Diisopropylethylamine → 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one

HRID 1749684Notes

Reaction equation

HRID 1749684 reaction equation
F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][C:34]([OH:36])=O.C(N(C(C)C)C(C)C)C.[C:46]([C:50]1[O:54][C:53]([C:55]2[C:56]([NH2:74])=[N:57][CH:58]=[C:59]([C:61]3[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]4[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]4)[N:62]=3)[N:60]=2)=[N:52][N:51]=1)([CH3:49])([CH3:48])[CH3:47]>C(#N)C>[NH2:74][C:56]1[N:57]=[CH:58][C:59]([C:61]2[N:65]([CH2:66][CH3:67])[N:64]=[C:63]([CH:68]3[CH2:69][CH2:70][N:71]([C:34](=[O:36])[CH2:33][CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[CH2:72][CH2:73]3)[N:62]=2)=[N:60][C:55]=1[C:53]1[O:54][C:50]([C:46]([CH3:47])([CH3:48])[CH3:49])=[N:51][N:52]=1

Participants

6

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 552690473-[(2-Tetrahydropyranyl)oxy]propanoic acidHCID 86727668HCID 86727668, compound

Product 1

HCID 867276661-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-oneYield 91%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
25 °C

Procedure

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 106 g, 279.51 mmol), was added portionwise to a stirred solution of 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (44.3 g, 254.10 mmol) and N-ethyl-N-isopropylpropan-2-amine (89 mL, 508.21 mmol) dissolved in acetonitrile (600 mL) at 25° C. The resulting solution was stirred at 25° C. for 20 min then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (101 g, 254.10 mmol) was added portionwise washing the last portion into the mixture as a slurry in acetonitrile (300 mL). After stirring for 1 hour the precipitate was collected by filtration, washing with acetonitrile and drying in vacuo to afford 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-one (128 g, 91%) as a beige solid. The filtrate was diluted with DCM (600 ml), washed with water, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 2 to 2.5% 7N ammonia in methanol with dichloromethane. A second crop of the desired product (40 g, 72.2 mmol, 28.4%) was obtained as a cream solid which was combined with the first crop: 1H NMR Spectrum: (DMSO-d6) 1.29-1.48 (16H, m), 1.48-1.75 (4H, m), 1.83-1.99 (2H, m), 2.48-2.68 (2H, m), 2.68-2.79 (1H, m), 2.87-2.99 (1H, m), 3.07-3.19 (1H, m), 3.32-3.42 (1H, m), 3.47-3.6 (1H, m), 3.64-3.75 (1H, m), 3.75-3.84 (1H, m), 3.84-3.95 (1H, m), 4.24-4.39 (1H, m), 4.47-4.6 (3H, m), 7.84 (2H, s), 8.79 (1H, s): Mass Spectrum [M+Na]+=577.

Workup

  1. washwashing the last portion into the mixture as a slurry in acetonitrile (300 mL)
  2. stirringAfter stirring for 1 hour the precipitate
  3. filtrationwas collected by filtration
  4. washwashing with acetonitrile
  5. customdrying in vacuo

Sources & evidence

ORD record
ord-3f20977c4d9a49d3a3f42ea3f36f912a
Source dataset
uspto-grants-2015_10
Patent number
US09156831B2

Reaction notes

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