Glycolic Acid → HCID 11386311, compound

HRID 1442994Notes

Reaction equation

HRID 1442994 reaction equation
[C:1]([OH:5])(=O)[CH2:2][OH:3].F[P-](F)(F)(F)(F)F.N1([O:22][C:23](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:53]=[CH:54][C:55]=1[F:56])[NH:34][C:35]1[C:44]2[C:39](=[CH:40][C:41]([OH:52])=[CH:42][C:43]=2[O:45][CH2:46][C@H:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)[N:38]=[CH:37][N:36]=1.[CH:57](N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:53]=[CH:54][C:55]=1[F:56])[NH:34][C:35]1[C:44]2[C:39](=[CH:40][C:41]([O:52][CH2:57][CH2:23][OH:22])=[CH:42][C:43]=2[O:45][CH2:46][C@H:47]2[CH2:51][CH2:50][CH2:49][N:48]2[C:1](=[O:5])[CH2:2][OH:3])[N:38]=[CH:37][N:36]=1

Participants

6

Reactant 4

HCID 757Glycolic Acid2×HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 136344271HCID 136344271, compound

Product 1

HCID 11386311HCID 11386311, compoundYield 42%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Glycolic acid (50 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 250 mg) were added sequentially, each in one portion, to a stirred solution of 4-[3-chloro-4-fluoro-anilino]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-7-ol (197 mg) and N,N-diisopropylethylamine (177 μl) in DCM (4 ml) at room temperature. The reaction mixture was stirred for 60 hours and then an additional portion of glycolic acid (20 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 100 mg) were added and the mixture was stirred for a further 5 hours. The reaction mixture was then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow oil, which was purified by column chromatography using 5% methanol in DCM as eluent to give the 4-[3-chloro-4-fluoro-anilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]-methoxy}-quinazolin-7-ol as a grey solid (96 mg, 42%); NMR Spectrum (DMSO-d6 at 373 K) 10.10 (brs, 1H), 9.60 (brs, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.70 (s, 2H), 4.60 (m, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 4.05 (m, 2H), 3.55-3.40 (m, 2H), 2.15-1.85 (m, 4H); Mass spectrum MH+ 449.

Workup

  1. customat room temperature
  2. stirringthe mixture was stirred for a further 5 hours
  3. washwashed with saturated aqueous sodium hydrogen carbonate
  4. dry with materialThe organic layer was dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customto leave a yellow oil, which
  7. customwas purified by column chromatography

Sources & evidence

ORD record
ord-11b7520d5b994b2b9b41769038a4e58e
Source dataset
uspto-grants-2010_02
Patent number
US07659279B2

Reaction notes

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