Sodium Carbonate → HCID 89422485, compound

HRID 1752423Notes

Reaction equation

HRID 1752423 reaction equation
Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[N:3]=1.[F:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[C:35]([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:8][C:6]1[CH:7]=[C:2]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:34][CH:33]=3)=[CH:23][CH:22]=2)[N:3]=[C:4]([C:9]([O:11][CH3:35])=[O:10])[N:5]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 221699964,6-Dichloropyrimidine-2-carboxylic acidHCID 666684382-[4-(4-Fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 89422485HCID 89422485, compoundYield 35%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of 4,6-dichloropyrimidine-2-carboxylic acid (1.931 g, 10.01 mmol) in dioxane (50 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.459 g, 11.01 mmol), 2M aqueous Na2CO3 (10.0 mL, 20.0 mmol), and PdCl2(dppf) (0.413 g, 0.506 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. for 5 h. After cooling, the reaction was partitioned between 100 mL EtOAc and 50 mL water. Some solid formed and was filtered off. The organic layers were separated and washed once more with 25 mL brine which caused more solid to form. The organic layer and the filtered solids were re-combined and evaporated in vacuo. To this residue was added MeOH (100 mL) and concentrated H2SO4 (1 mL). The mixture was heated at reflux for 2 h then cooled and quenched by addition of solid NaHCO3. The mixture was evaporated in vacuo and the residue chromatographed over silica gel with 5-30% EtOAc/hexanes. The product fractions were evaporated and the residue triturated with 10 mL 1:1 EtOAc/hexanes. The solid was filtered, rinsed twice with 2 mL 1:1 EtOAc/hexanes and air-dried to give methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxylate as a white powder (1.240 g, 3.46 mmol, 35% yield). LC/MS: m/z=359.2 [M+H]+.

Workup

  1. customThe reaction vessel was flushed with argon
  2. customsealed
  3. temperatureAfter cooling
  4. customthe reaction was partitioned between 100 mL EtOAc and 50 mL water
  5. customSome solid formed
  6. filtrationwas filtered off
  7. customThe organic layers were separated
  8. washwashed once more with 25 mL brine which
  9. customto form
  10. customevaporated in vacuo
  11. additionTo this residue was added MeOH (100 mL) and concentrated H2SO4 (1 mL)
  12. temperatureThe mixture was heated
  13. temperatureat reflux for 2 h
  14. temperaturethen cooled
  15. customquenched by addition of solid NaHCO3
  16. customThe mixture was evaporated in vacuo
  17. customthe residue chromatographed over silica gel with 5-30% EtOAc/hexanes
  18. customThe product fractions were evaporated
  19. customthe residue triturated with 10 mL 1:1 EtOAc/hexanes
  20. filtrationThe solid was filtered
  21. washrinsed twice with 2 mL 1:1 EtOAc/hexanes
  22. customair-dried

Sources & evidence

ORD record
ord-2e8267af54f149fb93200b8a52f5eab3
Source dataset
uspto-grants-2015_10
Patent number
US09163008B2

Reaction notes

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