Reaction #1509599

Reaction equation

Ts2O

ER-076349

Collidine

Pyridine

→

B-1939

Solvents

DCM

DCM

toluene

Conditions

Workup

1. 1
   OtherIn a clean dry
2. 2
   Concentrationconcentrated to dryness under reduced pressure
3. 3
   workup.DISSOLUTIONThe substrate was re-dissolved in anhydrous toluene (20 vol)
4. 4
   Concentrationconcentrated to dryness
5. 5
   workup.DISSOLUTIONThe substrate was dissolved in DCM (5 vol)
6. 6
   Otherthe internal temperature below −16° C. (1.02 eq)
7. 7
   Temperaturethen warmed to 0° C. over 20 minutes
8. 8
   workup.STIRRINGstirred for an additional 20 minutes
9. 9
   OtherThe reaction was quenched with water (2 vol)
10. 10
    OtherThe bath was removed
11. 11
    Temperatureto warm to room temperature (15-20° C.)
12. 12
    workup.STIRRINGstirred (20 minutes)
13. 13
    WashThe reaction was rinsed to a larger vessel
14. 14
    workup.ADDITIONwas added to the reaction
15. 15
    workup.STIRRINGThe reaction was stirred at room temperature for 15-36 hours
16. 16
    Otherformed in situ
17. 17
    ConcentrationThe reaction was concentrated to dryness or near dryness at reduced pressure
18. 18
    workup.ADDITIONThe resulting material was diluted with DCM (25-40 vol)
19. 19
    Washwashed pH 10 buffer (NaHCO3/Na2CO3 (aq), 10 vol)
20. 20
    ExtractionThe aqueous phase was back extracted with 25 vol of DCM
21. 21
    Concentrationthe combined organic layers were concentrated to dryness
22. 22
    OtherThe resulting free amine was purified by silica gel chromatography
23. 23
    ConcentrationThe pooled fractions were concentrated at reduced pressure
24. 24
    Otherto remove ACN
25. 25
    workup.ADDITIONThe resulting aqueous layer was diluted with DCM (40 vol) and with 30 vol of a pH 10
26. 26
    workup.ADDITIONThe layers were mixed well
27. 27
    Otherseparated
28. 28
    ExtractionThe aqueous phase was back extracted with 25 vol of DCM
29. 29
    Concentrationthe combined organic layers were concentrated to dryness
30. 30
    Filtrationfiltered as a solution in 3:1 DCM/pentane
31. 31
    Concentrationconcentrated to dryness (0.80 wts)

Procedure

In a clean dry reaction vessel (flask C) ER-076349 (1 wt, 1 eq) was dissolved in anhydrous toluene (20 vol) and concentrated to dryness under reduced pressure. The substrate was re-dissolved in anhydrous toluene (20 vol) and concentrated to dryness. The substrate was dissolved in DCM (5 vol), and the solution placed under an argon atmosphere. Collidine (0.66 wts, 4.0 eq) was added as a single portion. Pyridine, as a solution in DCM (Flask B), was added as a single portion (5 mole %). The resulting mixture in flask C was cooled to an internal temperature of −20 to −25° C. A DCM solution of Ts2O was added drop-wise keeping the internal temperature below −16° C. (1.02 eq). The reaction was stirred at −20 to −25° C. for 80 minutes then warmed to 0° C. over 20 minutes and stirred for an additional 20 minutes. The reaction was quenched with water (2 vol). The bath was removed, and the reaction allowed to warm to room temperature (15-20° C.) and stirred (20 minutes). The reaction was rinsed to a larger vessel using the IPA (100 vol) and aqueous ammonium hydroxide (100 vol) was added to the reaction. The reaction was stirred at room temperature for 15-36 hours, monitoring for the disappearance of the tosylate (ER-082892) and epoxide (ER-809681) which formed in situ. The reaction was concentrated to dryness or near dryness at reduced pressure. The resulting material was diluted with DCM (25-40 vol) and washed pH 10 buffer (NaHCO3/Na2CO3 (aq), 10 vol). The aqueous phase was back extracted with 25 vol of DCM and the combined organic layers were concentrated to dryness. The resulting free amine was purified by silica gel chromatography using a buffered ACN/water mobile phase. The pooled fractions were concentrated at reduced pressure to remove ACN. The resulting aqueous layer was diluted with DCM (40 vol) and with 30 vol of a pH 10 buffered stock solution (NaHCO3/Na2CO3). The layers were mixed well and separated. The aqueous phase was back extracted with 25 vol of DCM and the combined organic layers were concentrated to dryness. The resulting free amine was polish filtered as a solution in 3:1 DCM/pentane and concentrated to dryness (0.80 wts) to afford B-1939.

Source