Triethylamine → 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-1-(3-hydroxyazetidin-1-yl)-2-methylbut-3-yn-1-one

HRID 1398567Notes

Reaction equation

HRID 1398567 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:24])([CH3:23])[C:20](O)=[O:21])[CH:15]=3)[C:10]([CH3:25])=[N:9]2)[CH:5]=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH:51]1[CH2:54][CH:53]([OH:55])[CH2:52]1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:24])([CH3:23])[C:20]([N:51]4[CH2:54][CH:53]([OH:55])[CH2:52]4)=[O:21])[CH:15]=3)[C:10]([CH3:25])=[N:9]2)[CH:5]=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 27592903-Hydroxyazetidine hydrochloride2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 681819404-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoic acid

Product 1

HCID 601637434-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-1-(3-hydroxyazetidin-1-yl)-2-methylbut-3-yn-1-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoic acid (100 mg, 0.30 mmol) in DMF (3 mL) was introduced O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 18 hr at RT, the solution was re-treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 3 hr at RT, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2×5 mL extractions). The combined organic extracts were washed with water (5 mL) and brine (5 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (DCM containing a 2-10% gradient of methanol) furnished the title compound as a colorless solid: 1H NMR (500 MHz, DMSO) delta 1.64 (3H, s), 2.58 (3H, s), 3.58-3.75 (1H, m), 4.09-4.19 (1H, m), 4.19-4.28 (1H, m), 4.49 (1H, s), 4.63-4.76 (1H, m), 5.67-5.81 (1H, m), 6.14 (1H, d, J=17.5 Hz), 6.98 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.38 (1H, d, J=8.7 Hz), 7.87 (1H, dd, J=8.2, 1.8 Hz), 8.27 (1H, d, J=5.5 Hz), 8.87 (1H, s); LC-MS: m/z=+393.05 (M+H)+.

Workup

  1. waitAfter 3 hr at RT
  2. extractionextracted with EtOAc (2×5 mL extractions)
  3. washThe combined organic extracts were washed with water (5 mL) and brine (5 ml)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification of the residue by silica gel flash column chromatography (DCM containing a 2-10% gradient of methanol)

Sources & evidence

ORD record
ord-376891baaaf1479494aad16b4f74b551
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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