Acetic Acid → (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid

Temperature

130 °C

A solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (198 mg, 0.5 mmol) in 2:1:1 concentrated HCl:glacial acetic acid:water (8 mL) in a pressure bottle was stirred for 2 h at 60° C., then capped and stirred for 18 h at 130° C., cooled to room temperature, and uncapped. The solution was diluted with water (20 mL), then extracted with methylene chloride (20 mL) and concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in water (40 mL) and treated with DOWEX® 550A-OH resin (3 g) which had been rinsed with methanol. The mixture was stirred for 40 min, then filtered and the resin washed successively with water, methanol, methylene chloride, water, methanol, and methylene chloride. The resin was then stirred four times with 1N HCl (15 mL) and filtered, and the combined filtrates were concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in 1.5-2.0 mL water and subjected to HPLC gradient purification as follows: 0-25% B with A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile. The appropriate fractions were concentrated, treated three times with 1 N HCl (10 mL) and concentrated, treated three times with water (10 mL) and concentrated, then dissolved in water (10 mL), frozen, and lyophilized overnight to afford (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (114 mg, 79%) as a pale amber glass. NMR (D2O) δ 3.90 (d, J=13 Hz, 1 H), 3.71 (dd, J111.5 Hz, J2=8.5 Hz, 1 H), 3.46 (d, J=13 Hz, 1 H), 3.21 (t, J=12 Hz, 1 H), 2.50-2.65 (m, 1 H), 1.5-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.75 (m, 2 H). MS (m+1): 217.3; MS (m−H2O+1): 199.1.

1. customcapped
2. temperaturecooled to room temperature
3. extractionextracted with methylene chloride (20 mL)
4. concentrationconcentrated
5. additionThe residue was treated with water (20 mL)
6. concentrationconcentrated three times
7. customto remove excess HCl
8. dissolutiondissolved in water (40 mL)
9. additiontreated with DOWEX® 550A-OH resin (3 g) which
10. washhad been rinsed with methanol
11. stirringThe mixture was stirred for 40 min
12. filtrationfiltered
13. washthe resin washed successively with water, methanol, methylene chloride, water, methanol, and methylene chloride
14. stirringThe resin was then stirred four times with 1N HCl (15 mL)
15. filtrationfiltered
16. concentrationthe combined filtrates were concentrated
17. additionThe residue was treated with water (20 mL)
18. concentrationconcentrated three times
19. customto remove excess HCl
20. dissolutiondissolved in 1.5-2.0 mL water
21. customsubjected to HPLC gradient purification
22. concentrationThe appropriate fractions were concentrated
23. additiontreated three times with 1 N HCl (10 mL)
24. concentrationconcentrated
25. additiontreated three times with water (10 mL)
26. concentrationconcentrated
27. dissolutiondissolved in water (10 mL)
28. temperaturefrozen
29. waitlyophilized overnight

ORD record

ord-caf43128122041569e948a23f493f646

Source dataset

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09440995B2