Potassium Phosphate, Tribasic → HCID 66547940, compound

HRID 877767Notes

Reaction equation

HRID 877767 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]4[N:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=4)[CH2:12]3)=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][N:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]1=[O:46].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CN(C)C=O>[C:24]([C:21]1[CH:22]=[N:23][C:18]([N:13]2[CH2:14][C@H:15]([CH2:16][CH3:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:35]5[CH:34]=[CH:33][C:32](=[O:46])[N:31]([CH3:30])[CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[CH2:12]2)=[N:19][CH:20]=1)#[N:25]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 454801941-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 68290775HCID 68290775, compound

Product 1

HCID 66547940HCID 66547940, compoundYield 44.2%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

A mixture of 6-bromo-4-(((3S,4S)-1-(5-cyanopyrimidin-2-yl)-4-ethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol, from Step 1), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (31.0 mg, 0.132 mmol, from Step 2), and PdCl2(dppf)-CH2Cl2 adduct (7.17 mg, 8.79 μmol) was pumped under vacuum and backfilled with nitrogen three times. A 2 M aqueous solution of potassium phosphate tribasic (0.066 mL, 0.132 mmol) and N,N-dimethylformamide (0.5 mL) were added. The mixture was immediately pumped under vacuum and backfilled with nitrogen three times, sealed and placed in a 90° C. heating block for 3 h, then cooled to room temperature. The mixture was filtered to remove the insoluble material. The filtrate 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 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% 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 to give the title compound (9.4 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.16 (d, J=7.4 Hz, 1H), 8.77 (d, J=3.0 Hz, 1H), 8.67 (d, J=3.0 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.00-7.90 (m, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.48 (d, J=9.4 Hz, 1H), 5.09-4.91 (m, 1H), 4.09-3.94 (m, 2H), 3.85 (d, J=12.4 Hz, 1H), 3.51 (s, 3H), 2.66-2.55 (m, 1H), 1.64 (quin, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 484.2 (M+H); LC retention time: 1.19 min (analytical LCMS Method I).

Workup

  1. customsealed
  2. customplaced in a 90° C.
  3. temperatureheating block for 3 h
  4. filtrationThe mixture was filtered
  5. customto remove the insoluble material
  6. customThe filtrate was purified via preparative LC/MS with the following conditions
  7. customa 5-minute hold
  8. additionFractions containing the desired product
  9. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-e082c97e74fd473cb5da3926a9c39644
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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