol/ethyl acetate)
  8. customthe crystallized by trituration with ether

Sources & evidence

ORD record
ord-700fc3344a7a4f2085636a2ab559d85b
Source dataset
uspto-grants-2010_10
Patent number
US07820683B2

Reaction notes

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