Hydrochloric Acid → Macitentan

HRID 1484488Notes

Reaction equation

HRID 1484488 reaction equation
[CH3:1][CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:15][CH2:16][CH2:17][OH:18])[C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)(=[O:7])=[O:6].[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(O[K])(C)(C)C.Cl>C1(C)C=CC=CC=1.CN(C=O)C.O>[Br:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:9]([NH:8][S:5]([NH:4][CH2:3][CH2:2][CH3:1])(=[O:6])=[O:7])=[N:14][CH:13]=[N:12][C:11]=2[O:15][CH2:16][CH2:17][O:18][C:30]2[N:31]=[CH:32][C:27]([Br:26])=[CH:28][N:29]=2)=[CH:24][CH:23]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 6066655-Bromo-2-chloropyrimidineHCID 70813943N-[5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N′-propylsulfamideHCID 178418922HCID 178418922, compound

Product 1

HCID 16004692MacitentanYield 83.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (200 g; 0.46 mol; see Example 2 or 3) and 5-bromo-2-chloropyrimidine (117 g; 0.60 mol; 1.3 eq) were dissolved in toluene (3 L) and DMF (400 mL). The reaction mixture was warmed up to 50° C. and toluene (approx. 400 mL) was distilled our under reduced pressure. The mixture was cooled to 0° C. and tBuOK (156 g, 3 eq, 1.38 mol) was added portionwise. It was stirred at 20° C. for 1 h. Water (1 L) was added and the pH of the solution was adjusted to 3-5 using 33% aq. HCl. The mixture was heated to 50° C. and the layers were separated. The org. phase was treated with charcoal at 50° C. and filtered over Celite. The filter cake was rinsed with toluene. At 50° C., water (1 L) was added to the org. layer. The layers were separated. The org. layer was concentrated under reduced pressure to a total volume of 1 L and cooled to 0° C. The solid obtained was filtered off. It was rinsed with toluene and MeOH. The crude material was suspended in EA (1 L) and heated to 50° C. 300 mL of EA were distilled out and MeOH (400 mL) was added. The suspension was cooled down to 0° C. The solid was filtered off, rinsed with MeOH and dried under reduced pressure to afford the title compound as a white solid (225 g; 83% yield).

Workup

  1. distillationtoluene (approx. 400 mL) was distilled our under reduced pressure
  2. temperatureThe mixture was cooled to 0° C.
  3. temperatureThe mixture was heated to 50° C.
  4. customthe layers were separated
  5. additionphase was treated with charcoal at 50° C.
  6. filtrationfiltered over Celite
  7. washThe filter cake was rinsed with toluene
  8. additionAt 50° C., water (1 L) was added to the org
  9. customThe layers were separated
  10. concentrationlayer was concentrated under reduced pressure to a total volume of 1 L
  11. temperaturecooled to 0° C
  12. customThe solid obtained
  13. filtrationwas filtered off
  14. washIt was rinsed with toluene and MeOH
  15. temperatureheated to 50° C
  16. distillation300 mL of EA were distilled out and MeOH (400 mL)
  17. additionwas added
  18. temperatureThe suspension was cooled down to 0° C
  19. filtrationThe solid was filtered off
  20. washrinsed with MeOH
  21. customdried under reduced pressure

Sources & evidence

ORD record
ord-2dee1c520e734b919c6e6c0a6df3b0e2
Source dataset
uspto-grants-2016_08
Patent number
US09422249B2

Reaction notes

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