Sodium Carbonate → ethyl 4-(2-chloropyriMidin-4-yl)benzoate

HRID 591124Notes

Reaction equation

HRID 591124 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[N:21]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH:19]=[CH:18][N:17]=1

Participants

5

Reactant 3

HCID 10340Sodium CarbonateHCID 775312,4-DichloropyrimidineHCID 27343504-Ethoxycarbonylphenylboronic acid

Product 1

HCID 11065261ethyl 4-(2-chloropyriMidin-4-yl)benzoateYield 60%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-ethoxycarbonylphenyl boronic acid (23.11 g, 119 mmol), 2,4-dichloropyrimidine (16.90 g, 113 mmol), toluene (230 mL) and aqueous sodium carbonate (2 M, 56 mL) was stirred vigorously and nitrogen was bubbled through the suspension for 15 minutes. Tetrakis(triphenylphosphine)palladium[0](2.61 g, 2.26 mmol) was added. Nitrogen was bubbled through for another 10 min., the mixture was heated to 100° C., then at 75° C. overnight. The mixture was cooled, diluted with ethyl acetate (200 mL), water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml) and the two organic extracts were combined. The organics were washed with brine, filtered through sodium sulfate, concentrated, and the resultant solid was triturated with methanol (100 mL) and filtered. The solids were washed with methanol (2×30 mL) and air dried. This material was dissolved in acetonitrile (150 mL) and dichloromethane (200 mL), stirred with MP.TMT Pd-scavenging resin (Agronaut part number 800471) (7.5 g) over 2 days. The solution was filtered, the solids were washed with dichloromethane (2×100 mL), and the filtrate concentrated to give ethyl 4-(2-chloropyrimidin-4-yl)benzoate as anoff-white solid (17.73 g, 60%)—additional washing with dichloromethane yielded a further 1.38 g and 0.5 g of product. 1H NMR (300 MHz, d6-DMSO) δ 8.89 (1H, d, J=5.0 Hz); 8.32 (2H, d, J=8.7 Hz); 8.22 (1H, d, J=5.5 Hz); 8.12 (2H, d, J=8.7 Hz); 4.35 (2H, q, J=7.1 Hz); 1.34 (3H, t, J=7.1 Hz); LC-ESI-MS (method B): rt 7.3 min.; m/z 263.0/265.0 [M+H]+.

Workup

  1. customnitrogen was bubbled through the suspension for 15 minutes
  2. customNitrogen was bubbled through for another 10 min.
  3. customat 75° C.
  4. customovernight
  5. temperatureThe mixture was cooled
  6. additiondiluted with ethyl acetate (200 mL), water (100 mL)
  7. additionwas added
  8. customthe layers were separated
  9. extractionThe aqueous layer was extracted with ethyl acetate (100 ml)
  10. washThe organics were washed with brine
  11. filtrationfiltered through sodium sulfate
  12. concentrationconcentrated
  13. customthe resultant solid was triturated with methanol (100 mL)
  14. filtrationfiltered
  15. washThe solids were washed with methanol (2×30 mL) and air
  16. customdried
  17. dissolutionThis material was dissolved in acetonitrile (150 mL)
  18. stirringdichloromethane (200 mL), stirred with MP.TMT Pd-scavenging resin (Agronaut part number 800471) (7.5 g) over 2 days
  19. filtrationThe solution was filtered
  20. washthe solids were washed with dichloromethane (2×100 mL)
  21. concentrationthe filtrate concentrated

Sources & evidence

ORD record
ord-8ad531d7b1b547baac9cfffa143780e0
Source dataset
uspto-grants-2016_01
Patent number
US09238628B2

Reaction notes

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