Pyridine → Triphosgene

Temperature

60 °C

In a three-neck flask the solution of triphosgene (10.87 g, 36.63 mmol) in toluene (60 mL) is prepared at room temperature (23° C.), then the reactor is placed in an ice-water cooling bath. In a separate flask (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (20.0 g, 95.55 mmol, purity 99% (HPLC)) and pyridine (3.26 mL, 40.30 mmol) are placed in toluene (80 mL), while heating at 50-70° C. until the whole amount of solid is dissolved. After cooling down to room temperature, the clear toluene solution is transferred into a dropping funnel. The solution is added dropwise within ca. 10 min. to triphosgene in toluene solution. When the addition is complete, the cooling bath is removed and the reactor is submerged in an oil bath. Reaction mixture is heated at 70-80° C., in a mean time thick yellow solid slowly dissolves. Since reaction temperature reaches 50° C., heating and stirring is continued for 45 min., until disappearance of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline signal (TLC control in CH2Cl2—MeOH 95:5, v/v against substrate sample) is observed. After completion of the reaction the mixture is cooled down to room temperature (20-24° C.), filtered through celit to remove precipitated pyridinium hydrochloride. Celit layer is washed with toluene (20 mL). Toluene (145 mL) is removed under reduced pressure (0.1-0.15 mmHg) from the post-reaction mixture, while heating the condensing flask in a water bath at 60-65° C. The oily residue is dissolved in heptan (200 mL) at reflux and the hot solution is filtered through celit (20 g), washed with heptan before filtration. The celit layer is washed with hot heptan (2×50 mL) after filtration. The excess of solvent (170 mL) is removed under reduced pressure; the condensed solution to ca. ½ volume is left at 5° C. for 12 h. Crystalline, colorless solid is filtered off and washed with heptan (2×15 mL). (S)-1-Phenyl-1,2,3,4-tetrahydroisoquinolinecarbonyl chloride is obtained in 23.3 g, 90% yield; purity (HPLC) 98.4%; T(onset)=62.7° C.

1. customthe reactor is placed in an ice-water cooling bath
2. dissolutionis dissolved
3. temperatureAfter cooling down to room temperature
4. additionWhen the addition
5. customthe cooling bath is removed
6. customthe reactor is submerged in an oil bath
7. customReaction mixture
8. temperatureis heated at 70-80° C., in a mean time thick yellow solid
9. dissolutionslowly dissolves
10. customSince reaction temperature
11. customreaches 50° C.
12. temperatureheating
13. customAfter completion of the reaction the mixture
14. temperatureis cooled down to room temperature (20-24° C.)
15. filtrationfiltered through celit
16. customto remove
17. customprecipitated pyridinium hydrochloride
18. washCelit layer is washed with toluene (20 mL)
19. customToluene (145 mL) is removed under reduced pressure (0.1-0.15 mmHg) from the post-reaction mixture
20. temperaturewhile heating the condensing flask in a water bath at 60-65° C
21. dissolutionThe oily residue is dissolved in heptan (200 mL)
22. temperatureat reflux
23. filtrationthe hot solution is filtered through celit (20 g)
24. washwashed with heptan before filtration
25. washThe celit layer is washed with hot heptan (2×50 mL)
26. filtrationafter filtration
27. customThe excess of solvent (170 mL) is removed under reduced pressure
28. filtrationCrystalline, colorless solid is filtered off
29. washwashed with heptan (2×15 mL)

ORD record

ord-f83e8351fca647828bad2b656ea34174

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08436182B2