Citric Acid → N-[5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N′-propylsulfamide

HRID 1484489Notes

Reaction equation

HRID 1484489 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](Cl)[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)(=[O:7])=[O:6].CC([O-])(C)C.[K+].C([O:33][CH2:34][CH2:35][OH:36])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl[Ti](Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[CH3:1][CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:33][CH2:34][CH2:35][OH:36])[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)(=[O:7])=[O:6]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 242322-(Tert-butoxy)ethan-1-olHCID 23665647Potassium tert-butoxideHCID 71500858SulfaMide, N-[5-(4-broMophenyl)-6-chloro-4-pyriMidinyl]-N'-propyl-

Product 1

HCID 70813943N-[5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-N′-propylsulfamideYield 86%

Reagents, catalysts & solvents 3

HCID 24193Titanium TetrachlorideCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolvent2×

Conditions

Temperature
20 °C

Procedure

N-(5-(4-bromophenyl)-6-chloropyrimidin-4-yl)propane-1-sulfamide (100 g; 0.246 mol; see Preparation A) and KOtBu (110 g; 0.99 mol; 4.0 eq.) were charged into a 2 L reactor. Toluene (1 L) was added. The resulting suspension was stirred at 20° C. for 5 min. 2-(tert-butoxy)ethanol (97 mL; 0.74 mol; 3.0 eq.) was added dropwise. After completion of the addition, the reaction mixture was heated to 85° C. for 2 h. After completion of the reaction, the mixture was cooled down to 20° C. Water (0.5 L) was added, followed by the addition of 10% aq. citric acid (0.5 L). The layers were separated. The org. phase was washed with brine 3 times (0.5 L each) and azeotropically dried with toluene (1 L) to a volume of approx. 1 L. The reaction mixture was heated to 50° C. A 1M solution of TiCl4 in toluene (420 mL, 0.42 mol; 1.7 eq.) was added dropwise with vigorous stirring. After completion of the addition, it was stirred at 35° C. for 20 h. Water (0.75 L) was added and the resulting beige suspension was stirred for 15 h. It was filtered off, rinsed with toluene (300 mL) and dried to afford the title compound as a white solid (91 g; 86% yield; purity (LC-MS): 100% a/a).

Workup

  1. additionwere charged into a 2 L reactor
  2. additionAfter completion of the addition
  3. temperaturethe reaction mixture was heated to 85° C. for 2 h
  4. customAfter completion of the reaction
  5. temperaturethe mixture was cooled down to 20° C
  6. customThe layers were separated
  7. washphase was washed with brine 3 times (0.5 L each)
  8. dry with materialazeotropically dried with toluene (1 L) to a volume of approx. 1 L
  9. temperatureThe reaction mixture was heated to 50° C
  10. additionAfter completion of the addition, it
  11. stirringwas stirred at 35° C. for 20 h
  12. stirringthe resulting beige suspension was stirred for 15 h
  13. filtrationIt was filtered off
  14. washrinsed with toluene (300 mL)
  15. customdried

Sources & evidence

ORD record
ord-ab70cb4c6c1b474cb1988f4e00c1983c
Source dataset
uspto-grants-2016_08
Patent number
US09422249B2

Reaction notes

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