Triisopropyl phosphite → 2-[3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b: 4',3'-f]azepine

HRID 75221

Reaction equation

HRID 75221 reaction equation
[F:1][CH:2]([F:34])[C:3]1[C:7]([C:8]2[N:9](O)[C:10]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[C:11]=3[N:25]=2)=[C:6]([CH3:27])[N:5]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:4]=1.CN(C)C(=O)C.P(OC(C)C)(OC(C)C)OC(C)C>O>[F:34][CH:2]([F:1])[C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[C:11]=3[N:25]=2)=[C:6]([CH3:27])[N:5]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:4]=1

Participants

5

Reactant 3

HCID 8304Triisopropyl phosphiteHCID 31374DimethylacetamideHCID 668871612-[3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]imidazo[4,5-d]dipyrido[2,3-b: 4',3'-f]azepin-3(8H)-ol

Product 1

HCID 668870762-[3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b: 4',3'-f]azepine

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A solution of 2-[3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]imidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepin-3 (8H)-ol (1.94 g, 4.17 mmol) in N,N-dimethylacetamide (30 mL, 0.3226 mol) was heated at 160° C. for 2.5 hours with triisopropyl phosphite (4.0 mL, 0.0174 mol). The reaction was allowed to cool and then poured into 50 mL water. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The reaction was chromatographed on silica gel using 3% Et3N with ethyl acetate, and 3% MeOH/ethyl acetate to give the desired product. 1H NMR (CDCl3): δ 9.52 and 9.45 (brs, 1H), 7.87-8.11 (m, 4H), 6.74-7.61 (m, 3H), 6.10 and 6.13 (br s, 1H), 5.40 (dd, 1H), 4.11 (m, 1H), 3.71 (m, 1H), 2.80 (s, 3H), 2.44 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.60-1.80 (m, 3H). Mass spec(EI) m/z=450 (M+1).

Workup

  1. temperatureto cool
  2. extractionThe reaction was extracted with ethyl acetate
  3. washthe organic extracts were washed with water, saturated NaCl
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customThe reaction was chromatographed on silica gel using 3% Et3N with ethyl acetate, and 3% MeOH/ethyl acetate

Sources & evidence

ORD record
ord-b0be817df746483ea10091594fa3f226
Source dataset
uspto-grants-2014_09
Patent number
US08835423B2

Linked notes

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