Dimethylformamide → 4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoic acid

HRID 425944Notes

Reaction equation

HRID 425944 reaction equation
[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2C#N)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:14][C:15]([C:10]([CH3:17])([CH3:11])[CH3:9])=[CH:16][CH:17]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 3121834-Carboxyphenylboronic AcidHCID 211113802-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile

Product 1

HCID 211114574-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoic acidYield 160.6%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
88.5 °C

Procedure

2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 26.8 mmol), 4-carboxybenzeneboronic acid (4.9 g, 30.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.1 g, 95 mmol), dimethylformamide (72 mL), and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 96° C. over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.8, product at Rf 0.5 and an impurity at Rf 0.4. The mixture was cooled to 45° C. and filtered to remove the solids. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and 4 g of Celite and 2 g of Norit were added. The solids were collected by vacuum filtration through 4 g of Celite, washed with 30 mL of ethanol:water 1:1 and discarded The filtrate was cooled in an ice bath and acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to give 8.1 g (80% yield) 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoic acid as a dark solid.

Workup

  1. customequipped with a thermometer, a reflux condenser and magnetic stirring
  2. customThe mixture was purged with nitrogen
  3. temperatureThe mixture was cooled to 45° C.
  4. filtrationfiltered
  5. customto remove the solids
  6. additionThe filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13)
  7. temperaturecooled in an ice bath
  8. addition4 g of Celite and 2 g of Norit were added
  9. filtrationThe solids were collected by vacuum filtration through 4 g of Celite
  10. washwashed with 30 mL of ethanol:water 1:1
  11. temperaturewas cooled in an ice bath
  12. filtrationThe solids were collected by vacuum filtration
  13. washwashed with 20 mL water
  14. customdried under vacuum

Sources & evidence

ORD record
ord-4505272495504faabc4d85283aaf2cbc
Source dataset
uspto-grants-2012_01
Patent number
US08106197B2

Reaction notes

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