Cesium carbonate → 6-(3-Methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5'-(trifluoromethyl)-[2,3'-bipyridin]-6'-amine

HRID 1778185Notes

Reaction equation

HRID 1778185 reaction equation
Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:18]2[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]2)[N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([C:39]([F:42])([F:41])[F:40])[C:35]([NH2:38])=[N:36][CH:37]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:23][O:22][CH:20]1[CH2:21][N:18]([C:4]2[N:3]=[C:2]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=3)[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:17][O:16][CH2:15]4)[CH2:10][CH2:9]3)[CH:5]=2)[CH2:19]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 468641035-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amineHCID 1176783762-Chloro-6-(3-methoxy-1-azetidinyl)-4-[1-(3-oxetanyl)-4-piperidinyl]pyridine

Product 1

HCID 863039966-(3-Methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5'-(trifluoromethyl)-[2,3'-bipyridin]-6'-amineYield 61.5%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 218864351,4-Dioxane--water (1/1)Solvent

Procedure

To a solution of 2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (80 mg, 0.24 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (140 mg, 0.48 mmol) and cesium carbonate (160 mg, 0.48 mmol) in dioxane/H2O (5:1, 4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18 mg, 0.024 mmol) under nitrogen. The mixture was irradiated by microwave at 110° C. for 30 min. The reaction mixture was filtered, the filtrate was concentrated and purified by Prep-HPLC to afford 6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)-5′-(trifluoromethyl)-[2,3′-bipyridin]-6′-amine (68.3 mg 61.5%, yield). LCMS (ESI) [MH]+=464, 1HNMR (400 MHz, CDCl3), δ8.745(s,1H), δ8.363(s,1H), δ8.232(s,1H), δ8.832(s,1H), δ6.109(s,1H), δ5.642(s,2H), δ4.74- 4.67(m,4H), δ 4.39-4.22 (m, 3H), δ 3.94-3.90 (m, 2H), δ 3.63-3.56(m, 1H), δ 3.346(s, 3H), δ 2.980(d, J=10.8 Hz, 2H), δ 2.55-2.46 (m,1H), δ 2.06-1.99 (m, 1H), δ 1.93-1.87(m, 4H). LCMS:464.0(M+1).

Workup

  1. customThe mixture was irradiated by microwave at 110° C. for 30 min
  2. filtrationThe reaction mixture was filtered
  3. concentrationthe filtrate was concentrated
  4. custompurified by Prep-HPLC

Sources & evidence

ORD record
ord-e64f7fe26702424cae4d8555ec358784
Source dataset
uspto-grants-2016_02
Patent number
US09266862B2

Reaction notes

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