反应 #1509599

反应方程式

Ts2O

ER-076349

Collidine

Pyridine

→

B-1939

溶剂

DCM

DCM

toluene

反应条件

后处理

1. 1
   其他In a clean dry
2. 2
   浓缩concentrated to dryness under reduced pressure
3. 3
   workup.DISSOLUTIONThe substrate was re-dissolved in anhydrous toluene (20 vol)
4. 4
   浓缩concentrated to dryness
5. 5
   workup.DISSOLUTIONThe substrate was dissolved in DCM (5 vol)
6. 6
   其他the internal temperature below −16° C. (1.02 eq)
7. 7
   温度then warmed to 0° C. over 20 minutes
8. 8
   workup.STIRRINGstirred for an additional 20 minutes
9. 9
   其他The reaction was quenched with water (2 vol)
10. 10
    其他The bath was removed
11. 11
    温度to warm to room temperature (15-20° C.)
12. 12
    workup.STIRRINGstirred (20 minutes)
13. 13
    洗涤The 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
    其他formed in situ
17. 17
    浓缩The 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
    洗涤washed pH 10 buffer (NaHCO3/Na2CO3 (aq), 10 vol)
20. 20
    萃取The aqueous phase was back extracted with 25 vol of DCM
21. 21
    浓缩the combined organic layers were concentrated to dryness
22. 22
    其他The resulting free amine was purified by silica gel chromatography
23. 23
    浓缩The pooled fractions were concentrated at reduced pressure
24. 24
    其他to 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
    其他separated
28. 28
    萃取The aqueous phase was back extracted with 25 vol of DCM
29. 29
    浓缩the combined organic layers were concentrated to dryness
30. 30
    过滤filtered as a solution in 3:1 DCM/pentane
31. 31
    浓缩concentrated to dryness (0.80 wts)

实验过程

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.

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