Sulfuric Acid → (3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]-pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one

To a solution of tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 7) (99.5 g, 203.68 mmol) in 1,4-dioxane (750 mL) cooled with an ice/water bath to an internal temperature of 15° C. was added conc. sulphuric acid (75 mL, 1407 mmol) dropwise maintaining internal temperature below 20° C. over approximately 35 minutes. After complete addition, the reaction mixture was stirred at room temperature over 30 minutes. The reaction was poured into a beaker and washed in with ethyl acetate (400 mL) and a little water. The mixture was cooled to 15° C. and a solution of sodium carbonate (160 g in 1200 mL water) was added over 5 minutes. The mixture was filtered over a pad of celite and the remaining solids washed with ethyl acetate (400 mL). The filtrate phases were separated and the aqueous phase was extracted with ethyl acetate (2×400 mL). The combined organics were washed with brine (500 mL), dried over magnesium sulphate, filtered and evaporated to yield a foaming amber oil. This was twice dissolved in acetonitrile (100 mL) and evaporated and the resulting yellow foam dried under vacuum to give the title material (D8) in good purity by NMR, consistent spectroscopically with that produced by Method 1.

1. temperaturedropwise maintaining internal temperature below 20° C. over approximately 35 minutes
2. additionAfter complete addition
3. additionThe reaction was poured into a beaker
4. washwashed in with ethyl acetate (400 mL)
5. temperatureThe mixture was cooled to 15° C.
6. additiona solution of sodium carbonate (160 g in 1200 mL water) was added over 5 minutes
7. filtrationThe mixture was filtered over a pad of celite
8. washthe remaining solids washed with ethyl acetate (400 mL)
9. customThe filtrate phases were separated
10. extractionthe aqueous phase was extracted with ethyl acetate (2×400 mL)
11. washThe combined organics were washed with brine (500 mL)
12. dry with materialdried over magnesium sulphate
13. filtrationfiltered
14. customevaporated
15. customto yield a foaming amber oil
16. customevaporated
17. customthe resulting yellow foam dried under vacuum

ORD record

ord-a6f83e0f39af4a17b346ae92470ee692

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09376445B2