Sodium Carbonate → N3'-(2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)-[4,4'-bipyridine]-2,3'-diamine

HRID 716197Notes

Reaction equation

HRID 716197 reaction equation
Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:13]2[N:14]=[C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1.ClC1C=CN=CC=1NC1N2N=C(C3C(F)=CC=CC=3F)C=CC2=CN=1.[NH2:51][C:52]1[CH:57]=[C:56](B(O)O)[CH:55]=[CH:54][N:53]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([NH:8][C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[C:56]3[CH:55]=[CH:54][N:53]=[C:52]([NH2:51])[CH:57]=3)=[N:10][CH:11]=2)[N:14]=1

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 23546911B-(2-Amino-4-pyridinyl)boronic acidHCID 70982399N-(4-bromopyridin-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amineHCID 70982735N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine

Product 1

HCID 70983177N3'-(2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)-[4,4'-bipyridine]-2,3'-diamineYield 17%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

A glass microwave reaction vessel was charged with a 1:1 mixture of N-(4-bromopyridin-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine and N-(4-chloropyridin-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine (Example 29, step 1, 85 mg), (2-aminopyridin-4-yl)boronic acid (44 mg, 0.31 mmol, CombiPhos Catalysis, Inc., Princeton, N.J.), Pd(PPh3)4 (12 mg, 10.6 μmol) and 2 M Na2CO3 (0.33 mL) in dioxane (1.5 mL). The reaction was stirred and heated in a microwave at 130° C. for 25 min. The mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by prep HPLC method 4. The desired fractions were collected and concentrated. The residue was partitioned between 30 mL of EtOAc and 5 mL of 0.5 M NaOH. The organic solution was washed with brine (5 mL), dried over Na2SO4 and concentrated to afford N3′-(2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)-[4,4′-bipyridine]-2,3′-diamine (15 mg, 17% yield) as an orange solid. MS (ESI, pos. ion) m/z: 415.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.88 (s, 1 H), 8.34 (d, J=4.89 Hz, 1 H), 8.16 (d, J=5.09 Hz, 1 H), 7.75 (d, J=9.39 Hz, 1 H), 7.39 (m, 2 H), 7.34 (s, 1 H), 7.14 (d, J=4.89 Hz, 1 H), 7.05 (t, J=8.22 Hz, 2 H), 6.78-6.85 (m, 1 H), 6.63 (s, 1 H), 6.53 (dt, J=9.39, 1.76 Hz, 1 H), 4.55 (br., 2 H).

Workup

  1. customA glass microwave reaction vessel
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×)
  4. dry with materialThe combined organic layers were dried over anh. Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by prep HPLC method 4
  8. customThe desired fractions were collected
  9. concentrationconcentrated
  10. customThe residue was partitioned between 30 mL of EtOAc and 5 mL of 0.5 M NaOH
  11. washThe organic solution was washed with brine (5 mL)
  12. dry with materialdried over Na2SO4
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-b200884d20ff4818825db67eab32fc25
Source dataset
uspto-grants-2015_11
Patent number
US09187486B2

Reaction notes

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