Dimethylformamide → 4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid

HRID 425942Notes

Reaction equation

HRID 425942 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]=2[C:12]#[N:13])=[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>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.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:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]

Participants

7

Reactant 4

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

Product 1

HCID 211112774-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acidYield 83.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
85.5 °C

Procedure

2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 29.6 mmol), 4-carboxybenzeneboronic acid (5.4 g, 32.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.8 g, 70.0 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 90° 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 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture was cooled to 45° C. The sticky solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. 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 stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 20 mL of water. The solids were discarded. The filtrate was cooled in an ice bath 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 8.5 g (83% yield) of 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid as a very 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. filtrationThe sticky solids were collected by vacuum filtration
  5. washwashed with 30 mL of ethanol:water 1:1
  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. filtrationThe solids were collected by vacuum filtration
  9. washwashed with 20 mL of water
  10. temperatureThe filtrate was cooled in an ice bath
  11. filtrationThe solids were collected by vacuum filtration
  12. washwashed with 20 mL water
  13. customdried under vacuum

Sources & evidence

ORD record
ord-827ea967a8124084b219c0a4ed5bc5d0
Source dataset
uspto-grants-2012_01
Patent number
US08106197B2

Reaction notes

Loading…