Nitrogen → HCID 68350435, compound

HRID 877843Notes

Reaction equation

HRID 877843 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][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=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:35]5[CH:34]=[N:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[C:15]3([CH2:16][CH2:17][CH2:18]3)[CH2:14]2)=[O:20])[CH2:23][CH2:22]1)#[N:25]

Participants

8

Reactant 5

HCID 947NitrogenHCID 6344DichloromethaneHCID 62657Potassium Phosphate, TribasicHCID 2734368(6-Methoxypyridin-3-yl)boronic acidHCID 68291243HCID 68291243, compound

Product 1

HCID 68350435HCID 68350435, compoundYield 52.4%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
105 °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 from Step 3 of Example 320 (15.0 mg, 0.033 mmol), 2-Methoxy-5-pyridineboronic acid (10.03 mg, 0.066 mmol) in 1,4-dioxane (437 μl) and potassium phosphate (2.0M) (49.2 μl, 0.098 mmol) was degassed for several minutes with N2 gas. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (2.70 mg, 3.28 μmol) was added, degassing was continued for 1 more minute. The vial was sealed, and the contents were heated @ 105° C. for 50 minutes. HPLC and LC/MS indicated that the reaction had essentially proceeded to completion as no starting material was detected. (m/e 486.24, no Bromine pattern, M+H for desired product). After cooling to room temperature the reaction was diluted with methanol, filtered through a VWR 0.45 micron Nylon filter disc and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 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: 15-100% B over 15 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 8.4 mg of the title compound. LC/MS: m/e 486.0 (M+H). 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.44 (dd, J=7.9, 2.5 Hz, 1H), 8.17 (d, J=9.4 Hz, 1H), 7.96 (ddd, J=8.4, 4.5, 2.5 Hz, 1H), 7.91 (dd, J=12.1, 1.7 Hz, 1H), 7.21-6.99 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.88 (d, J=1.5 Hz, 1H), 4.36 (dd, J=10.9, 5.0 Hz, 0.5H), 4.25 (d, J=10.9 Hz, 1H), 4.11 (d, J=10.9 Hz, 1H), 4.08 (d, J=2.5 Hz, 0.5H), 3.96 (d, J=1.5 Hz, 3H), 3.90 (dd, J=12.9, 4.5 Hz, 0.5H), 3.84-3.71 (m, 0.5H), 2.54-1.96 (m, 6H), 1.84-1.40 (m, 4H)

Workup

  1. customdegassing
  2. customThe vial was sealed
  3. temperatureAfter cooling to room temperature the reaction
  4. additionwas diluted with methanol
  5. filtrationfiltered through a VWR 0.45 micron Nylon
  6. filtrationfilter disc
  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-a59b4e1bc7e942ec95969383e709b330
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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