Potassium Phosphate, Tribasic → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(2-cyano-5-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

HRID 924148Notes

Reaction equation

HRID 924148 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:35]3[CH:36]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=3[C:33]#[N:34])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 221807884-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 89908257(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(2-cyano-5-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Reagents, catalysts & solvents 1

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

Conditions

Temperature
120 °C

Procedure

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 50 mg, 0.108 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (32 mg, 0.130 mmol), PdCl2(dppf) (7.91 mg, 10.81 μmol) and K3PO4 (68.8 mg, 0.324 mmol) were added to a vial and flushed with argon. Dioxane (1 mL) was added and the mixture was stirred at 120° C. for 1.5 h. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column 2-EP, from 17% to 22% in 6 min). The purified product was lyophilized in water/min. vol. MeCN to afford the title product as a slightly yellow powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=503.1/505.2 [M+H]+.

Workup

  1. customflushed with argon
  2. additionDioxane (1 mL) was added
  3. customThe solvent was evaporated off under reduced pressure
  4. customthe crude product was purified by preparative SFC (Column 2-EP, from 17% to 22% in 6 min)

Sources & evidence

ORD record
ord-44095c70907f4b2dbb10e360f19caaf4
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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