Dichloromethane → 4-(4,6-Dichloro-5-(2-methoxyphenoxy)pyrimidin-2-yl)picolinonitrile

HRID 1871589Notes

Reaction equation

HRID 1871589 reaction equation
O=P(Cl)(Cl)[Cl:3].C(N(C(C)C)CC)(C)C.O[C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=C(O)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=O)[CH:33]=2)[N:17]=1.Cl[CH2:42][Cl:43]>>[Cl:3][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:42]([Cl:43])[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:40])[CH:33]=2)[N:17]=1

Participants

5

Reactant 4

HCID 6344DichloromethaneHCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 178489619HCID 178489619, compound

Product 1

HCID 114629344-(4,6-Dichloro-5-(2-methoxyphenoxy)pyrimidin-2-yl)picolinonitrileYield 86%

Conditions

Temperature
20 °C

Procedure

Within 20 min. 61 ml (633 mmol) of POCl3 were added dropwise to 34 ml (200 mmol) of diisopropyl ethylamine at 5° C. to 10° C. followed by stirring at 5° C. to 10° C. for 15 min. Then 23.5 g (66 mmol) of 4-[4,6-dihydroxy-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-2-carboxylic acid amide were added in four portions under cooling followed by stirring at 90° C. for 25 hr. The reaction mixture was cooled down to 20° C. and transferred to a new flask together with 50 ml of dichloromethane. Volatile components (i.e. excess of POCl3) was removed by evaporation from 20° C. to 70° C. followed by re-distillation with 100 ml of toluene. After adding 250 ml of dichloromethane to the residue (88 g of a black oil) the solution was heated to 35° C. to 40° C. and 80 ml of de-ionized water were added dropwise within 30 min. whereby the pH was kept constant by the subsequent addition of 28% NaOH solution (60 ml) within 5 to 6 hr. The mixture was stirred at 35° C. to 40° C. for 30 min. followed by removal of dichloromethane by distillation. The resulting suspension was allowed to cool down to 20° C. and was stirred for additional 2 hr. The solid was filtered off under suction, washed with 500 ml of water and dried at 70° C., 2000 Pa for 16 hr. There were obtained 21.3 g (86% of theory) of 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-2-carbonitrile with a HPLC purity of 94.3% (w/w).

Workup

  1. temperatureunder cooling
  2. stirringby stirring at 90° C. for 25 hr
  3. customVolatile components (i.e. excess of POCl3) was removed by evaporation from 20° C. to 70° C.
  4. distillationfollowed by re-distillation with 100 ml of toluene
  5. additionAfter adding 250 ml of dichloromethane to the residue (88 g of a black oil) the solution
  6. temperaturewas heated to 35° C. to 40° C.
  7. addition80 ml of de-ionized water were added dropwise within 30 min. whereby the pH
  8. additionwas kept constant by the subsequent addition of 28% NaOH solution (60 ml) within 5 to 6 hr
  9. stirringThe mixture was stirred at 35° C. to 40° C. for 30 min.
  10. customfollowed by removal of dichloromethane by distillation
  11. temperatureto cool down to 20° C.
  12. stirringwas stirred for additional 2 hr
  13. filtrationThe solid was filtered off under suction
  14. washwashed with 500 ml of water
  15. customdried at 70° C.
  16. wait2000 Pa for 16 hr

Sources & evidence

ORD record
ord-520029fc20cc41a5808a9ff85f6c3ded
Source dataset
uspto-grants-2000_08
Patent number
US06103902

Reaction notes

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