Diisopropylethylamine → 3-(2-Aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

HRID 1717545Notes

Reaction equation

HRID 1717545 reaction equation
[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][NH:30][CH2:29]2)[CH:25]=[CH:24][N:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][N:30]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=3[NH:12][C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])=[O:7])[CH2:29]2)[CH:25]=[CH:24][N:23]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 220256632-(2-Fluoro-4-iodoanilino)-3,4-difluorobenzoic acidHCID 670516283-(2-Aminopyrimidin-4-yl)azetidin-3-ol

Product 1

HCID 594690153-(2-Aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olYield 7.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (201 mg, 0.512 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 0.52 mmol), benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (293 mg, 0.563 mmol) and N,N-diisopropylethylamine (270 uL, 2.82 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 20 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound 3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (22 mg, 7%). 1H NMR (400 MHz, CD3OD): 8.23-8.20 (d, 1H), 7.48-7.43 (d, 1H), 7.35-7.32 (m, 2H), 7.09-7.00 (m, 1H), 6.88-6.84 (d, 1H), 6.70-6.63 (t, 1H), 4.59-4.54 (d, 1H), 4.45-4.40 (d, 1H), 4.23-4.18 (d, 1H), 3.04-3.99 (t, 1H); MS (EI) for C20H15F3IN5O2: 542 (MH+).

Workup

  1. customThe mixture was partitioned between ethyl acetate and saturated sodium bicarbonate
  2. customThe organic layer was separated
  3. washwashed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationthe filtrate concentrated in vacuo
  7. customThe residue was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-62b63c06f0a14e6aa705b663a463562b
Source dataset
uspto-grants-2010_09
Patent number
US07803839B2

Reaction notes

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