Diisopropylethylamine → 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

HRID 1990202Notes

Reaction equation

HRID 1990202 reaction equation
[OH:1][CH2:2][C@@H:3]([O:6][C:7]1[CH:8]=[C:9]([O:22][C:23]2[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH:10]=[C:11]([C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:12]=1)[CH2:4][CH3:5].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1.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>CN(C=O)C.O>[N:33]1([C:29]([C:26]2[N:27]=[CH:28][C:23]([O:22][C:9]3[CH:10]=[C:11]([CH:12]=[C:7]([O:6][C@H:3]([CH2:2][OH:1])[CH2:4][CH3:5])[CH:8]=3)[C:13]([NH:15][C:16]3[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=3)=[O:14])=[N:24][CH:25]=2)=[O:30])[CH2:36][CH2:35][CH2:34]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12308726Azetidine hydrochlorideHCID 536296535-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid

Product 1

HCID 160397613-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of 5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid (12 mg, 0.03 mmol), azetidine hydrochloride (4 mg, 0.06 mmol), HATU (14 mg, 0.04 mmol) and DIPEA (0.02 mL, 0.11 mmol) in DMF (1 mL) was stirred at RT over the weekend. Water (15 mL) was added and the solution extracted with ethyl acetate (25 mL). The ethyl acetate layer was washed with brine (20 mL), dried (MgSO4), and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product along with 15% of a co-eluting impurity (5 mg). 1H NMR δ (CDCl3): 0.92 (t, 3H), 0.97 (t, 0.45H), 1.69 (quin, 2H), 1.76 (m, 0.3H), 2.34 (quin, 2H), 3.76 (m, 2H), 3.86 (s, 3H), 4.23 (t, 2H), 4.49 (sextet, 1H), 4.66 (t, 2H), 4.77 (m, 0.15H), 6.93 (t, 1H), 6.99 (d, 1H), 7.34 (s, 1H), 7.46 (s, 1H), 7.50 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H), 10.68 (s, 1H), 10.78 (s, 0.15H); m/z 468 (M+H)+

Workup

  1. extractionthe solution extracted with ethyl acetate (25 mL)
  2. washThe ethyl acetate layer was washed with brine (20 mL)
  3. dry with materialdried (MgSO4)
  4. customevaporated to a residue which
  5. customwas chromatographed by preparative HPLC on C18 reversed phase
  6. washeluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA)

Sources & evidence

ORD record
ord-ec8b96660d5848d4b52f40da3fe3fac2
Source dataset
uspto-grants-2010_01
Patent number
US07642259B2

Reaction notes

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