Borane → (R)-2-ethylpiperazine dihydrochloride

(2R)-2-Aminobutanoic acid (1.57 g, 15.22 mmol) was dissolved in ethanol (40 mL) and the solution treated with thionyl chloride (5 mL, 63.8 mmol). The reaction mixture was heated at reflux for 70 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was azeotroped with toluene (50 mL) to give a clear oil. The oil (2.78 g, 16.58 mmol) was dissolved in dichloromethane (50 mL) and the solution treated with carbobenzyloxyglycine (3.47 g, 16.58 mmol), 1-hydroxybenzotriazole hydrate (2.55 g, 16.65 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.18 g, 16.59 mmol) and triethylamine (6.9 mL, 49.5 mmol). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was washed with water, citric acid, brine and sodium hydrogencarbonate solution and then dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:pentane 50:50. The crude product (4.22 g, 13.08 mmol) was dissolved in methanol (100 mL) and the solution treated with 10% Pd/C (450 mg) and stirred under 60 psi of hydrogen at room temperature for 18 hours. The reaction mixture was filtered through Arbocel® and the filtrate concentrated in vacuo. The residue (1.6 g, 11.25 mmol) was dissolved in 1,2-dimethoxyethane (25 mL) and the solution treated with a 1M solution of borane in tetrahydrofuran (45 mL, 45 mmol). The reaction mixture was heated to reflux for 18 hours, then quenched with methanol and stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and the residue dissolved in methanol (50 mL) and treated with a saturated solution of hydrogen chloride in dioxane (15 mL). The solution was refluxed for 2 hours, then concentrated in vacuo and the residue dissolved in ether (50 mL). The solution was concentrated in vacuo to yield the title product as a yellow oil that solidifed on standing.

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 70 hours
3. temperatureThe reaction mixture was cooled
4. concentrationconcentrated in vacuo
5. customThe residue was azeotroped with toluene (50 mL)
6. customto give a clear oil
7. washThe reaction mixture was washed with water, citric acid, brine and sodium hydrogencarbonate solution
8. dry with materialdried over magnesium sulphate
9. concentrationconcentrated in vacuo
10. customThe residue was purified by column chromatography on silica gel eluting with ethyl acetate:pentane 50:50
11. filtrationThe reaction mixture was filtered through Arbocel®
12. concentrationthe filtrate concentrated in vacuo
13. temperatureThe reaction mixture was heated
14. temperatureto reflux for 18 hours
15. customquenched with methanol
16. stirringstirred at room temperature for 30 minutes
17. concentrationThe reaction mixture was concentrated in vacuo
18. dissolutionthe residue dissolved in methanol (50 mL)
19. additiontreated with a saturated solution of hydrogen chloride in dioxane (15 mL)
20. temperatureThe solution was refluxed for 2 hours
21. concentrationconcentrated in vacuo
22. dissolutionthe residue dissolved in ether (50 mL)
23. concentrationThe solution was concentrated in vacuo

ORD record

ord-d9b2903d09e645af8dd92ec855bf2418

Source dataset

uspto-grants-2007_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07262192B2