Ammonia → HCID 59312738, compound

Temperature

-35 °C

A solution of Intermediate 5 (18.21 g, 21.60 mmol) in dimethoxyethane (300 mL) was added over about 20 minutes to liquid ammonia (approx. 400 mL) kept at −35 to −50° C. (bath temp). Sodium metal (4.0 g, in 0.2 g portions that were quickly washed with heptane prior to addition) was added to the ammonia solution over a period of 30 minutes ensuring that the reaction temperature was maintained at about −35° C. (bath temp). The deep blue reaction mixture was allowed to stir for 3 h. Analysis by TLC (50% EtOAc in Heptanes and 10% MeOH in DCM) indicated an incomplete reaction so additional sodium metal (1.0 g, divided into 0.5 g portions) was added over the course of about 10 minutes as described above. The reaction was stirred for an additional 2 h, whereupon the reaction was judged to be complete by TLC and LC-MS analysis. The reaction was quenched by the careful addition of isopropanol (10 mL, added dropwise over about 15 minutes), followed by 1:1 isopropanol-MeOH (80 mL over 30 minutes), and MeOH (40 mL over 30 minutes). The reaction mixture was stirred for 1 h and water (15 mL) was then added over 15 minutes. The ammonia was allowed to evaporate (several hours or overnight) and then water (300 mL) was added to the reaction. The mixture was extracted with EtOAc (3×350 mL). The organic solution was dried over anhydrous MgSO4. Removal of the drying agent and evaporation of the solvent gave a white solid (7.96 g). The aqueous solution was treated with brine (400 mL) and re-extracted with dichloromethane (3×300 mL). The combined dichloromethane extracts were dried (MgSO4), filtered and evaporated to afford additional white solid (4.53 g). The combined yield of Intermediate 7 was 12.49 g, which was used directly in the next step.

1. customkept at −35 to −50° C.
2. washSodium metal (4.0 g, in 0.2 g portions that were quickly washed with heptane
3. additionto addition)
4. additionwas added to the ammonia solution over a period of 30 minutes
5. customThe deep blue reaction mixture
6. additionwas added over the course of about 10 minutes
7. stirringThe reaction was stirred for an additional 2 h, whereupon the reaction
8. customThe reaction was quenched by the careful addition of isopropanol (10 mL
9. additionadded dropwise over about 15 minutes),
10. customfollowed by 1:1 isopropanol-MeOH (80 mL over 30 minutes), and MeOH (40 mL over 30 minutes)
11. stirringThe reaction mixture was stirred for 1 h
12. additionwater (15 mL) was then added over 15 minutes
13. customto evaporate (several hours or overnight)
14. additionwater (300 mL) was added to the reaction
15. extractionThe mixture was extracted with EtOAc (3×350 mL)
16. dry with materialThe organic solution was dried over anhydrous MgSO4
17. customRemoval of the drying agent and evaporation of the solvent

ORD record

ord-ecdb5d4587ba46bbaa49580916af5b23

Source dataset

uspto-grants-2014_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08722727B2