Potassium Phosphate, Tribasic → 4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino)-6-(1-methyl-1H-indol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 1507982Notes

Reaction equation

HRID 1507982 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([C@H:14]([OH:16])[CH3:15])[CH2:12][OH:13])=[C:8]([C:17]([NH2:19])=[O:18])[CH:7]=[N:6][N:5]2[CH:20]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.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>[OH:13][CH2:12][C@@H:11]([NH:10][C:9]1[C:4]2[N:5]([CH:20]=[C:2]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([CH3:21])[CH:23]=[CH:24]4)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:17]([NH2:19])=[O:18])[C@H:14]([OH:16])[CH3:15]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27598671-Methyl-1H-indole-5-boronic acidHCID 682919156-bromo-4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 665473304-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino)-6-(1-methyl-1H-indol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 85.7%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of 6-bromo-4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino) pyrrolo[1,2-b]pyridazine-3-carboxamide (25 mg, 0.073 mmol), (1-methyl-1H-indol-5-yl)boronic acid (38.2 mg, 0.219 mmol), PdCl2(dppf)-CH2Cl2 adduct (11.90 mg, 0.015 mmol) and potassium phosphate, tribasic, 2M (0.182 mL, 0.364 mmol) in DMA (0.5 mL) was heated to 95° C. for 45 minutes. After cooling to rt, the reaction mixture was filtered and 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. 1H NMR (500 MHz, DMSO-d6) δ 10.65 (d, J=8.4 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.93 (d, J=1.0 Hz, 1H), 7.57 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.31 (dd, J=6.7, 2.2 Hz, 2H), 6.43 (d, J=3.0 Hz, 1H), 5.13-4.89 (m, 2H), 4.27-4.08 (m, 2H), 3.80 (s, 3H), 3.73-3.61 (m, 2H), 1.13 (d, J=6.4 Hz, 3H). to afford the title compound (24.6 mg, 85% yield). MS (ES+) m/z: 394.1 (M+H); LC retention time: 1.27 min (analytical HPLC Method P).

Workup

  1. temperatureAfter cooling to rt
  2. filtrationthe reaction mixture was filtered
  3. customthe filtrate was purified via preparative LC/MS with the following conditions
  4. customa 5-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-d1a6bc2cc5b5434b8e8ed414f5fa1583
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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