4-Chlorophenol → 165383-52-8

HRID 1976285Notes

Reaction equation

HRID 1976285 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[N:13]2[C:14]([C@@H:18](O)[CH3:19])=[CH:15][CH:16]=[N:17][C:12]2=[N:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl-].[Mg+2].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:18]([C:14]2[N:13]3[N:9]=[CH:10][N:11]=[C:12]3[N:17]=[CH:16][CH:15]=2)[CH3:19])=[CH:4][CH:3]=1

Participants

7

Reactant 5

HCID 46844-ChlorophenolHCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylate2×HCID 5360315Magnesium ChlorideHCID 53998193HCID 53998193, compound

Product 1

HCID 1480409165383-52-8Yield 37.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
7.5 °C

Procedure

A reactor was loaded with 4chlorophenol (2.89 kg), (S)-1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (3.69 kg), triphenylphosphine (5.9 kg) and tetrahydrofuran (69I). The suspension was cooled to 5-10° C. and diisopropyl azodicarboxylate (4.79 kg) was added over 2 hours. After complete addition of diisopropyl azodicarboxylate the solution was stirred while warming to ambient temperature. Magnesium chloride (anhydrous; 4.3 kg; ˜2 eq) was added and the reaction mixture was heated under reflux for 1 hour. Cooling to 10° C. yielded a suspension which was collected by filtration. The filter pad was washed with tetrahydrofuran (10 I). The mother liquor was refilled into the reactor and tetrahydrofuran replaced with toluene by distillation of inert diluent (100 I) and addition of toluene (100 I) at the same rate. When the inert diluent exchange was complete the solution was cooled to ambient temperature and extracted twice with water. The organic phase was separated, filtered, then charged to the reaction vessel. Toluene (64 I) was distilled off, propan-2ol (128 I) added, and the solvent mixture (123 I) was then distilled off. After this solvent exchange the reaction mixture was slowly cooled to ambient temperature for crystallization of the product. The product was filtered off and washed with propan-2-ol (10 I). (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine, (2.29 kg) was isolated after drying in vacuo at 40° C. HPLC-analysis: 99.92%; chiral HPLC: ee=100%. No triphenylphosphine oxide was detectable by HPLC analysis.

Workup

  1. temperaturewhile warming to ambient temperature
  2. temperaturethe reaction mixture was heated
  3. temperatureunder reflux for 1 hour
  4. temperatureCooling to 10° C.
  5. customyielded a suspension which
  6. filtrationwas collected by filtration
  7. washThe filter pad was washed with tetrahydrofuran (10 I)
  8. additionThe mother liquor was refilled into the reactor and tetrahydrofuran
  9. distillationreplaced with toluene by distillation of inert diluent (100 I) and addition of toluene (100 I) at the same rate
  10. temperaturewas cooled to ambient temperature
  11. extractionextracted twice with water
  12. customThe organic phase was separated
  13. filtrationfiltered
  14. additioncharged to the reaction vessel
  15. distillationToluene (64 I) was distilled off
  16. additionpropan-2ol (128 I) added
  17. distillationthe solvent mixture (123 I) was then distilled off
  18. temperatureAfter this solvent exchange the reaction mixture was slowly cooled to ambient temperature for crystallization of the product
  19. filtrationThe product was filtered off
  20. washwashed with propan-2-ol (10 I)

Sources & evidence

ORD record
ord-23a570ae29ed489d881f7e0ef77fb027
Source dataset
uspto-grants-2001_05
Patent number
US06225469B1

Reaction notes

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