Pyridine → HCID 86707901, compound

HRID 877750Notes

Reaction equation

HRID 877750 reaction equation
[C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]3[C:23]4[N:24]([CH:31]=[C:32]([N:34]5[CH2:38][CH2:37][C@H:36]([OH:39])[C:35]5=[O:40])[CH:33]=4)[N:25]=[CH:26][C:27]=3[C:28]([NH2:30])=[O:29])[C:17]([CH3:42])([CH3:41])[CH2:16]2)=[N:13][CH:14]=1)#[N:8].C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1.CN(C1C=CN=CC=1)C>[C:1]([O:39][C@H:36]1[CH2:37][CH2:38][N:34]([C:32]2[CH:33]=[C:23]3[C:22]([NH:21][C@@H:18]4[CH2:19][CH2:20][N:15]([C:12]5[N:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][N:11]=5)[CH2:16][C:17]4([CH3:42])[CH3:41])=[C:27]([C:28](=[O:29])[NH2:30])[CH:26]=[N:25][N:24]3[CH:31]=2)[C:35]1=[O:40])(=[O:5])[CH2:2][CH2:3][CH3:4]

Participants

7

Reactant 4

HCID 1049PyridineHCID 8471TriethylamineHCID 8855Butyryl chloride2×HCID 68291665HCID 68291665, compound

Product 1

HCID 86707901HCID 86707901, compoundYield 22.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Butyryl chloride (4 μl, 0.034 mmol) was added to a stirred suspension of 4-(((R)-1-(5-cyanopyrimidin-2-yl)-3,3-dimethylpiperidin-4-yl)amino)-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (15 mg, 0.031 mmol, from Example 115) and triethylamine (0.013 mL, 0.092 mmol) in tetrahydrofuran (0.5 mL). After 2 h at room temperature, no reaction was observed. Pyridine (5.0 μl, 0.061 mmol), DMAP (0.5 mg, 4.09 μmol) and additional butyryl chloride (3.5 μl, 0.034 mmol) were added. After 24 h at room temperature, the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 25 minutes, then a 10-minute hold at 55% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3.9 mg, 22% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.51 (s, 2H), 8.12 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 5.54 (t, J=8.4 Hz, 1H), 4.45 (d, J=13.4 Hz, 1H), 4.17 (dd, J=10.2, 3.7 Hz, 1H), 3.95 (td, J=9.7, 2.5 Hz, 1H), 3.87-3.79 (m, 1H), 3.52-3.44 (m, 1H), 3.22 (d, J=13.4 Hz, 1H), 2.80-2.70 (m, 1H), 2.47-2.35 (m, 2H), 2.25-2.15 (m, 2H), 1.87-1.77 (m, 1H), 1.69 (sxt, J=7.3 Hz, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 0.97 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 560.4 (M+H); LC retention time: 1.98 min (analytical LCMS Method I).

Workup

  1. waitAfter 24 h at room temperature
  2. customthe crude material was purified via preparative LC/MS with the following conditions
  3. waitGradient: 15-100% B over 25 minutes
  4. customa 5-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation
  7. customThe material was further purified via preparative LC/MS with the following conditions
  8. waitGradient: 15-55% B over 25 minutes
  9. customa 10-minute hold
  10. additionFractions containing the desired product
  11. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-b291cac3752140b5a06f14122809b63b
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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