Potassium Phosphate, Tribasic → HCID 68292153, compound

HRID 877836Notes

Reaction equation

HRID 877836 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@:15]([F:17])([CH3:16])[CH2:14][N:13]([C:18]([C:20]4([C:23]#[N:24])[CH2:22][CH2:21]4)=[O:19])[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(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:23]([C:20]1([C:18]([N:13]2[CH2:14][C@@:15]([F:17])([CH3:16])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[O:19])[CH2:21][CH2:22]1)#[N:24]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 68350414HCID 68350414, compound

Product 1

HCID 68292153HCID 68292153, compoundYield 51.2%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-fluoro-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (16 mg, 0.036 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.82 mg, 0.071 mmol), PdCl2(dppf) (2.61 mg, 3.56 mmol) and 2.0 M aqueous solution of potassium phosphate tribasic (0.071 mL, 0.142 mmol) in N,N-dimethylformamide (1 mL) was deoxygenated by bubbling N2 through the mixture for 5 min and heated to 90° C. under N2 for 1 h. 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 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% 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 (8.3 mg, 51% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.16 (d, J=8.4 Hz, 1H), 7.90-7.74 (m, 3H), 7.06 (d, J=19.3 Hz, 1H), 5.03-4.87 (m, 1H), 4.38-4.20 (m, 2H), 4.01-3.93 (m, 3H), 3.88-3.54 (m, 2H), 1.99-1.47 (m, 7H); MS (ES+) m/z: 451.2 (M+H); LC retention time: 1.09 min (analytical LCMS Method I).

Workup

  1. customwas deoxygenated
  2. customby bubbling N2 through the mixture for 5 min
  3. customThe crude material 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-fe662d17f1f240b9b483dcd86eac3430
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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