Dimethylformamide → HCID 21111262, compound

HRID 425940Notes

Reaction equation

HRID 425940 reaction equation
Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 3121834-Carboxyphenylboronic AcidHCID 21111493HCID 21111493, compound

Product 1

HCID 21111262HCID 21111262, compoundYield 24.8%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
45 °C

Procedure

5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (Example I(e), 9.00 g, 27.0 mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.9 mmol), potassium carbonate (13.1 g, 95.0 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° C. to 98° C. over a period of 4 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 many small impurities. The mixture was cooled to 45° C. The 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 5 mL of water. The filtrate was cooled in an ice bath and acidified to pH 7.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 2.5 g of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and a second compound as a brown solid in a ratio of about 1:1 by 1H-NMR. This material was discarded. The filtrate was acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 3.6 g (36% yield) of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid as a brown solid containing a 5-10% impurity by 1H-NMR.

Workup

  1. customequipped with a thermometer, a reflux condenser and magnetic stirring
  2. customThe mixture was purged with nitrogen
  3. temperaturegradually heated from 81° C. to 98° C. over a period of 4 hr
  4. filtrationThe 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 5 mL of water
  10. temperatureThe filtrate was cooled in an ice bath
  11. filtrationThe solids were collected by vacuum filtration
  12. washwashed with 10 mL of ethanol:water 1:1
  13. customdried under vacuum

Sources & evidence

ORD record
ord-3c68d086ff9348b7901a23df49071bce
Source dataset
uspto-grants-2012_01
Patent number
US08106197B2

Reaction notes

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