Isopropylamine → (3R)-N-Isopropylpyrrolidine-3-carboxamide

To (3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (150 mg, 0.70 mmol) in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 1-hydroxybenzotriazole (94 mg, 0.70 mmol) were added. The mixture was stirred at room temperature for 5 min, followed by addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (150 mg, 0.77 mmol). The mixture was then stirred for 20 min. 2-Propanamine (59 μL, 0.69 mmol) was added and the mixture was stirred overnight. The mixture was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated, and purified by preparative LCMS using pH 2 buffer to give desired boc-protected intermediate. The product fractions were concentrated and treated with 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 30 min, at which time the mixture was concentrated and dissolved in DCM/MeOH and treated with Trisamine resin (Silicycle) for 30 min. The resulting mixture was filtered and the solvents were evaporated to give the desired compound (63 mg, 58%) which was used in the next step without further purification. LCMS calc. for C8H17N2O (M+H)+: m/z=157.1. found: 157.2.

1. stirringThe mixture was then stirred for 20 min
2. stirringthe mixture was stirred overnight
3. washwashed with saturated aqueous sodium bicarbonate
4. customThe aqueous layer was separated
5. extractionextracted with additional ethyl acetate
6. dry with materialThe combined organic layers were dried over magnesium sulfate
7. concentrationconcentrated
8. custompurified by preparative LCMS
9. customto give desired boc-
10. concentrationThe product fractions were concentrated
11. additiontreated with 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 30 min, at which time the mixture
12. concentrationwas concentrated
13. dissolutiondissolved in DCM/MeOH
14. additiontreated with Trisamine resin (Silicycle) for 30 min
15. filtrationThe resulting mixture was filtered
16. customthe solvents were evaporated

ORD record

ord-f6e70d26971048b284d5e8b4f46067de

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09227985B2