Triethylamine → HCID 117734966, compound

Temperature

0 °C

A one-necked round-bottom flask was charged with amino(4-methylphenyl)acetic acid (10 g, 60.5 mmol), 1,4-dioxane (300 mL) and 1M NaOH (170 mL). To the resulting solution di-tert-butyl dicarbonate (19.8 g, 90.8 mmol) was added and the solution stirred at room temperature overnight. The dioxane was removed under reduced pressure and the aqueous solution was adjusted to pH 4 with 3M HCl and the product extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent removed under reduced pressure to afford [(tert-butoxycarbonyl)amino](4-methylphenyl)acetic acid as a white solid (15.2 g, y=95%). 1H NMR (DMSO-d6) δ (ppm): 7.44 (d, 1H, J=7.4 Hz), 7.27 (d, 2H, J=7.2 Hz), 7.14 (d, 2H, J=7.3 Hz), 5.03 (d, 1H, J=5.4 Hz), 2.28 (s, 3H), 1.38 (s, 9H). MS (ES1+) m/z: 266.42 (M+1). A one-necked round-bottom flask was charged with [(tert-butoxycarbonyl)amino](4-methylphenyl)acetic acid (16 g, 60.5 mmol), DCM (500 mL) and triethylamine (16.7 mL, 121 mmol). The resulting solution was cooled to 0° C. and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC, 13.9 g, 72.6 mmol) and 1-hydroxybenzotriazole (HOBT, 9.8 g, 72.6 mmol) were added. The mixture was stirred for 40 min at 0° C. Then 1-(tetrahydrofuran-2-yl)methanamine (10.6 mL, 103 mmol) was added and the solution stirred at room temperature overnight. After 18 h the reaction was complete (HPLC-MS analysis). The solution was washed with water (2×150 mL), 1M HCl (2×150 mL), and brine (2×150 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to afford a white solid which was taken up in 100 mL of n-hexane and triturated at room temperature for 2 h. The precipitate was filtered and dried under vacuum at 50° C. for 4 h. The solid was dissolved in 100 mL of 1,4-dioxane and 25 mL of 4M HCl solution in dioxane were added. The resulting solution was stirred at room temperature overnight. After solvent removal under vacuum, the residue was taken up in diethyl ether (40 mL) and triturated at room temperature for 2 h. The precipitate was filtered and dried under vacuum at 50° C. to afford Intermediate C as a white solid (11.6 g, y=67% over two steps). 1H NMR (DMSO-d6) δ (ppm): 8.75 (br s, 3H), 7.45 (d, 2H, J=7.5 Hz), 7.22 (d, 2H, J=7.4 Hz), 4.91 (br s, 1H), 3.90-3.51 (m, 4H), 3.22-3.04 (m, 2H), 2.28 (s, 3H), 1.85-1.26 (m, 4H). MS (ES1+) m/z: 249.04 (M+1).

1. stirringthe solution stirred at room temperature overnight
2. waitAfter 18 h the reaction was complete
3. washThe solution was washed with water (2×150 mL), 1M HCl (2×150 mL), and brine (2×150 mL)
4. dry with materialThe organic layers were dried over Na2SO4
5. filtrationfiltered
6. customthe solvent was removed under reduced pressure
7. customto afford a white solid which
8. customtriturated at room temperature for 2 h
9. filtrationThe precipitate was filtered
10. customdried under vacuum at 50° C. for 4 h
11. dissolutionThe solid was dissolved in 100 mL of 1,4-dioxane
12. addition25 mL of 4M HCl solution in dioxane were added
13. stirringThe resulting solution was stirred at room temperature overnight
14. customAfter solvent removal under vacuum
15. customtriturated at room temperature for 2 h
16. filtrationThe precipitate was filtered
17. customdried under vacuum at 50° C.

ORD record

ord-2feb49a52fae4fffbae16933bda1b9a1

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409876B2