Glycolic Acid → N-[2-({4-[4-(3-{[(2,5-Difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]-2-hydroxyacetamide

HRID 239433Notes

Reaction equation

HRID 239433 reaction equation
[C:1]([OH:5])(=O)[CH2:2][OH:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:39][CH2:40][CH2:41][NH:42][C:43]1[N:48]=[C:47]([C:49]2[S:53][C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])=[N:51][C:50]=2[C:58]2[C:59]([F:76])=[C:60]([NH:64][S:65]([C:68]3[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=3[F:75])(=[O:67])=[O:66])[CH:61]=[CH:62][CH:63]=2)[CH:46]=[CH:45][N:44]=1>CN(C=O)C.CCOC(C)=O>[F:75][C:69]1[CH:70]=[CH:71][C:72]([F:74])=[CH:73][C:68]=1[S:65]([NH:64][C:60]1[C:59]([F:76])=[C:58]([C:50]2[N:51]=[C:52]([C:54]([CH3:56])([CH3:55])[CH3:57])[S:53][C:49]=2[C:47]2[CH:46]=[CH:45][N:44]=[C:43]([NH:42][CH2:41][CH2:40][NH:39][C:1](=[O:5])[CH2:2][OH:3])[N:48]=2)[CH:63]=[CH:62][CH:61]=1)(=[O:67])=[O:66]

Participants

7

Reactant 4

HCID 757Glycolic Acid3×HCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57989685N-{3-[5-{2-[(2-Aminoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Product 1

HCID 57989673N-[2-({4-[4-(3-{[(2,5-Difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]-2-hydroxyacetamideYield 46.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of glycolic acid (0.040 g, 0.50 mmol), HATU (0.19 g, 0.50 mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL) was added to a stirring solution of N-{3-[5-{2-[(2-aminoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.25 mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL). The reaction was stirred for 1 h. LCMS analysis indicated approximately 50% conversion to product. An additional 2.0 equivalents of activated glycolic acid was added and the reaction was allowed to stir for an additional 1 h. LCMS analysis indicated the starting material was still not completely consumed so an additional 2.0 equivalents of activated glycolic acid was added and the reaction was stirred for an addition 1 h. The reaction was diluted with EtOAc, washed with water (×5) and a saturated aqueous brine solution (×2). The organic layer was dried over MgSO4, filtered and the filtrate was concentrated onto silica gel and purified by flash chromatography to afford the title compound (0.072 g, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (br. s., 1H), 8.04 (d, J=5.1 Hz, 1H), 7.77-7.98 (m, 1H), 7.15-7.65 (m, 7H), 5.81-6.01 (m, 1H), 5.49 (t, J=5.2 Hz, 1H), 3.80 (d, J=5.3 Hz, 2H), 3.29 (br. s., 2H), 1.40 (s, 9H). MS (ES+): 621 [M+H]+.

Workup

  1. stirringto stir for an additional 1 h
  2. additionwas added
  3. stirringthe reaction was stirred for an addition 1 h
  4. washwashed with water (×5)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationthe filtrate was concentrated onto silica gel
  8. custompurified by flash chromatography

Sources & evidence

ORD record
ord-741bacebd08842df9d6a15431022e7f2
Source dataset
uspto-grants-2014_02
Patent number
US08642759B2

Reaction notes

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