Nitrogen → HCID 68291679, compound

HRID 877842Notes

Reaction equation

HRID 877842 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[C:15]4([CH2:18][CH2:17][CH2:16]4)[CH2:14][N:13]([C:19]([C:21]4([C:24]#[N:25])[CH2:23][CH2:22]4)=[O:20])[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:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N.ClCCl>O1CCOCC1.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:24]([C:21]1([C:19]([N:13]2[CH2:12][CH:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[C:15]3([CH2:18][CH2:17][CH2:16]3)[CH2:14]2)=[O:20])[CH2:22][CH2:23]1)#[N:25]

Participants

8

Reactant 5

HCID 947NitrogenHCID 6344DichloromethaneHCID 62657Potassium Phosphate, TribasicHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 68291243HCID 68291243, compound

Product 1

HCID 68291679HCID 68291679, compoundYield 54.9%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A solution of (+/−)-6-bromo-4-((6-(1-cyanocyclopropanecarbonyl)-6-azaspiro[3.4]octan-8-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (15.09 mg, 0.033 mmol) and 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13.73 mg, 0.066 mmol) in 1,4-dioxane (440 μL) and 2M aq. potassium phosphate (49.5 μL, 0.099 mmol) was degassed for several minutes with N2 gas. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.71 mg, 3.30 μmol) was added and degassing was continued for 1 additional minute. The vial was sealed and the contents were heated @ 110° C. for 1.5 hr. LC/MS and HPLC indicated that no starting material remained (m/e 459.26, no Br pattern, M+H for desired product). After cooling to rt, the reaction was diluted with methanol, filtered and evaporated. 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: 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 afford 8.3 mg of the title compound. 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.13 (d, J=8.9 Hz, 1H), 7.83 (d, J=3.5 Hz, 1H), 7.76 (d, J=5.0 Hz, 2H), 7.06-6.90 (m, 1H), 4.80-4.70 (m, 1H), 4.39-4.34 (m, 0.5 H), 4.29-4.10 (m, 1H), 4.05 (dd, J=11.4, 2.5 Hz, 0.5H), 3.94 (s, 3H), 3.91-3.70 (m, 2H), 2.54-1.99 (m, 6H), 1.83-1.38 (m, 4H).

Workup

  1. customdegassing
  2. customThe vial was sealed
  3. temperatureAfter cooling to rt
  4. additionthe reaction was diluted with methanol
  5. filtrationfiltered
  6. customevaporated
  7. customThe crude material was purified via preparative LC/MS with the following conditions
  8. customa 5-minute hold
  9. additionFractions containing the desired product
  10. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-6fc848ffd2c5490aa302ca09702c5d0a
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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