Potassium Phosphate, Tribasic → 3-(2-(4-(1-Acetylpiperidin-4-yl)thiazol-2-ylamino)pyridin-4-yloxy)isonicotinonitrile hydrochloride

HRID 1972150Notes

Reaction equation

HRID 1972150 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:16]=[N:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[S:19][CH:20]=[C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)[N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:1].[C:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:21]2[N:22]=[C:18]([NH:17][C:2]3[CH:7]=[C:6]([O:8][C:9]4[CH:16]=[N:15][CH:14]=[CH:13][C:10]=4[C:11]#[N:12])[CH:5]=[CH:4][N:3]=3)[S:19][CH:20]=2)[CH2:24][CH2:25]1)(=[O:31])[CH3:30]

Participants

6

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 249946573-(2-Chloropyridin-4-yloxy)isonicotinonitrileHCID 596100361-(4-(2-Aminothiazol-4-yl)piperidin-1-yl)ethanone

Product 1

HCID 248641403-(2-(4-(1-Acetylpiperidin-4-yl)thiazol-2-ylamino)pyridin-4-yloxy)isonicotinonitrile hydrochlorideYield 12.71%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
90 °C

Procedure

3-(2-Chloropyridin-4-yloxy)isonicotinonitrile (0.0650 g, 0.281 mmol) (prepared as in Example 2), 1-(4-(2-aminothiazol-4-yl)piperidin-1-yl)ethanone (0.0822 g, 0.365 mmol), potassium phosphate (0.137 g, 0.421 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.00642 g, 0.00701 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.00812 g, 0.0140 mmol) were combined and the vessel was capped with rubber septum. The vessel was evacuated and purged with nitrogen three times. Toluene (2 mL) and degassed water (2 mL) were added and the resulting mixture was heated to 90° C. and agitated overnight. After cooling the mixture was diluted with 50 ml of ethyl acetate and washed with sodium bicarbonate, brine, dried and evaporated. The crude product was purified by preparative HPLC (Parallex) and converted to HCl salt by treatment with 2M HCl in ether to provide the title compound (0.0150 g, 12.71% yield) as white solid. 1H NMR (CDCl3) δ 1.52-1.62 (m, 2H), 1.98-2.06 (m, 2H), 2.10 (s, 3H), 2.65 (t, 1H), 2.80 (t, 1H), 3.13 (t, 1H), 3.85(d, 1H), 4.66 (d, 1H), 6.35 (s, 1H), 6.45 (s, 1H), 6.50 (d, 1H), 7.15 (s, 1H), 7.40 (d, 1H), 8.05 (s, 1H), 9.01 (bs, 1H).

Workup

  1. customthe vessel was capped with rubber septum
  2. customThe vessel was evacuated
  3. custompurged with nitrogen three times
  4. customToluene (2 mL) and degassed water (2 mL)
  5. additionwere added
  6. temperatureAfter cooling the mixture
  7. additionwas diluted with 50 ml of ethyl acetate
  8. washwashed with sodium bicarbonate, brine
  9. customdried
  10. customevaporated
  11. customThe crude product was purified by preparative HPLC (Parallex)

Sources & evidence

ORD record
ord-bf0d8478606b4740be904a1bd26e21fb
Source dataset
uspto-grants-2013_04
Patent number
US08431713B2

Reaction notes

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